Korabecny J

General

Full name : Korabecny Jan

First name : Jan

Mail : University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove

Zip Code :

City :

Country : Czech Republic

Email : jan.korabecny@fnhk.cz

Phone : +42072477096

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Website : \/\/eng.fnhk.cz\/cbv\/our-team\/korabecny-jan

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References (113)

Title : Carltonine-Derived Compounds for Targeted Butyrylcholinesterase Inhibition - Pidany_2024_RSC.Med.Chem__
Author(s) : Pidany F , Kroustkova J , Jenco J , Breiterova K , Muckovab L , Novakova L , Kunes J , Fibigar J , Kucera T , Novak M , Sorf A , Hrabinova M , Pulkrabkova L , Janousek J , Soukup O , Jun D , Korabecny J , Cahlikova L
Ref : RSC Med Chem , : , 2024
Abstract : The investigation into human butyrylcholinesterase (hBChE) inhibitors as therapeutic agents for Alzheimer's disease (AD) holds significant promise, addressing both symptomatic relief and disease progression. In the pursuit of novel drug candidates with selective BChE inhibition pattern, we focused on naturally occurring template structures, specifically Amaryllidaceae alkaloids of the carltonine-type. Herein, we explored a series of compounds implementing an innovative chemical scaffold built on the 3- and 4-benzyloxy-benzylamino chemotype. Notably, compounds 28 (hBChE IC50 = 0.171 0.063 M) and 33 (hBChE IC50 = 0.167 0.018 M) emerged as top-ranked hBChE inhibitors. In silico simulations elucidated the binding modes of these compounds within hBChE. CNS availability was predicted using the BBB score algorithm, corroborated by in vitro permeability assessments with the most potent derivatives. Compound 33 was also inspected for aqueous solubility, microsomal and plasma stability. Chemoinformatics analysis validated these hBChE inhibitors for oral administration, indicating favorable gastrointestinal absorption in compliance with Lipinski's and Veber's rules. Safety assessments, crucial for the chronic administration typical in AD treatment, were conducted through cytotoxicity testing on human neuroblastoma (SH-SY5Y) and hepatocellular carcinoma (HepG2) cell line
ESTHER : Pidany_2024_RSC.Med.Chem__
PubMedSearch : Pidany_2024_RSC.Med.Chem__
PubMedID:

Title : Phenoxytacrine derivatives: Low-toxicity neuroprotectants exerting affinity to ifenprodil-binding site and cholinesterase inhibition - Misiachna_2024_Eur.J.Med.Chem_266_116130
Author(s) : Misiachna A , Svobodova B , Netolicky J , Chvojkova M , Kleteckova L , Prchal L , Novak M , Hrabinova M , Kucera T , Muckova L , Moravcova Z , Karasova JZ , Pejchal J , Blazek F , Malinak D , Hakenova K , Krausova BH , Kolcheva M , Ladislav M , Korabecny J , Pahnke J , Vales K , Horak M , Soukup O
Ref : Eur Journal of Medicinal Chemistry , 266 :116130 , 2024
Abstract : Tacrine (THA), a long withdrawn drug, is still a popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity is still an issue and must be considered in drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored the chemical space with 30 novel derivatives, with a focus on low hepatotoxicity, anticholinesterase action, and antagonism at the GluN1/GluN2B subtype of the NMDA receptor. Applying the down-selection process based on in vitro and in vivo pharmacokinetic data, two candidates, I-52 and II-52, selective GluN1/GluN2B inhibitors thanks to the interaction with the ifenprodil-binding site, have entered in vivo pharmacodynamic studies. Finally, compound I-52, showing only minor affinity to AChE, was identified as a lead candidate with favorable behavioral and neuroprotective effects using open-field and prepulse inhibition tests, along with scopolamine-based behavioral and NMDA-induced hippocampal lesion models. Our data show that compound I-52 exhibits low toxicity often associated with NMDA receptor ligands, and low hepatotoxicity, often related to THA-based compounds.
ESTHER : Misiachna_2024_Eur.J.Med.Chem_266_116130
PubMedSearch : Misiachna_2024_Eur.J.Med.Chem_266_116130
PubMedID: 38218127

Title : Uncharged mono- and bisoximes: In search of a zwitterion to countermeasure organophosphorus intoxication - Gorecki_2024_Chem.Biol.Interact__110941
Author(s) : Gorecki L , Markova A , Hepnarova V , Zivna N , Junova L , Hrabinova M , Janousek J , Kobrlova T , Prchal L , Jun D , Soukup O , Horn G , Worek F , Marek J , Korabecny J
Ref : Chemico-Biological Interactions , :110941 , 2024
Abstract : The current study imposes a new class of organophosphorus (OP)-inhibited cholinesterase reactivators by conceptualizing a family of asymmetric bisoximes with various reactivating scaffolds. Several novel nucleophilic warheads were investigated, putting forward 29 novel reactivating options, by evaluating their nucleophilicity and ability to directly decompose OP compounds. Adopting the so-called zwitterionic strategy, 17 mono-oxime and nine bisoxime reactivators were discovered with major emphasis on the bifunctional-moiety approach. Compounds were compared with clinically used standards and other known experimentally highlighted reactivators. Our results clearly favor the concept of asymmetric bisoximes as leading reactivators in terms of efficacy and versatility. These top-ranked compounds were characterized in detail by reactivation kinetics parameters and evaluated for potential CNS availability. The highlighted molecules 55, 57, and 58 with various reactivating warheads, surpassed the reactivating potency of pralidoxime and several notable uncharged reactivators. The versatility of lead drug candidate 55 was also inspected on OP-inhibited butyrylcholinesterase, revealing a much higher rate compared to existing clinical antidotes.
ESTHER : Gorecki_2024_Chem.Biol.Interact__110941
PubMedSearch : Gorecki_2024_Chem.Biol.Interact__110941
PubMedID: 38493910

Title : Morphing cholinesterase inhibitor amiridine into multipotent drugs for the treatment of Alzheimer's disease - Mezeiova_2024_Biomed.Pharmacother_173_116399
Author(s) : Mezeiova E , Prchal L , Hrabinova M , Muckova L , Pulkrabkova L , Soukup O , Misiachna A , Janousek J , Fibigar J , Kucera T , Horak M , Makhaeva GF , Korabecny J
Ref : Biomed Pharmacother , 173 :116399 , 2024
Abstract : The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-d-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridine-based drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.
ESTHER : Mezeiova_2024_Biomed.Pharmacother_173_116399
PubMedSearch : Mezeiova_2024_Biomed.Pharmacother_173_116399
PubMedID: 38492439

Title : A-agents, misleadingly known as Novichoks: a narrative review - Opravil_2023_Arch.Toxicol__
Author(s) : Opravil J , Pejchal J , Finger V , Korabecny J , Rozsypal T , Hrabinova M , Muckova L , Hepnarova V , Konecny J , Soukup O , Jun D
Ref : Archives of Toxicology , : , 2023
Abstract : "Novichok" refers to a new group of nerve agents called the A-series agents. Their existence came to light in 2018 after incidents in the UK and again in 2020 in Russia. They are unique organophosphorus-based compounds developed during the Cold War in a program called Foliant in the USSR. This review is based on original chemical entities from Mirzayanov's memoirs published in 2008. Due to classified research, a considerable debate arose about their structures, and hence, various structural moieties were speculated. For this reason, the scientific literature is highly incomplete and, in some cases, contradictory. This review critically assesses the information published to date on this class of compounds. The scope of this work is to summarize all the available and relevant information, including the physicochemical properties, chemical synthesis, mechanism of action, toxicity, pharmacokinetics, and medical countermeasures used to date. The environmental stability of A-series agents, the lack of environmentally safe decontamination, their high toxicity, and the scarcity of information on post-contamination treatment pose a challenge for managing possible incidents.
ESTHER : Opravil_2023_Arch.Toxicol__
PubMedSearch : Opravil_2023_Arch.Toxicol__
PubMedID: 37612377

Title : Highly selective butyrylcholinesterase inhibitors related to Amaryllidaceae alkaloids - Design, synthesis, and biological evaluation - Pidany_2023_Eur.J.Med.Chem_252_115301
Author(s) : Pidany F , Kroustkova J , Al Mamun A , Suchankova D , Brazzolotto X , Nachon F , Chantegreil F , Dolezal R , Pulkrabkova L , Muckova L , Hrabinova M , Finger V , Kufa M , Soukup O , Jun D , Jenco J , Kunes J , Novakova L , Korabecny J , Cahlikova L
Ref : Eur Journal of Medicinal Chemistry , 252 :115301 , 2023
Abstract : Butyrylcholinesterase (BChE) is one of the most frequently implicated enzymes in the advanced stage of Alzheimer's disease (AD). As part of our endeavors to develop new drug candidates for AD, we have focused on natural template structures, namely the Amaryllidaceae alkaloids carltonine A and B endowed with high BChE selectivity. Herein, we report the design, synthesis, and in vitro evaluation of 57 novel highly selective human BChE (hBChE) inhibitors. Most synthesized compounds showed hBChE inhibition potency ranging from micromolar to low nanomolar scale. Compounds that revealed BChE inhibition below 100 nM were selected for detailed biological investigation. The CNS-targeted profile of the presented compounds was confirmed theoretically by calculating the BBB score algorithm, these data were corroborated by determining the permeability in vitro using PAMPA-assay for the most active derivatives. The study highlighted compounds 87 (hBChE IC(50) = 3.8 +/- 0.2 nM) and 88 (hBChE IC(50) = 5.7 +/- 1.5 nM) as the top-ranked BChE inhibitors. Compounds revealed negligible cytotoxicity for the human neuroblastoma (SH-SY5Y) and hepatocellular carcinoma (HepG2) cell lines compared to BChE inhibitory potential. A crystallographic study was performed to inspect the binding mode of compound 87, revealing essential interactions between 87 and hBChE active site. In addition, multidimensional QSAR analyses were applied to determine the relationship between chemical structures and biological activity in a dataset of designed agents. Compound 87 is a promising lead compound with potential implications for treating the late stages of AD.
ESTHER : Pidany_2023_Eur.J.Med.Chem_252_115301
PubMedSearch : Pidany_2023_Eur.J.Med.Chem_252_115301
PubMedID: 36996715
Gene_locus related to this paper: human-BCHE

Title : Tacrine First-Phase Biotransformation and Associated Hepatotoxicity: A Possible Way to Avoid Quinone Methide Formation - Novak_2023_ACS.Chem.Biol_18_1993
Author(s) : Novak M , Vajrychova M , Koutsilieri S , Sismanoglou DC , Kobrlova T , Prchal L , Svobodova B , Korabecny J , Zarybnicky T , Raisova-Stuchlikova L , Skalova L , Lauschke VM , Kucera R , Soukup O
Ref : ACS Chemical Biology , 18 :1993 , 2023
Abstract : Tacrine was withdrawn from clinical use as a drug against Alzheimer's disease in 2013, mainly due to drug-induced liver injury. The culprit of tacrine-associated hepatotoxicity is believed to be the 7-OH-tacrine metabolite, a possible precursor of quinone methide (Q(meth)), which binds to intracellular -SH proteins. In our study, several different animal and human models (liver microsomes, primary hepatocytes, and liver slices) were used to investigate the biotransformation and hepatotoxicity of tacrine and its 7-substituted analogues (7-methoxy-, 7-phenoxy-, and 7-OH-tacrine). Our goal was to find the most appropriate in vitro model for studying tacrine hepatotoxicity and, through rational structure modifications, to develop derivatives of tacrine that are less prone to Q(meth) formation. Our results show that none of animal models tested accurately mimic human tacrine biotransformation; however, the murine model seems to be more suitable than the rat model. Tacrine metabolism was overall most accurately mimicked in three-dimensional (3D) spheroid cultures of primary human hepatocytes (PHHs). In this system, tacrine and 7-methoxytacrine were hydroxylated to 7-OH-tacrine, whereas 7-phenoxytacrine formed, as expected, only trace amounts. Surprisingly, however, our study showed that 7-OH-tacrine was the least hepatotoxic (7-OH-tacrine < tacrine < 7-methoxytacrine < 7-phenoxytacrine) even after doses had been adjusted to achieve the same intracellular concentrations. The formation of Q(meth)-cysteine and Q(meth)-glutathione adducts after human liver microsome incubation was confirmed by all of the studied tacrine derivatives, but these findings were not confirmed after incubation with 3D PHH spheroids. Therefore, the presented data call into question the suggested previously hypothesized mechanism of toxicity, and the results open new avenues for chemical modifications to improve the safety of novel tacrine derivatives.
ESTHER : Novak_2023_ACS.Chem.Biol_18_1993
PubMedSearch : Novak_2023_ACS.Chem.Biol_18_1993
PubMedID: 37622522

Title : UHPLC-Orbitrap study of the first phase tacrine in vitro metabolites and related Alzheimer's drug candidates using human liver microsomes - Novak_2023_J.Pharm.Biomed.Anal_224_115154
Author(s) : Novak M , Svobodova B , Konecny J , Kuratkova A , Nevosadova L , Prchal L , Korabecny J , Lauschke VM , Soukup O , Kucera R
Ref : J Pharm Biomed Anal , 224 :115154 , 2023
Abstract : Tacrine was the first drug used in the therapy of Alzheimer's disease (AD) and is one of the leading structures frequently pursued in the drug discovery of novel candidates for tackling AD. However, because tacrine has been withdrawn from the market due to its hepatotoxicity, ascribed to specific metabolites, concerns are high about the toxicity profile of newly developed compounds related to tacrine. From the point of view of drug safety, the formation of metabolites must be uncovered and analyzed. Bearing in mind that the main culprit of tacrine hepatotoxicity is its biotransformation to hydroxylated metabolites, human liver microsomes were used as a biotransformation model. Our study aims to clarify phase I metabolites of three potentially non-toxic tacrine derivatives (7-methoxytacrine, 6-chlorotacrine, 7-phenoxytacrine) and to semi-quantitatively determine the relative amount of individual metabolites as potential culprits of tacrine-based hepatotoxicity. For this purpose, a new selective UHPLC-Orbitrap method has been developed. Applying UHPLC-Orbitrap method, two as yet unpublished tacrine and 7-methoxytacrine monohydroxylated metabolites have been found and completely characterized, and the separation of ten dihydroxylated tacrine and 7-methoxytacrine metabolites was achieved for the first time. Moreover, the structures of several new metabolites of 7-phenoxytacrine and 6-chlorotacrine have been identified. In addition, the relative amount of these newly observed metabolites was determined. Based on the results and known facts about the toxicity of tacrine metabolites published so far, it appears that 7-phenoxytacrine and 6-chlorotacrine could be substantially less hepatotoxic compared to tacrine, and could potentially pave the way for metabolically safe molecules applicable in AD therapy.
ESTHER : Novak_2023_J.Pharm.Biomed.Anal_224_115154
PubMedSearch : Novak_2023_J.Pharm.Biomed.Anal_224_115154
PubMedID: 36442458

Title : Differentiated SH-SY5Y neuroblastoma cells as a model for evaluation of nerve agent-associated neurotoxicity - Pulkrabkova_2023_Arch.Toxicol__
Author(s) : Pulkrabkova L , Muckova L , Hrabinova M , Sorf A , Kobrlova T , Jost P , Bezdekova D , Korabecny J , Jun D , Soukup O
Ref : Archives of Toxicology , : , 2023
Abstract : Organophosphorus compounds (OPs) involving life-threatening nerve agents (NA) have been known for several decades. Despite a clear mechanism of their lethality caused by the irreversible inhibition of acetylcholinesterase (AChE) and manifested via overstimulation of peripheral nicotinic and muscarinic acetylcholine (ACh) receptors, the mechanism for central neurotoxicity responsible for acute or delayed symptoms of the poisoning has not been thoroughly uncovered. One of the reasons is the lack of a suitable model. In our study, we have chosen the SH-SY5Y model in both the differentiated and undifferentiated state to study the effects of NAs (GB, VX and A234). The activity of expressed AChE in cell lysate assessed by Ellman's method showed 7.3-times higher activity in differentiated SH-SY5Y cells in contrast to undifferentiated cells, and with no involvement of BuChE as proved by ethopropazine (20 microM). The activity of AChE was found to be, in comparison to untreated cells, 16-, 9.3-, and 1.9-times lower upon A234, VX, and GB (100 microM) administration respectively. The cytotoxic effect of given OPs expressed as the IC(50) values for differentiated and undifferentiated SH-SY5Y, respectively, was found 12 mM and 5.7 mM (A234), 4.8 mM and 1.1 mM (VX) and 2.6 mM and 3.8 mM (GB). In summary, although our results confirm higher AChE expression in the differentiated SH-SY5Y cell model, the such higher expression does not lead to a more pronounced NA cytotoxic effect. On the contrary, higher expression of AChE may attenuate NA-induced cytotoxicity by scavenging the NA. Such finding highlights a protective role for cholinesterases by scavenging Novichoks (A-agents). Second, we confirmed the mechanism of cytotoxicity of NAs, including A-agents, can be ascribed rather to the non-specific effects of OPs than to AChE-mediated effects.
ESTHER : Pulkrabkova_2023_Arch.Toxicol__
PubMedSearch : Pulkrabkova_2023_Arch.Toxicol__
PubMedID: 37221426

Title : Structure-Guided Design of N-Methylpropargylamino-Quinazoline Derivatives as Multipotent Agents for the Treatment of Alzheimer's Disease - Svobodova_2023_Int.J.Mol.Sci_24_
Author(s) : Svobodova B , Pulkrabkova L , Panek D , Misiachna A , Kolcheva M , Andrys R , Handl J , Capek J , Nyvltova P , Rousar T , Prchal L , Hepnarova V , Hrabinova M , Muckova L , Tosnerova D , Karabanovich G , Finger V , Soukup O , Horak M , Korabecny J
Ref : Int J Mol Sci , 24 : , 2023
Abstract : Alzheimer's disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and N-methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into a single molecule represents a more promising approach for treating AD, and is expected to yield greater benefits in alleviating symptoms and slowing disease progression. In the present study, we designed, synthesized, and biologically evaluated 24 novel N-methylpropargylamino-quinazoline derivatives. Initially, compounds were thoroughly inspected by in silico techniques determining their oral and CNS availabilities. We tested, in vitro, the compounds' effects on cholinesterases and monoamine oxidase A/B (MAO-A/B), as well as their impacts on NMDAR antagonism, dehydrogenase activity, and glutathione levels. In addition, we inspected selected compounds for their cytotoxicity on undifferentiated and differentiated neuroblastoma SH-SY5Y cells. We collectively highlighted II-6h as the best candidate endowed with a selective MAO-B inhibition profile, NMDAR antagonism, an acceptable cytotoxicity profile, and the potential to permeate through BBB. The structure-guided drug design strategy applied in this study imposed a novel concept for rational drug discovery and enhances our understanding on the development of novel therapeutic agents for treating AD.
ESTHER : Svobodova_2023_Int.J.Mol.Sci_24_
PubMedSearch : Svobodova_2023_Int.J.Mol.Sci_24_
PubMedID: 37298087

Title : Neurotoxicity evoked by organophosphates and available countermeasures - Pulkrabkova_2022_Arch.Toxicol__
Author(s) : Pulkrabkova L , Svobodova B , Konecny J , Kobrlova T , Muckova L , Janousek J , Pejchal J , Korabecny J , Soukup O
Ref : Archives of Toxicology , : , 2022
Abstract : Organophosphorus compounds (OP) are a constant problem, both in the military and in the civilian field, not only in the form of acute poisoning but also for their long-lasting consequences. No antidote has been found that satisfactorily protects against the toxic effects of organophosphates. Likewise, there is no universal cure to avert damage after poisoning. The key mechanism of organophosphate toxicity is the inhibition of acetylcholinesterase. The overstimulation of nicotinic or muscarinic receptors by accumulated acetylcholine on a synaptic cleft leads to activation of the glutamatergic system and the development of seizures. Further consequences include generation of reactive oxygen species (ROS), neuroinflammation, and the formation of various other neuropathologists. In this review, we present neuroprotection strategies which can slow down the secondary nerve cell damage and alleviate neurological and neuropsychiatric disturbance. In our opinion, there is no unequivocal approach to ensure neuroprotection, however, sooner the neurotoxicity pathway is targeted, the better the results which can be expected. It seems crucial to target the key propagation pathways, i.e., to block cholinergic and, foremostly, glutamatergic cascades. Currently, the privileged approach oriented to stimulating GABA(A)R by benzodiazepines is of limited efficacy, so that antagonizing the hyperactivity of the glutamatergic system could provide an even more efficacious approach for terminating OP-induced seizures and protecting the brain from permanent damage. Encouraging results have been reported for tezampanel, an antagonist of GluK1 kainate and AMPA receptors, especially in combination with caramiphen, an anticholinergic and anti-glutamatergic agent. On the other hand, targeting ROS by antioxidants cannot or already developed neuroinflammation does not seem to be very productive as other processes are also involved.
ESTHER : Pulkrabkova_2022_Arch.Toxicol__
PubMedSearch : Pulkrabkova_2022_Arch.Toxicol__
PubMedID: 36335468

Title : Non-covalent acetylcholinesterase inhibitors: In vitro screening and molecular modeling for novel selective insecticides - Hepnarova_2022_Toxicol.In.Vitro__105463
Author(s) : Hepnarova V , Hrabinova M , Muckova L , Kucera T , Schmidt M , Dolezal R , Gorecki L , Hrabcova V , Korabecny J , Mezeiova E , Jun D , Pejchal J
Ref : Toxicol In Vitro , :105463 , 2022
Abstract : Insecticides represent the most crucial element in the integrated management approach to malaria and other vector-borne diseases. The evolution of insect resistance to long-used substances and the toxicity of organophosphates (OPs) and carbamates are the main factors contributing to the development of new, environmentally safe pesticides. In our work, fourteen compounds of 7-methoxytacrine-tacrine heterodimers were tested for their insecticidal effect. Compounds were evaluated in vitro on insect acetylcholinesterase from Anopheles gambiae (AgAChE) and Musca domestica (MdAChE). The evaluation was executed in parallel with testing on human erythrocyte acetylcholinesterase (HssAChE) and human butyrylcholinesterase (HssBChE) using a modified Ellman's method. Compound efficacy was determined as IC(50) values for the respective enzymes and selectivity indexes were expressed to compare the interspecies selectivity. Docking studies were performed to predict the binding modes of selected compounds. K1328 and K1329 provided high HssAChE/AgAChE selectivity outperforming standard pesticides (carbofuran and bendiocarb), and thus can be considered as suitable lead structure for novel anticholinesterase insecticides.
ESTHER : Hepnarova_2022_Toxicol.In.Vitro__105463
PubMedSearch : Hepnarova_2022_Toxicol.In.Vitro__105463
PubMedID: 36041654

Title : Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer's Activity Profile - Makhaeva_2022_Molecules_27_
Author(s) : Makhaeva GF , Kovaleva NV , Boltneva NP , Rudakova EV , Lushchekina SV , Astakhova TY , Serkov IV , Proshin AN , Radchenko EV , Palyulin VA , Korabecny J , Soukup O , Bachurin SO , Richardson RJ
Ref : Molecules , 27 : , 2022
Abstract : Using two ways of functionalizing amiridine-acylation with chloroacetic acid chloride and reaction with thiophosgene-we have synthesized new homobivalent bis-amiridines joined by two different spacers-bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) -as potential multifunctional agents for the treatment of Alzheimer's disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug-drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a-c exhibited an IC(50)(AChE) = 2.9-1.4 microM, IC(50)(BChE) = 0.13-0.067 microM, and 14-18% propidium displacement at 20 microM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Abeta(42) aggregation. Conjugates 3 had no effect on Abeta(42) self-aggregation, whereas compounds 5c-e (m = 4, 5, 6) showed mild (13-17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2-2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood-brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c-e appear promising for future optimization and development as multitarget anti-AD agents.
ESTHER : Makhaeva_2022_Molecules_27_
PubMedSearch : Makhaeva_2022_Molecules_27_
PubMedID: 35164325

Title : Countermeasures in organophosphorus intoxication: pitfalls and prospects - Gorecki_2022_Trends.Pharmacol.Sci__
Author(s) : Gorecki L , Soukup O , Korabecny J
Ref : Trends in Pharmacological Sciences , : , 2022
Abstract : High lethality, fast action, and simple synthesis make nerve agents (NAs) the most dreaded chemical weapons (CWs) of mass destruction in the world. Disturbances of the autonomic nervous system and neuromuscular junction (NMJ) by NAs and organophosphorus (OP) insecticides lead to cholinergic crisis and skeletal muscle paralysis. Current medical intervention has remained mostly unchanged since their first discovery in the 1950s. Within this overview, we have followed their development, clinical successes, and failures and discuss the major demerits of available antidotes. In current times, with precision medicine becoming increasingly relevant in various fields of medicine, the antidotal approach should be broadened to better cope with individual cases of NA intoxication. When possible, countermeasures could be targeted directly to achieve a better patient prognosis. As the threat of NA misuse and accidental cases of OP insecticide intoxication are still omnipresent, advancement of intervention expertise and further research in this field should be supported.
ESTHER : Gorecki_2022_Trends.Pharmacol.Sci__
PubMedSearch : Gorecki_2022_Trends.Pharmacol.Sci__
PubMedID: 35643835

Title : Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities - Chrienova_2022_J.Enzyme.Inhib.Med.Chem_37_2605
Author(s) : Chrienova Z , Nepovimova E , Andrys R , Dolezal R , Janockova J , Muckova L , Fabova L , Soukup O , Oleksak P , Valis M , Korabecny J , Marco-Contelles J , Kuca K
Ref : J Enzyme Inhib Med Chem , 37 :2605 , 2022
Abstract : Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC(50) = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC(50) = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC(50) = 0.095 +/- 0.001 microM; hBChE: IC(50) = 0.093 +/- 0.003 microM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC(50) = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC(50) (hAChE) = 1.472 +/- 0.024 microM; IC(50) (hBChE) = 0.659 +/- 0.077 microM; IC(50) (hMAO-B) = 40.39 +/- 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.
ESTHER : Chrienova_2022_J.Enzyme.Inhib.Med.Chem_37_2605
PubMedSearch : Chrienova_2022_J.Enzyme.Inhib.Med.Chem_37_2605
PubMedID: 36131624

Title : UHPLC-HRMS study of pharmacokinetics of a novel hybrid cholinesterase inhibitor K1234: A comparison between in silico, in vitro and in vivo data - Mzik_2022_J.Pharm.Biomed.Anal_219_114898
Author(s) : Mzik M , Sestak V , Mezeiova E , Korabecny J , Hroch M , Pejchal J , Karasova-Zdarova J
Ref : J Pharm Biomed Anal , 219 :114898 , 2022
Abstract : Alzheimer's disease (AD) is one of the most common forms of dementia. Current anti-AD therapeutics exploit the cholinergic hypothesis of its pathophysiology; they aim to inhibit cerebral cholinesterases. K1234 is a novel hybrid molecule derived from Huperzine A and 7-MEOTA-huperzine which shows increased potency in acetylcholinesterase inhibition in vitro compared to the compounds themselves. The study focused on description of the pharmacokinetic behaviour of K1234, blood-brain barrier penetration, identification of the main in vitro and in vivo metabolites. K1234 is relatively non-toxic compound, that is rapidly absorbed after i.p. administration reaching C(max) within minutes, with extensive distribution into tissues and fast metabolism in mice. The dominant metabolic pathway appears to be glucuronidation of the parent molecule and its phase-I metabolites. The passage of K1234 across the blood-brain-barrier in mice appears to be limited, as it reached only approximately one third of the AUC of plasma.
ESTHER : Mzik_2022_J.Pharm.Biomed.Anal_219_114898
PubMedSearch : Mzik_2022_J.Pharm.Biomed.Anal_219_114898
PubMedID: 35779353

Title : Synthesis of New Biscoumarin Derivatives, In Vitro Cholinesterase Inhibition, Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells - Hudacova_2021_Int.J.Mol.Sci_22_
Author(s) : Hudacova M , Hamuakova S , Konkoova E , Jendzelovsky R , Vargova J , Sevc J , Fedorocko P , Soukup O , Janockova J , Ihnatova V , Kucera T , Bzonek P , Novakova N , Jun D , Junova L , Korabecny J , Kuca K , Kozurkova M
Ref : Int J Mol Sci , 22 : , 2021
Abstract : A series of novel C4-C7-tethered biscoumarin derivatives (12a-e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC(50) = 6.30 microM) and butyrylcholinesterase (BChE, IC(50) = 49 microM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood-brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer's disease.
ESTHER : Hudacova_2021_Int.J.Mol.Sci_22_
PubMedSearch : Hudacova_2021_Int.J.Mol.Sci_22_
PubMedID: 33917200

Title : Discovery of sustainable drugs for Alzheimer's disease: cardanol-derived cholinesterase inhibitors with antioxidant and anti-amyloid properties - de Andrade Ramos_2021_RSC.Med.Chem_12_1154
Author(s) : de Andrade Ramos G , Souza de Oliveira A , Bartolini M , Naldi M , Liparulo I , Bergamini C , Uliassi E , Wu L , Fraser PE , Abreu M , Kiametis AS , Gargano R , Silveira ER , Brand GD , Prchal L , Soukup O , Korabecny J , Bolognesi ML , Soares Romeiro LA
Ref : RSC Med Chem , 12 :1154 , 2021
Abstract : As part of our efforts to develop sustainable drugs for Alzheimer's disease (AD), we have been focusing on the inexpensive and largely available cashew nut shell liquid (CNSL) as a starting material for the identification of new acetylcholinesterase (AChE) inhibitors. Herein, we decided to investigate whether cardanol, a phenolic CNSL component, could serve as a scaffold for improved compounds with concomitant anti-amyloid and antioxidant activities. Ten new derivatives, carrying the intact phenolic function and an aminomethyl functionality, were synthesized and first tested for their inhibitory potencies towards AChE and butyrylcholinesterase (BChE). 5 and 11 were found to inhibit human BChE at a single-digit micromolar concentration. Transmission electron microscopy revealed the potential of five derivatives to modulate Abeta aggregation, including 5 and 11. In HORAC assays, 5 and 11 performed similarly to standard antioxidant ferulic acid as hydroxyl scavenging agents. Furthermore, in in vitro studies in neuronal cell cultures, 5 and 11 were found to effectively inhibit reactive oxygen species production at a 10 microM concentration. They also showed a favorable initial ADME/Tox profile. Overall, these results suggest that CNSL is a promising raw material for the development of potential disease-modifying treatments for AD.
ESTHER : de Andrade Ramos_2021_RSC.Med.Chem_12_1154
PubMedSearch : de Andrade Ramos_2021_RSC.Med.Chem_12_1154
PubMedID: 34355181

Title : Development of versatile and potent monoquaternary reactivators of acetylcholinesterase - Gorecki_2021_Arch.Toxicol__
Author(s) : Gorecki L , Hepnarova V , Karasova JZ , Hrabinova M , Courageux C , Dias J , Kucera T , Kobrlova T , Muckova L , Prchal L , Malinak D , Jun D , Musilek K , Worek F , Nachon F , Soukup O , Korabecny J
Ref : Archives of Toxicology , : , 2021
Abstract : To date, the only treatments developed for poisoning by organophosphorus compounds, the most toxic chemical weapons of mass destruction, have exhibited limited efficacy and versatility. The available causal antidotes are based on reactivation of the enzyme acetylcholinesterase (AChE), which is rapidly and pseudo-irreversibly inhibited by these agents. In this study, we developed a novel series of monoquaternary reactivators combining permanently charged moieties tethered to position 6- of 3-hydroxypyridine-2-aldoxime reactivating subunit. Highlighted representatives (21, 24, and 27; also coded as K1371, K1374, and K1375, respectively) that contained 1-phenylisoquinolinium, 7-amino-1-phenylisoquinolinium and 4-carbamoylpyridinium moieties as peripheral anionic site ligands, respectively, showed efficacy superior or comparable to that of the clinically used standards. More importantly, these reactivators exhibited wide-spectrum efficacy and were minutely investigated via determination of their reactivation kinetics in parallel with molecular dynamics simulations to study their mechanisms of reactivation of the tabun-inhibited AChE conjugate. To further confirm the potential applicability of these candidates, a mouse in vivo assay was conducted. While K1375 had the lowest acute toxicity and the most suitable pharmacokinetic profile, the oxime K1374 with delayed elimination half-life was the most effective in ameliorating the signs of tabun toxicity. Moreover, both in vitro and in vivo, the versatility of the agents was substantially superior to that of clinically used standards. Their high efficacy and broad-spectrum capability make K1374 and K1375 promising candidates that should be further investigated for their potential as nerve agents and insecticide antidotes.
ESTHER : Gorecki_2021_Arch.Toxicol__
PubMedSearch : Gorecki_2021_Arch.Toxicol__
PubMedID: 33517499

Title : Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies - Al Mamun_2021_Int.J.Mol.Sci_22_
Author(s) : Al Mamun A , Pidany F , Hulcova D , Marikova J , Kucera T , Schmidt M , Catapano MC , Hrabinova M , Jun D , Muckova L , Kunes J , Janousek J , Andrys R , Novakova L , Perinova R , Maafi N , Soukup O , Korabecny J , Cahlikova L
Ref : Int J Mol Sci , 22 : , 2021
Abstract : Alzheimer's disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1-20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC(50) values below 1 microM. The most potent one, compound 6, showed nanomolar range activity with an IC(50) value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.
ESTHER : Al Mamun_2021_Int.J.Mol.Sci_22_
PubMedSearch : Al Mamun_2021_Int.J.Mol.Sci_22_
PubMedID: 34361074

Title : Derivatives of montanine-type alkaloids and their implication for the treatment of Alzheimer's disease: Synthesis, biological activity and in silico study - Maafi_2021_Bioorg.Med.Chem.Lett_51_128374
Author(s) : Maafi N , Pidany F , Marikova J , Korabecny J , Hulcova D , Kucera T , Schmidt M , Shammari LA , Spulak M , Carmen Catapano M , Mecava M , Prchal L , Kunes J , Janousek J , Kohelova E , Jenco J , Novakova L , Cahlikova L
Ref : Bioorganic & Medicinal Chemistry Lett , 51 :128374 , 2021
Abstract : Alzheimes disease (AD) is the most common neurodegenerative disorder, characterized by neuronal loss and cognitive impairment. Currently, very few drugs are available for AD treatment, and a search for new therapeutics is urgently needed. Thus, in the current study, twenty-eight new derivatives of montanine-type Amaryllidaceae alkaloids were synthesized and evaluated for their ability to inhibit human recombinant acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). Three derivatives (1n, 1o, and 1p) with different substitution patterns demonstrated significant selective inhibitory potency for hAChE (IC(50) < 5 microM), and one analog, 1v, showed selective hBuChE inhibition activity (IC(50) = 1.73 +/- 0.05 microM). The prediction of CNS availability, as disclosed by the BBB score, suggests that the active compounds in this survey should be able pass through the blood-brain barrier (BBB). Cytotoxicity screening and docking studies were carried out for the two most pronounced cholinesterase inhibitors, 1n and 1v.
ESTHER : Maafi_2021_Bioorg.Med.Chem.Lett_51_128374
PubMedSearch : Maafi_2021_Bioorg.Med.Chem.Lett_51_128374
PubMedID: 34555506

Title : Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-d-Aspartate receptors - Gorecki_2021_Eur.J.Med.Chem_219_113434
Author(s) : Gorecki L , Misiachna A , Damborsky J , Dolezal R , Korabecny J , Cejkova L , Hakenova K , Chvojkova M , Karasova JZ , Prchal L , Novak M , Kolcheva M , Kortus S , Vales K , Horak M , Soukup O
Ref : Eur Journal of Medicinal Chemistry , 219 :113434 , 2021
Abstract : Tacrine is a classic drug whose efficacy against neurodegenerative diseases is still shrouded in mystery. It seems that besides its inhibitory effect on cholinesterases, the clinical benefit is co-determined by NMDAR-antagonizing activity. Our previous data showed that the direct inhibitory effect of tacrine, as well as its 7-methoxy derivative (7-MEOTA), is ensured via a "foot-in-the-door" open-channel blockage, and that interestingly both tacrine and 7-MEOTA are slightly more potent at the GluN1/GluN2A receptors when compared with the GluN1/GluN2B receptors. Here, we report that in a series of 30 novel tacrine derivatives, designed for assessment of structure-activity relationship, blocking efficacy differs among different compounds and receptors using electrophysiology with HEK293 cells expressing the defined types of NMDARs. Selected compounds (4 and 5) potently inhibited both GluN1/GluN2A and GluN1/GluN2B receptors; other compounds (7 and 23) more effectively inhibited the GluN1/GluN2B receptors; or the GluN1/GluN2A receptors (21 and 28). QSAR study revealed statistically significant model for the data obtained for inhibition of GluN1/Glu2B at -60 mV expressed as IC(50) values, and for relative inhibition of GluN1/Glu2A at +40 mV caused by a concentration of 100 microM. The models can be utilized for a ligand-based virtual screening to detect potential candidates for inhibition of GluN1/Glu2A and/or GluN1/Glu2B subtypes. Using in vivo experiments in rats we observed that unlike MK-801, the tested novel compounds did not induce hyperlocomotion in open field, and also did not impair prepulse inhibition of startle response, suggesting minimal induction of psychotomimetic side effects. We conclude that tacrine derivatives are promising compounds since they are centrally available subtype-specific inhibitors of the NMDARs without detrimental behavioral side-effects.
ESTHER : Gorecki_2021_Eur.J.Med.Chem_219_113434
PubMedSearch : Gorecki_2021_Eur.J.Med.Chem_219_113434
PubMedID: 33892271

Title : Design and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease - Hamulakova_2021_Future.Med.Chem__
Author(s) : Hamulakova S , Kudlickova Z , Janovec L , Mezencev R , Deckner ZJ , Chernoff YO , Janockova J , Ihnatova V , Bzonek P , Novakova N , Hepnarova V , Hrabinova M , Jun D , Korabecny J , Soukup O , Kuca K
Ref : Future Med Chem , : , 2021
Abstract : The authors report on the synthesis and biological evaluation of new compounds whose structure combines tacrine and indole moieties. Tacrine-indole heterodimers were designed to inhibit cholinesterases and beta-amyloid formation, and to cross the blood-brain barrier. The most potent new acetylcholinesterase inhibitors were compounds 3c and 4d (IC(50) = 25 and 39 nM, respectively). Compound 3c displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound 4d (selectivity index: IC(50) [butyrylcholinesterase]/IC(50) [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound 3c inhibited beta-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds 3c and 4d displayed a high probability of crossing the blood-brain barrier. The results support the potential of 3c for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.
ESTHER : Hamulakova_2021_Future.Med.Chem__
PubMedSearch : Hamulakova_2021_Future.Med.Chem__
PubMedID: 33829876

Title : Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer's disease treatment - Makhaeva_2021_Bioorg.Chem_112_104974
Author(s) : Makhaeva GF , Lushchekina SV , Kovaleva NV , Yu Astakhova T , Boltneva NP , Rudakova EV , Serebryakova OG , Proshin AN , Serkov IV , Trofimova TP , Tafeenko VA , Radchenko EV , Palyulin VA , Fisenko VP , Korabecny J , Soukup O , Richardson RJ
Ref : Bioorg Chem , 112 :104974 , 2021
Abstract : We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC(50) for AChE = 1.83 +/- 0.03 microM (K(i) = 1.50 +/- 0.12 and alphaK(i) = 2.58 +/- 0.23 microM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced beta-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 +/- 0.03 and 0.39 +/- 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pK(a) values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.
ESTHER : Makhaeva_2021_Bioorg.Chem_112_104974
PubMedSearch : Makhaeva_2021_Bioorg.Chem_112_104974
PubMedID: 34029971

Title : 7-phenoxytacrine is a dually acting drug with neuroprotective efficacy in vivo - Kaniakova_2021_Biochem.Pharmacol__114460
Author(s) : Kaniakova M , Korabecny J , Holubova K , Kleteckova L , Chvojkova M , Hakenova K , Prchal L , Novak M , Dolezal R , Hepnarova V , Svobodova B , Kucera T , Lichnerova K , Krausova B , Horak M , Vales K , Soukup O
Ref : Biochemical Pharmacology , :114460 , 2021
Abstract : N-methyl-D-aspartate receptors (NMDARs) are a subclass of glutamate receptors, which play an essential role in excitatory neurotransmission, but their excessive overactivation by glutamate leads to excitotoxicity. NMDARs are hence a valid pharmacological target for the treatment of neurodegenerative disorders; however, novel drugs targeting NMDARs are often associated with specific psychotic side effects and abuse potential. Motivated by currently available treatment against neurodegenerative diseases involving the inhibitors of acetylcholinesterase (AChE) and NMDARs, administered also in combination, we developed a dually-acting compound 7-phenoxytacrine (7-PhO-THA) and evaluated its neuropsychopharmacological and drug-like properties for potential therapeutic use. Indeed, we have confirmed the dual potency of 7-PhO-THA, i.e. potent and balanced inhibition of both AChE and NMDARs. We discovered that it selectively inhibits the GluN1/GluN2B subtype of NMDARs via an ifenprodil-binding site, in addition to its voltage-dependent inhibitory effect at both GluN1/GluN2A and GluN1/GluN2B subtypes of NMDARs. Furthermore, whereas NMDA-induced lesion of the dorsal hippocampus confirmed potent anti-excitotoxic and neuroprotective efficacy, behavioral observations showed also a cholinergic component manifesting mainly in decreased hyperlocomotion. From the point of view of behavioral side effects, 7-PhO-THA manages to avoid these, notably those analogous to symptoms of schizophrenia. Thus, CNS availability and the overall behavioral profile are promising for subsequent investigation of therapeutic use.
ESTHER : Kaniakova_2021_Biochem.Pharmacol__114460
PubMedSearch : Kaniakova_2021_Biochem.Pharmacol__114460
PubMedID: 33571502

Title : Phenothiazine-Tacrine Heterodimers: Pursuing Multitarget Directed Approach in Alzheimer's Disease - Gorecki_2021_ACS.Chem.Neurosci__
Author(s) : Gorecki L , Uliassi E , Bartolini M , Janockova J , Hrabinova M , Hepnarova V , Prchal L , Muckova L , Pejchal J , Karasova JZ , Mezeiova E , Benkova M , Kobrlova T , Soukup O , Petralla S , Monti B , Korabecny J , Bolognesi ML
Ref : ACS Chem Neurosci , : , 2021
Abstract : Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called "multitarget directed ligand" approach and designed 36 novel tacrine-phenothiazine heterodimers which were in vitro evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound 1dC as a potent and selective acetylcholinesterase inhibitor with IC(50) = 8 nM and 1aA as a potent butyrylcholinesterase inhibitor with IC(50) = 15 nM. Selected hybrids, namely, 1aC, 1bC, 1cC, 1dC, and 2dC, showed a significant inhibitory activity toward tau((306-336)) peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, 1dC and 2dC exerted a remarkable ability to inhibit self-induced Abeta(1-42) aggregation. Notwithstanding, in vitro studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when 1dC was administered to mice at 14 mg/kg (i.p.). 1dC was also able to permeate to the CNS as shown by in vitro and in vivo models. The maximum brain concentration was close to the IC(50) value for acetylcholinesterase inhibition with a relatively slow elimination half-time. 1dC showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile.
ESTHER : Gorecki_2021_ACS.Chem.Neurosci__
PubMedSearch : Gorecki_2021_ACS.Chem.Neurosci__
PubMedID: 33852284

Title : Structure Elucidation and Cholinesterase Inhibition Activity of Two New Minor Amaryllidaceae Alkaloids - Marikova_2021_Molecules_26_
Author(s) : Marikova J , Al Mamun A , Shammari LA , Korabecny J , Kucera T , Hulcova D , Kunes J , Malanik M , Vaskova M , Kohelova E , Novakova L , Cahlikova L , Pour M
Ref : Molecules , 26 : , 2021
Abstract : Two new minor Amaryllidaceae alkaloids were isolated from Hippeastrum x hybridum cv. Ferrari and Narcissus pseudonarcissus cv. Carlton. The chemical structures were identified by various spectroscopic (one- and two-dimensional (1D and 2D) NMR, circular dichroism (CD), high-resolution mass spectrometry (HRMS) and by comparison with literature data of similar compounds. Both isolated alkaloids were screened for their human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) inhibition activity. One of the new compounds, a heterodimer alkaloid of narcikachnine-type, named narciabduliine (2), showed balanced inhibition potency for both studied enzymes, with IC(50) values of 3.29 +/- 0.73 microM for hAChE and 3.44 +/- 0.02 microM for hBuChE. The accommodation of 2 into the active sites of respective enzymes was predicted using molecular modeling simulation.
ESTHER : Marikova_2021_Molecules_26_
PubMedSearch : Marikova_2021_Molecules_26_
PubMedID: 33652925

Title : Huprine Y - tryptophan heterodimers with potential implication to Alzheimer's disease treatment - Mezeiova_2021_Bioorg.Med.Chem.Lett__128100
Author(s) : Mezeiova E , Hrabinova M , Hepnarova V , Jun D , Janockova J , Muckova L , Prchal L , Kristofikova Z , Kucera T , Gorecki L , Chalupova K , Kunes J , Hroudova J , Soukup O , Korabecny J
Ref : Bioorganic & Medicinal Chemistry Lett , :128100 , 2021
Abstract : The search for novel and effective therapeutics for Alzheimer's disease (AD) is the main quest that remains to be resolved. The goal is to find a disease-modifying agent able to confront the multifactorial nature of the disease positively. Herewith, a family of huprineY-tryptophan heterodimers was prepared, resulting in inhibition of cholinesterase and neuronal nitric oxide synthase enzymes, with effect against amyloid-beta (Abeta) and potential ability to cross the blood-brain barrier. Their cholinesterase pattern of behavior was inspected using kinetic analysis in tandem with docking studies. These heterodimers exhibited a promising pharmacological profile with strong implication in AD.
ESTHER : Mezeiova_2021_Bioorg.Med.Chem.Lett__128100
PubMedSearch : Mezeiova_2021_Bioorg.Med.Chem.Lett__128100
PubMedID: 33984470

Title : Monoterpene indole alkaloids from Vinca minor L. (Apocynaceae): Identification of new structural scaffold for treatment of Alzheimer's disease - Vrabec_2021_Phytochemistry_194_113017
Author(s) : Vrabec R , Marikova J , Locarek M , Korabecny J , Hulcova D , Hosalkova A , Kunes J , Chlebek J , Kucera T , Hrabinova M , Jun D , Soukup O , Andrisano V , Jenco J , Safratova M , Novakova L , Opletal L , Cahlikova L
Ref : Phytochemistry , 194 :113017 , 2021
Abstract : One undescribed indole alkaloid together with twenty-two known compounds have been isolated from aerial parts of Vinca minor L. (Apocynaceae). The chemical structures of the isolated alkaloids were determined by a combination of MS, HRMS, 1D, and 2D NMR techniques, and by comparison with literature data. The NMR data of several alkaloids have been revised, corrected, and missing data have been supplemented. Alkaloids isolated in sufficient quantity were screened for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7) and butyrylcholinesterase (BuChE; E.C. 3.1.1.8) inhibitory activity. Selected compounds were also evaluated for prolyl oligopeptidase (POP; E.C. 3.4.21.26), and glycogen synthase 3beta-kinase (GSK-3beta; E.C. 2.7.11.26) inhibition potential. Significant hBuChE inhibition activity has been shown by (-)-2-ethyl-3[2-(3-ethylpiperidinyl)-ethyl]-1H-indole with an IC(50) value of 0.65 +/- 0.16 microM. This compound was further studied by enzyme kinetics, along with in silico techniques, to reveal the mode of inhibition. This compound is also predicted to cross the blood-brain barrier (BBB) through passive diffusion.
ESTHER : Vrabec_2021_Phytochemistry_194_113017
PubMedSearch : Vrabec_2021_Phytochemistry_194_113017
PubMedID: 34798410

Title : Discovery of multifunctional anti-Alzheimers agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and gamma-aminobutyric acid transporters - Pasieka_2021_Eur.J.Med.Chem_218_113397
Author(s) : Pasieka A , Panek D , Jonczyk J , Godyn J , Szalaj N , Latacz G , Tabor J , Mezeiova E , Chantegreil F , Dias J , Knez D , Lu J , Pi R , Korabecny J , Brazzolotto X , Gobec S , Hofner G , Wanner K , Wieckowska Q , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 218 :113397 , 2021
Abstract : Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: beta-secretase enzyme (BACE1) and amyloid beta (Abeta) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and gamma-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 microM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 microM; inhibition of Abeta aggregation = 57.9% at 10 microM; mGAT1 IC50 = 10.96 microM; and mGAT2 IC50 = 19.05 microM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 microM and IC50 = 2.95 microM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease.
ESTHER : Pasieka_2021_Eur.J.Med.Chem_218_113397
PubMedSearch : Pasieka_2021_Eur.J.Med.Chem_218_113397
PubMedID: 33838585

Title : Cholinesterase Research - Korabecny_2021_Biomolecules_11_
Author(s) : Korabecny J , Soukup O
Ref : Biomolecules , 11 : , 2021
Abstract : Cholinesterases are fundamental players in the peripheral and central nervous systems. These serine hydrolases are presented by a two-membered family, namely acetylcholinesterase (AChE, E.C. 3.1.1.7) and butyrylcholinesterase (BChE, E.C. 3.1.1.8). Under physiological conditions, AChE terminates the action of acetylcholine at synapses. AChE is also implicated in the differentiation of embryonic stem cells, neuritogenesis, cell adhesion, synaptogenesis, activation of dopamine neurons, amyloid beta fiber assembly, haematopoiesis and thrombopoiesis, or regulation of glutamate-mediated hippocampal activity. Many compounds target to inhibit this enzyme in order to symptomatically counteract low cholinergic tone; however, irreversible AChE blockade may have fatal consequences. This phenomenon is typical for a class of highly toxic compoundsnerve agents and pesticides. The role of BChE is still extensively discussed; it plays an important role in cholinergic mediation, it contributes to neurogenesis, and has a detoxifying effect towards different xenobiotic drugs. It is also assumed that BChE overtakes the function of AChE in the case of malfunction or later stages of Alzheimer's disease (AD). Based on the abovementioned, both AChE and BChE are considered as highly relevant targets in the field of medicinal chemistry. For neurodegenerative disorders such as AD, there is a strong consensus that AChE/BChE reversible inhibitors can, at least temporarily, alleviate the symptoms associated with the disorder, and enhance the cognitive performance of individuals. Other cholinesterase ligands, namely cholinesterase reactivators, typically endowed with strong nucleophilic function, can revert the irreversible action of organophosphorus compounds (nerve agents and pesticides). However, there are many other areas of research involving AChE and BChE, for example, pesticides; inflammation; and other neuronal disorders such as Lewy body dementia, Parkinsons disease, myasthenia gravis, and so on. The scope of this Special Issue of Biomolecules, 'Cholinesterase Research' was to provide a broad and updated overview of all the aspects that encompass cholinesterase research. The collection includes cholinesterase structural aspects, drug design and development, in vitro biochemical studies, animal studies, and computational approaches, all devoted primarily to cholinesterases. Computational studies focus mostly on the structural and dynamical aspects of cholinesterases: first of all a comprehensive review of cholinesterase modelling and simulation was provided by De Boer and colleagues [1]. It analyses AChE/BChE structure and function using computer-based modelling and simulation techniques using different models of both enzymes. It also discusses key structural similarities in the active site gorges of the two enzymes, such as flexibility, binding site location, and function, as well as differences, such as gorge volume and binding site residue composition. Catalytic studies are also described, with an emphasis on the mechanism of acetylcholine hydrolysis by each enzyme and novel mutants that increase catalytic efficiency. The review also explores the inhibitory properties of several compounds currently approved by the FDA and other experimental drugs through Monte Carlo-based docking calculations and molecular dynamics simulations. The study by Jonczyk and colleagues [2] explores molecular mechanisms determining the efficiency and selectivity of individual oximes to reactivate AChE/BChE blocked by sarin and tabun. The study investigated the reactivation of AChE and BChE by selected oximes using molecular docking methods. It identified amino acids essential for effective reactivation and those responsible for the selectivity of individual oximes against inhibited AChE/BChE. The observation made herein can significantly contribute to support the search for new effective reactivators. The paper of Lushchekina et al. [3] investigated the effect of different concentrations of sucrose on the protein and water dynamics in cholinesterases. It revealed a non-linear correlation with increasing sucrose concentration, i.e., first a decrease in the dynamics at 5 wt% followed by a gain at 10 wt% sucrose. The explanation of this phenomenon is that sucrose molecules interact with the surface of the protein and the entrance of the gorge at a lower concentration through the water layer, damping the motions at the surface, but increasing them inside the gorge. When increasing the sucrose concentration more, the sucrose molecules replace some of the water molecules at the surface, permitting again more water molecules to enter the gorge and opening simultaneously new pathways, among them the hypothesized backdoor to the gorge. The study by Zueva and colleagues [4] is a kinetic study corroborated by molecular modelling simulation of human AChE inhibition by fluorinated acetophenone derivative, namely 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (TFK). TFK was found to be a competitive type inhibitor reaching steady state inhibition slowly. It is speculated that after binding, TFK acylates the active serine, forming a hemiketal; the disruption of such complex, i.e., deacylation is slow. Modelling of interactions between TFK and AChE active site by QM/MM showed that the 'isomerization' step of enzyme-inhibitor complex leads to a complex similar to substrate tetrahedral intermediate, a so-called transition state analog, followed by a labile covalent intermediate. TFK can be classified as a slow-binding inhibitor with potential dual effect that could be of interest in palliative therapy of AD or protection of central AChE against organophosphorus compounds. When it comes to a development of novel chemical compounds targeting cholinestarases both in the inhibitory and reactivation manner, the Special Issue contains the following experimental studies: the article by Konecny et al. [5] describes the design, synthesis and biological evaluation of a series of 15 novel fluoren-9-amine derivatives as dually active cholinesterase inhibitors and N-methyl-d-aspartate receptor (NMDAR) antagonists. The study builds on the concept of so-called multi-target directed ligands (MTDLs) that are believed to provide higher benefit compared to single-oriented drugs. The compounds under the study were initially in silico screened for CNS and oral availability, fitting all the prediction models used. Ongoing assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits of NMDAR, along with a low cytotoxicity profile in the CHO-K1 cell line. Compounds were found to be highly selective BChE inhibitors with antagonistic activity on the NMDARs. The group of Florian Nachon compared in vitro and in vivo efficacy, and toxicity of a hybrid tetrahydroacridine pyridinaldoxime reactivator, namely KM297, with pralidoxime [6]. The study revealed that bloodbrain barrier crossing capacity of KM297 in vitro exceeds the permeability coefficient of pralidoxime twice. However, KM297 is also endowed with higher cytotoxicity, particularly on bone marrow-derived cells. Its strong cholinesterase inhibition potency seems to be correlated to its low protective efficacy in mice exposed to paraoxon. Ventilatory monitoring of KM297-treated mice by double-chamber plethysmography displayed toxic effects at the selected therapeutic dose. Natural compounds and their effect on the cholinesterases are involved as well. Namely, the article by Amat-ur-Rasool and colleagues [7] screened methanolic extracts from seven commonly cultivated plants for their nutraceutical potential with particular emphasis on AChE/BChE inhibition and antioxidant capacity. The majority of extracts inhibited AChE and BChE, with henna and eucalyptus extracts highlighted as the most potent ones. Moreover, all plant extracts were able to scavenge free radicals in a concentration-dependent manner, with eucalyptus being the most potent antioxidant. The article by Al Mamun and colleagues [8] describes the isolation of thirteen known and three previously undescribed alkaloids of belladine structural type. Notably, significant human BChE inhibition was demonstrated by newly described alkaloids carltonine A and carltonine B, representing a new scaffold for generation of a novel structural type of BChE inhibitors with highly selective pattern over AChE. Finally, the effect of clinically used donepezil has been investigated: the study of Audira and colleagues [9] is dedicated to donepezil, a currently approved drug for mild-to-moderate stages of AD. The study exploits a zebrafish model to analyze potential adverse effects of donepezil on the short-term memory, behavioral and biochemical changes. Donepezil caused a slight improvement in the short-term memory of zebrafish and induced significant elevation in aggressiveness, while the novel tank and shoaling tests revealed anxiolytic-like behavior. The latter can be ascribed to alterations associated with an elevation of oxytocin and a reduction in cortisol levels in the brain. Thus, chronic waterborne exposure to donepezil can severely induce adverse effects on normal zebrafish in a dose-dependent manner. In another article by Al-Hamed et al. [10], postoperative administration of donepezil on bone healing was studied in the group of Sprague-Dawley rats. After two weeks of donepezil administration, rats were euthanized, and their bones were analyzed by Micro-CT and histology, with the authors concluding that bone defects and implant osseointegration were significantly reduced compared to the saline-treated rats. Histomorphometric analysis pointed to lower immune cell infiltration in bone defects as the possible culprit for disrupted bone healing. To conclude, this Special Issue describes important findings related to cholinesterases physiological and pathological roles, their involvement in metabolic studies, and the influence of different modulators (inhibitors, reactivators) on their activity. All these findings may broaden the knowledge and the impact on clinical and pharmacological applications of different small molecules targeted to AChE/BChE.
ESTHER : Korabecny_2021_Biomolecules_11_
PubMedSearch : Korabecny_2021_Biomolecules_11_
PubMedID: 34439787

Title : (+\/-)-BIGI-3h: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3beta Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease - Ismaili_2021_ACS.Chem.Neurosci__
Author(s) : Ismaili L , Monnin J , Etievant A , Arribas RL , Viejo L , Refouvelet B , Soukup O , Janockova J , Hepnarova V , Korabecny J , Kucera T , Jun D , Andrys R , Musilek K , Baguet A , Garcia-Frutos EM , De Simone A , Andrisano V , Bartolini M , de los Rios C , Marco-Contelles J , Haffen E
Ref : ACS Chem Neurosci , : , 2021
Abstract : Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3beta and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (+/-)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both tau protein and beta-amyloid peptide. The in vivo studies have shown that (+/-)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.
ESTHER : Ismaili_2021_ACS.Chem.Neurosci__
PubMedSearch : Ismaili_2021_ACS.Chem.Neurosci__
PubMedID: 33797877

Title : Effects of Novel Tacrine Derivatives on Mitochondrial Energy Metabolism and Monoamine Oxidase Activity-In Vitro Study - Hroudova_2021_Mol.Neurobiol_58_1102
Author(s) : Hroudova J , Novakova T , Korabecny J , Malinak D , Gorecki L , Fisar Z
Ref : Molecular Neurobiology , 58 :1102 , 2021
Abstract : The trends of novel AD therapeutics are focused on multitarget-directed ligands (MTDLs), which combine cholinesterase inhibition with additional biological properties such as antioxidant properties to positively affect neuronal energy metabolism as well as mitochondrial function. We examined the in vitro effects of 10 novel MTDLs on the activities of mitochondrial enzymes (electron transport chain complexes and citrate synthase), mitochondrial respiration, and monoamine oxidase isoform (MAO-A and MAO-B) activity. The drug-induced effects of 7-MEOTA-adamantylamine heterodimers (K1011, K1013, K1018, K1020, and K1022) and tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers (K1046, K1053, K1056, K1060, and K1065) were measured in pig brain mitochondria. Most of the substances inhibited complex I- and complex II-linked respiration at high concentrations; K1046, K1053, K1056, and K1060 resulted in the least inhibition of mitochondrial respiration. Citrate synthase activity was not significantly inhibited by the tested substances; the least inhibition of complex I was observed for compounds K1060 and K1053, while both complex II/III and complex IV activity were markedly inhibited by K1011 and K1018. MAO-A was fully inhibited by K1018 and K1065, and MAO-B was fully inhibited by K1053 and K1065; the other tested drugs were partial inhibitors of both MAO-A and MAO-B. The tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers K1046, K1053, and K1060 seem to be the most suitable molecules for subsequent in vivo studies. These compounds had balanced inhibitory effects on mitochondrial respiration, with low complex I and complex II/III inhibition and full or partial inhibition of MAO-B activity.
ESTHER : Hroudova_2021_Mol.Neurobiol_58_1102
PubMedSearch : Hroudova_2021_Mol.Neurobiol_58_1102
PubMedID: 33089424

Title : Discovery of novel berberine derivatives with balanced cholinesterase and prolyl oligopeptidase inhibition profile - Sobolova_2020_Eur.J.Med.Chem_203_112593
Author(s) : Sobolova K , Hrabinova M , Hepnarova V , Kucera T , Kobrlova T , Benkova M , Janockova J , Dolezal R , Prchal L , Benek O , Mezeiova E , Jun D , Soukup O , Korabecny J
Ref : Eur Journal of Medicinal Chemistry , 203 :112593 , 2020
Abstract : Berberine, a naturally occurring compound, possesses an interesting multipotent pharmacological profile potentially applicable for Alzheimer's disease (AD) treatment. In this study, a series of novel 22 berberine derivatives was developed and tested in vitro. Berberine core was substituted at position 9-O of its aromatic ring region. All the hybrids under the study revealed multi-targeted profile inhibiting prolyl oligopeptidase, acetylcholinesterase and butyrylcholinesterase highlighting 4a, 4g, 4j, 4l and 4s possessing balanced activities in the micromolar range. The top-ranked candidates in terms of the most pronounced potency against POP, AChE and BChE can be classified as 4d, 4u and 4v, bearing 4-methylbenzyl, (naphthalen-2-yl)methylene and 1-phenoxyethyl moieties, respectively. In vitro data were corroborated by detailed kinetic analysis of the selected lead molecules. 4d, 4u and 4v were also inspected for their potential to inhibit aggregation of two abberant proteins in AD, namely amyloid beta and tau, indicating their potential disease-modifying properties. To explain the results of our study, we carried out docking simulation to the active sites of the respective enzyme with the best berberine derivatives, along with QSAR study. We also investigated compounds' potential permeability through blood-brain barrier by applying parallel artificial membrane permeation assay and addressed their cytotoxicity profile.
ESTHER : Sobolova_2020_Eur.J.Med.Chem_203_112593
PubMedSearch : Sobolova_2020_Eur.J.Med.Chem_203_112593
PubMedID: 32688201

Title : Tacrine - Benzothiazoles: Novel class of potential multitarget anti-Alzheimes drugs dealing with cholinergic, amyloid and mitochondrial systems - Nepovimova_2020_Bioorg.Chem_107_104596
Author(s) : Nepovimova E , Svobodova L , Dolezal R , Hepnarova V , Junova L , Jun D , Korabecny J , Kucera T , Gazova Z , Motykova K , Kubackova J , Bednarikova Z , Janockova J , Jesus C , Cortes L , Pina J , Rostohar D , Serpa C , Soukup O , Aitken L , Hughes RE , Musilek K , Muckova L , Jost P , Chvojkova M , Vales K , Valis M , Chrienova Z , Chalupova K , Kuca K
Ref : Bioorg Chem , 107 :104596 , 2020
Abstract : A series of tacrine - benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid beta (Abeta) aggregation and mitochondrial enzyme ABAD, whose interaction with Abeta leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Abeta aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC(50) value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 microM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound - 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.
ESTHER : Nepovimova_2020_Bioorg.Chem_107_104596
PubMedSearch : Nepovimova_2020_Bioorg.Chem_107_104596
PubMedID: 33421953

Title : Pursuing the Complexity of Alzheimer's Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists - Konecny_2020_Biomolecules_11_
Author(s) : Konecny J , Misiachna A , Hrabinova M , Pulkrabkova L , Benkova M , Prchal L , Kucera T , Kobrlova T , Finger V , Kolcheva M , Kortus S , Jun D , Valko M , Horak M , Soukup O , Korabecny J
Ref : Biomolecules , 11 : , 2020
Abstract : Alzheimer's disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood-brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.
ESTHER : Konecny_2020_Biomolecules_11_
PubMedSearch : Konecny_2020_Biomolecules_11_
PubMedID: 33375115

Title : Functionalized aromatic esters of the Amaryllidaceae alkaloid haemanthamine and their in vitro and in silico biological activity connected to Alzheimer's disease - Perinova_2020_Bioorg.Chem_100_103928
Author(s) : Perinova R , Maafi N , Korabecny J , Kohelova E , De Simone A , Al Mamun A , Hulcova D , Markova J , Kucera T , Jun D , Safratova M , Marikova J , Andrisano V , Jenco J , Kunes J , Martinez A , Novakova L , Cahlikova L
Ref : Bioorg Chem , 100 :103928 , 2020
Abstract : A novel series of aromatic esters (1a-1m) related to the Amaryllidaceae alkaloid (AA) haemanthamine were designed, synthesized and tested in vitro with particular emphasis on the treatment of neurodegenerative diseases. Some of the synthesized compounds revealed promising acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory profile. Significant human AChE (hAChE) inhibition was demonstrated by 11-O-(3-nitrobenzoyl)haemanthamine (1j) with IC50value of 4.0 +/- 0.3 microM. The strongest human BuChE (hBuChE) inhibition generated 1-O-(2-methoxybenzoyl)haemanthamine (1g) with IC50 value 3.3 +/- 0.4 microM. Moreover, 11-O-(2-chlorbenzoyl)haemanthamine (1m) was able to inhibit both enzymes in dose-dependent manner. The mode of hAChE and hBuChE inhibition was minutely inspected using enzyme kinetic analysis in tandem with in silico experiments, the latter elucidating crucial interaction in 1j-, 1m-hAChE and 1g-, 1m-hBuChE complexes. The blood-brain barrier (BBB) permeability was investigated applying the parallel artificial membrane permeation assay (PAMPA) to predict the CNS availability of the compounds.
ESTHER : Perinova_2020_Bioorg.Chem_100_103928
PubMedSearch : Perinova_2020_Bioorg.Chem_100_103928
PubMedID: 32450384

Title : Alkaloids of Zephyranthes citrina (Amaryllidaceae) and their implication to Alzheimer's disease: Isolation, structural elucidation and biological activity - Kohelova_2020_Bioorg.Chem_107_104567
Author(s) : Kohelova E , Marikova J , Korabecny J , Hulcova D , Kucera T , Jun D , Chlebek J , Jenco J , Safratova M , Hrabinova M , Ritomska A , Malanik M , Perinova R , Breiterova K , Kunes J , Novakova L , Opletal L , Cahlikova L
Ref : Bioorg Chem , 107 :104567 , 2020
Abstract : Twenty known Amaryllidaceae alkaloids of various structural types, and one undescribed alkaloid of narcikachnine-type, named narcieliine (3), have been isolated from fresh bulbs of Zephyranthes citrina. The chemical structures of the isolated alkaloids were elucidated by a combination of MS, HRMS, 1D and 2D NMR, and CD spectroscopic techniques, and by comparison with literature data. The absolute configuration of narcieliine (3) has also been determined. Compounds isolated in a sufficient quantity were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8), and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human AChE/BuChE (hAChE/hBuChE) inhibitory activity was demonstrated by the newly described alkaloid narcieliine (3), with IC(50) values of 18.7 +/- 2.3 microM and 1.34 +/- 0.31 microM, respectively. This compound is also predicted to cross the blood-brain barrier (BBB) through passive diffusion. The in vitro data were further supported by in silico studies of 3 in the active site of hAChE/hBuChE.
ESTHER : Kohelova_2020_Bioorg.Chem_107_104567
PubMedSearch : Kohelova_2020_Bioorg.Chem_107_104567
PubMedID: 33387730

Title : Amaryllidaceae Alkaloids of Belladine-Type from Narcissus pseudonarcissus cv. Carlton as New Selective Inhibitors of Butyrylcholinesterase - Al Mamun_2020_Biomolecules_10_
Author(s) : Al Mamun A , Marikova J , Hulcova D , Janousek J , Safratova M , Novakova L , Kucera T , Hrabinova M , Kunes J , Korabecny J , Cahlikova L
Ref : Biomolecules , 10 : , 2020
Abstract : Thirteen known (1-12 and 16) and three previously undescribed Amaryllidaceae alkaloids of belladine structural type, named carltonine A-C (13-15), were isolated from bulbs of Narcissus pseudonarcissus cv. Carlton (Amaryllidaceae) by standard chromatographic methods. Compounds isolated in sufficient amounts, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8) and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human BuChE (hBUChE) inhibitory activity was demonstrated by newly described alkaloids carltonine A (13) and carltonine B (14) with IC50 values of 913 +/- 20 nM and 31 +/- 1 nM, respectively. Both compounds displayed a selective inhibition pattern for hBuChE with an outstanding selectivity profile over AChE inhibition, higher than 100. The in vitro data were further supported by in silico studies of the active alkaloids 13 and 14 in the active site of hBuChE.
ESTHER : Al Mamun_2020_Biomolecules_10_
PubMedSearch : Al Mamun_2020_Biomolecules_10_
PubMedID: 32455879

Title : From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia - Mezeiova_2020_Bioorg.Chem_103_104179
Author(s) : Mezeiova E , Janockova J , Konecny J , Kobrlova T , Benkova M , Dolezal R , Prchal L , Karasova-Zdarova J , Soukup O , Korabecny J
Ref : Bioorg Chem , 103 :104179 , 2020
Abstract : YNT-185 is the first known small molecule acting as orexin 2 receptor (OX(2)R) agonist with implication to narcolepsy treatment, served as a template scaffold in generating a small set of seven compounds with predictive affinity to OX(2)R. The design of the new small molecules was driven mostly by improving physicochemical properties of the parent drug YNT-185 in parallel with in silico studies, later suggesting their favorable binding modes within the active site of OX(2)R. We obtained seven new potential OX(2)R binders that were evaluated in vitro for their CNS availability, cytotoxicity, and behavior pattern on OX(2)R. Out of them, 15 emerged as the most potent modulator of OX(2)R, which, contrary to YNT-185, displayed inverse mode of action, i.e. antagonist profile. 15 was also submitted to an in vivo experiment revealing its ability to permeate through BBB into the brain with a short half-life.
ESTHER : Mezeiova_2020_Bioorg.Chem_103_104179
PubMedSearch : Mezeiova_2020_Bioorg.Chem_103_104179
PubMedID: 32891860

Title : Cysteine-Targeted Insecticides against A. gambiae Acetylcholinesterase Are Neither Selective nor Reversible Inhibitors - Gorecki_2020_ACS.Med.Chem.Lett_11_65
Author(s) : Gorecki L , Andrys R , Schmidt M , Kucera T , Psotka M , Svobodova B , Hrabcova V , Hepnarova V , Bzonek P , Jun D , Kuca K , Korabecny J , Musilek K
Ref : ACS Med Chem Lett , 11 :65 , 2020
Abstract : Acetylcholinesterase cysteine-targeted insecticides against malaria vector Anopheles gambia and other mosquitos have already been introduced. We have applied the olefin metathesis for the preparation of cysteine-targeted insecticides in high yields. The prepared compounds with either a succinimide or maleimide moiety were evaluated on Anopheles gambiae and human acetylcholinesterase with relatively high irreversible inhibition of both enzymes but poor selectivity. The concept of cysteine binding was not proved by several methods, and poor stability was observed of the chosen most potent/selective compounds in a water/buffer environment. Thus, our findings do not support the proposed concept of cysteine-targeted selective insecticides for the prepared series of succinimide or maleimide compounds.
ESTHER : Gorecki_2020_ACS.Med.Chem.Lett_11_65
PubMedSearch : Gorecki_2020_ACS.Med.Chem.Lett_11_65
PubMedID: 31938465

Title : Synthesis, in vitro screening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators - Malinak_2020_J.Enzyme.Inhib.Med.Chem_35_478
Author(s) : Malinak D , Dolezal R , Hepnarova V , Hozova M , Andrys R , Bzonek P , Racakova V , Korabecny J , Gorecki L , Mezeiova E , Psotka M , Jun D , Kuca K , Musilek K
Ref : J Enzyme Inhib Med Chem , 35 :478 , 2020
Abstract : The series of symmetrical and unsymmetrical isoquinolinium-5-carbaldoximes was designed and prepared for cholinesterase reactivation purposes. The novel compounds were evaluated for intrinsic acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) inhibition, when the majority of novel compounds resulted with high inhibition of both enzymes and only weak inhibitors were selected for reactivation experiments on human AChE or BChE inhibited by sarin, VX, or paraoxon. The AChE reactivation for all used organophosphates was found negligible if compared to the reactivation ability of obidoxime. Importantly, two compounds were found to reactivate BChE inhibited by sarin or VX better to obidoxime at human attainable concentration. One compound resulted as better reactivator of NEMP (VX surrogate)-inhibited BChE than obidoxime. The in vitro results were further rationalized by molecular docking studies showing future directions on designing potent BChE reactivators.
ESTHER : Malinak_2020_J.Enzyme.Inhib.Med.Chem_35_478
PubMedSearch : Malinak_2020_J.Enzyme.Inhib.Med.Chem_35_478
PubMedID: 31910701

Title : Aromatic Esters of the Crinane Amaryllidaceae Alkaloid Ambelline as Selective Inhibitors of Butyrylcholinesterase - Marikova_2020_J.Nat.Prod__
Author(s) : Marikova J , Ritomska A , Korabecny J , Perinova R , Al Mamun A , Kucera T , Kohelova E , Hulcova D , Kobrlova T , Kunes J , Novakova L , Cahlikova L
Ref : Journal of Natural Products , : , 2020
Abstract : A total of 20 derivatives (1-20) of the crinane-type alkaloid ambelline were synthesized. These semisynthetic derivatives were assessed for their potency to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). To predict central nervous system (CNS) availability, logBB was calculated, and the data correlated well with those obtained from the parallel artificial membrane permeability assay (PAMPA). All compounds should be able to permeate the blood-brain barrier (BBB) according to the obtained results. A total of 7 aromatic derivatives (5, 6, 7, 9, 10, 12, and 16) with different substitution patterns showed inhibitory potency against human serum BuChE (IC50 < 5 muM), highlighting the three top-ranked compounds as follows: 11-O-(1-naphthoyl)ambelline (16), 11-O-(2-methylbenzoyl)ambelline (6), and 11-O-(2-methoxybenzoyl)ambelline (9) with IC50 values of 0.10 +/- 0.01, 0.28 +/- 0.02, and 0.43 +/- 0.04 muM, respectively. Notably, derivatives 6, 7, 9, and 16 displayed selective human BuChE (hBuChE) inhibition profiles with a selectivity index > 100. The in vitro results were supported by computational studies predicting plausible binding modes of the compounds in the active sites of hBuChE.
ESTHER : Marikova_2020_J.Nat.Prod__
PubMedSearch : Marikova_2020_J.Nat.Prod__
PubMedID: 32309949

Title : Interaction of Synthesized Nitrogen enriched Graphene Quantum Dots with Novel Anti-Alzheimer's Drugs: Spectroscopic Insights - Sharma_2020_J.Biomol.Struct.Dyn_38_1822
Author(s) : Sharma S , Singh N , Nepovimova E , Korabecny J , Kuca K , Satnami ML , Ghosh KK
Ref : J Biomol Struct Dyn , 38 :1822 , 2020
Abstract : Alzheimer's disease (AD) is considered as one of widespread dementia with no approved diagnosis, cure or prevention. Currently, only symptomatic relief can be provided upon administration of anti-AD drugs generally belonging to a category of anticholinesterases and antagonists of N-methyl-D-aspartate (NMDA) receptors. In present investigation, a sensing platform has been designed for studying recently developed anti-AD drugs viz., PC-25 (N-(2-{4-[(4-bromophenyl)methyl]piperazin-1-yl}ethyl)-7-methoxy-1,2,3,4-tetrahydr oacridin-9-amine trihydrochloride), PC-37 (7-methoxy-N-(2-{4-[(3-methylphenyl)methyl]piperazin-1-yl}ethyl)-1,2,3,4-tetrahyd roacridin-9-amine trihydrochloride) and PC-48 (N-(2-{4-[(3-bromophenyl) methyl]piperazin-1-yl}ethyl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine trihydrochloride) and two known standard tacrine (THA) and donepezil drugs for their estimation of in vitro potency towards AD using spectroscopic method. Anti-AD drugs have been accounted for individually with highly fluorescent nitrogen doped graphene quantum dots (NGQDs). The designed anti-AD drugs exerted the efficacy related to cholinergic hypothesis of AD. While the enzyme action is sensed by interacted species of NGQDs and acetylcholine, the fluorescence of NGQDs is quenched by the hydrolyzing action of acetylcholinesterase (AChE) enzyme but the lost fluorescence is recovered back upon addition of anti-AD drugs. These alterations in fluorescence of NGQDs are expected to have biological relevance akin to sensing. Moreover, these results advocate that out of all the drugs tested PC-37 displayed maximum inhibition efficiency. Our investigations suggest that synthesized drugs have the AD treating potential and can be entrusted in the near future for AD treatment. The validation parameters such as LOD, LOQ and recovery (%) were calculated in the range of 2.87 mM, 9.58 mM and 85-96%, respectively.
ESTHER : Sharma_2020_J.Biomol.Struct.Dyn_38_1822
PubMedSearch : Sharma_2020_J.Biomol.Struct.Dyn_38_1822
PubMedID: 31096863

Title : Tacroximes: novel unique compounds for the recovery of organophosphorus-inhibited acetylcholinesterase - Gorecki_2019_Future.Med.Chem_11_2625
Author(s) : Gorecki L , Junova L , Kucera T , Hepnarova V , Prchal L , Kobrlova T , Muckova L , Soukup O , Korabecny J
Ref : Future Med Chem , 11 :2625 , 2019
Abstract : Aim: Organophosphorus compounds are irreversible inhibitors of AChE. Without immediate countermeasure, intoxication leads quickly to death. None of the clinically-used causal antidotes can ensure a good prognosis for any poisoned patient. When fallen into the wrong hands, organophosphates represent a serious threat to mankind. Results & methodology: Herein, we describe two novel compounds as unique merged molecules built on a tacrine scaffold against organophosphorus intoxication. These reactivators of AChE have balanced physicochemical properties, and should be able to cross the blood-brain barrier with a slightly lowered cytotoxicity profile compared to reference tacrine. Conclusion: Their efficiency compared with pralidoxime and obidoxime was proved against dichlorvos.
ESTHER : Gorecki_2019_Future.Med.Chem_11_2625
PubMedSearch : Gorecki_2019_Future.Med.Chem_11_2625
PubMedID: 31556693

Title : In vitro investigating of anticancer activity of new 7-MEOTA-tacrine heterodimers - Janockova_2019_J.Enzyme.Inhib.Med.Chem_34_877
Author(s) : Janockova J , Korabecny J , Plsikova J , Babkova K , Konkolova E , Kucerova D , Vargova J , Koval J , Jendzelovsky R , Fedorocko P , Kasparkova J , Brabec V , Rosocha J , Soukup O , Hamulakova S , Kuca K , Kozurkova M
Ref : J Enzyme Inhib Med Chem , 34 :877 , 2019
Abstract : A combination of biochemical, biophysical and biological techniques was used to study calf thymus DNA interaction with newly synthesized 7-MEOTA-tacrine thiourea 12-17 and urea heterodimers 18-22, and to measure interference with type I and II topoisomerases. Their biological profile was also inspected in vitro on the HL-60 cell line using different flow cytometric techniques (cell cycle distribution, detection of mitochondrial membrane potential dissipation, and analysis of metabolic activity/viability). The compounds exhibited a profound inhibitory effect on topoisomerase activity (e.g. compound 22 inhibited type I topoisomerase at 1 microM concentration). The treatment of HL-60 cells with the studied compounds showed inhibition of cell growth especially with hybrids containing thiourea (14-17) and urea moieties (21 and 22). Moreover, treatment of human dermal fibroblasts with the studied compounds did not indicate significant cytotoxicity. The observed results suggest beneficial selectivity of the heterodimers as potential drugs to target cancer cells.
ESTHER : Janockova_2019_J.Enzyme.Inhib.Med.Chem_34_877
PubMedSearch : Janockova_2019_J.Enzyme.Inhib.Med.Chem_34_877
PubMedID: 30938202

Title : Tacrine and its 7-methoxy derivate\; time-change concentration in plasma and brain tissue and basic toxicological profile in rats - Karasova_2019_Drug.Chem.Toxicol__1
Author(s) : Karasova JZ , Soukup O , Korabecny J , Hroch M , Krejciova M , Hrabinova M , Misik J , Novotny L , Hepnarova V , Kuca K
Ref : Drug & Chemical Toxicology , :1 , 2019
Abstract :
ESTHER : Karasova_2019_Drug.Chem.Toxicol__1
PubMedSearch : Karasova_2019_Drug.Chem.Toxicol__1
PubMedID: 31257938

Title : Combination of Memantine and 6-Chlorotacrine as Novel Multi-Target Compound against Alzheimer's Disease - Kaniakova_2019_Curr.Alzheimer.Res_16_821
Author(s) : Kaniakova M , Nepovimova E , Kleteckova L , Skrenkova K , Holubova K , Chrienova Z , Hepnarova V , Kucera T , Kobrlova T , Vales K , Korabecny J , Soukup O , Horak M
Ref : Curr Alzheimer Res , 16 :821 , 2019
Abstract : BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is characterized as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment based on acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate receptors (NMDAR) antagonist is effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature of the disease. In this context, the so-called "multi-targeting" approach has been established. OBJECTIVES: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity mediated by the NMDAR receptors. METHODS: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine. Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and predicted the ability to cross the blood-brain barrier. RESULTS: A novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood-brain barrier via passive diffusion. Finally, the MTDL design strategy was indicated by in vivo results which showed that the novel 6-Cl-THA-memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine. CONCLUSION: We conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.
ESTHER : Kaniakova_2019_Curr.Alzheimer.Res_16_821
PubMedSearch : Kaniakova_2019_Curr.Alzheimer.Res_16_821
PubMedID: 30819076

Title : Search for multifunctional agents against Alzheimer's disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives - Jonczyk_2019_Bioorg.Chem_90_103084
Author(s) : Jonczyk J , Lodarski K , Staszewski M , Godyn J , Zareba P , Soukup O , Janockova J , Korabecny J , Salat K , Malikowska-Racia N , Hebda M , Szalaj N , Filipek B , Walczynski K , Malawska B , Bajda M
Ref : Bioorg Chem , 90 :103084 , 2019
Abstract : In the search for new treatments for complex disorders such as Alzheimer's disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood-brain barrier penetration in test conditions. The most promising compound, A12, chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA2=8.27), inhibitory activity against both AChE (IC50=13.96muM), and BuChE (IC50=14.62muM). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice.
ESTHER : Jonczyk_2019_Bioorg.Chem_90_103084
PubMedSearch : Jonczyk_2019_Bioorg.Chem_90_103084
PubMedID: 31271942

Title : In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier - Chlebek_2019_Molecules_24_
Author(s) : Chlebek J , Korabecny J , Dolezal R , Stepankova S , Perez DI , Hostalkova A , Opletal L , Cahlikova L , Macakova K , Kucera T , Hrabinova M , Jun D
Ref : Molecules , 24 : , 2019
Abstract : In recent studies, several alkaloids acting as cholinesterase inhibitors were isolated from Corydalis cava (Papaveraceae). Inhibitory activities of (+)-thalictricavine (1) and (+)-canadine (2) on human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) were evaluated with the Ellman's spectrophotometric method. Molecular modeling was used to inspect the binding mode of compounds into the active site pocket of hAChE. The possible permeability of 1 and 2 through the blood(-)brain barrier (BBB) was predicted by the parallel artificial permeation assay (PAMPA) and logBB calculation. In vitro, 1 and 2 were found to be selective hAChE inhibitors with IC50 values of 0.38 +/- 0.05 microM and 0.70 +/- 0.07 microM, respectively, but against hBChE were considered inactive (IC50 values > 100 microM). Furthermore, both alkaloids demonstrated a competitive-type pattern of hAChE inhibition and bind, most probably, in the same AChE sub-site as its substrate. In silico docking experiments allowed us to confirm their binding poses into the active center of hAChE. Based on the PAMPA and logBB calculation, 2 is potentially centrally active, but for 1 BBB crossing is limited. In conclusion, 1 and 2 appear as potential lead compounds for the treatment of Alzheimer's disease.
ESTHER : Chlebek_2019_Molecules_24_
PubMedSearch : Chlebek_2019_Molecules_24_
PubMedID: 30959739

Title : Oxime K203: a drug candidate for the treatment of tabun intoxication - Gorecki_2019_Arch.Toxicol_93_673
Author(s) : Gorecki L , Soukup O , Kucera T , Malinak D , Jun D , Kuca K , Musilek K , Korabecny J
Ref : Archives of Toxicology , 93 :673 , 2019
Abstract : For over 60 years, researchers across the world have sought to deal with poisoning by nerve agents, the most toxic and lethal chemical weapons. To date, there is no efficient causal antidote with sufficient effect. Every trialed compound fails to fulfil one or more criteria (e.g. reactivation potency, broad reactivation profile). In this recent contribution, we focused our attention to one of the promising compounds, namely the bis-pyridinium reactivator K203. The oxime K203 is very often cited as the best reactivator against tabun poisoning. Herein, we provide all the available literature data in comprehensive and critical review to address whether K203 could be considered as a new drug candidate against organophosphorus poisoning with the stress on tabun. We describe its development from the historical point of view and review all available in vitro as well as in vivo data to date. K203 is easily accessible by a relatively simple two-step synthesis. It is well accommodated in the enzyme active gorge of acetylcholinesterase providing suitable interactions for reactivation, as shown by molecular docking simulations. According to a literature survey, in vitro data for tabun-inhibited AChE are extraordinary. However, in vivo efficiency remains unconvincing. The K203 toxicity profile did not show any perturbations compared to clinically used standards; on the other hand versatility of K203 does not exceed currently available oximes. In summary, K203 does not seem to address current issues associated with the organophosphorus poisoning, especially the broad profile against all nerve agents. However, its reviewed efficacy entitles K203 to be considered as a backup or tentative replacement for obidoxime and trimedoxime, currently only available anti-tabun drugs.
ESTHER : Gorecki_2019_Arch.Toxicol_93_673
PubMedSearch : Gorecki_2019_Arch.Toxicol_93_673
PubMedID: 30564897

Title : Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease - Chalupova_2019_Eur.J.Med.Chem_168_491
Author(s) : Chalupova K , Korabecny J , Bartolini M , Monti B , Lamba D , Caliandro R , Pesaresi A , Brazzolotto X , Gastellier AJ , Nachon F , Pejchal J , Jarosova M , Hepnarova V , Jun D , Hrabinova M , Dolezal R , Karasova JZ , Mzik M , Kristofikova Z , Misik J , Muckova L , Jost P , Soukup O , Benkova M , Setnicka V , Habartova L , Chvojkova M , Kleteckova L , Vales K , Mezeiova E , Uliassi E , Valis M , Nepovimova E , Bolognesi ML , Kuca K
Ref : Eur Journal of Medicinal Chemistry , 168 :491 , 2019
Abstract : A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC50 values of 6.3 and 9.1nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Abeta42 self-aggregation (58.6+/-5.1% at 50muM) as well as hAChE-induced Abeta40 aggregation (48.3+/-6.3% at 100muM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.
ESTHER : Chalupova_2019_Eur.J.Med.Chem_168_491
PubMedSearch : Chalupova_2019_Eur.J.Med.Chem_168_491
PubMedID: 30851693
Gene_locus related to this paper: torca-ACHE

Title : Derivatives of the beta-Crinane Amaryllidaceae Alkaloid Haemanthamine as Multi-Target Directed Ligands for Alzheimer's Disease - Kohelova_2019_Molecules_24_
Author(s) : Kohelova E , Perinova R , Maafi N , Korabecny J , Hulcova D , Marikova J , Kucera T , Martinez Gonzalez L , Hrabinova M , Vorcakova K , Novakova L , De Simone A , Havelek R , Cahlikova L
Ref : Molecules , 24 : , 2019
Abstract : Twelve derivatives 1a-1m of the beta-crinane-type alkaloid haemanthamine were developed. All the semisynthetic derivatives were studied for their inhibitory potential against both acetylcholinesterase and butyrylcholinesterase. In addition, glycogen synthase kinase 3beta (GSK-3beta) inhibition potency was evaluated in the active derivatives. In order to reveal the availability of the drugs to the CNS, we elucidated the potential of selected derivatives to penetrate through the blood-brain barrier (BBB). Two compounds, namely 11-O-(2-methylbenzoyl)-haemanthamine (1j) and 11-O-(4-nitrobenzoyl)-haemanthamine (1m), revealed the most intriguing profile, both being acetylcholinesterase (hAChE) inhibitors on a micromolar scale, with GSK-3beta inhibition properties, and predicted permeation through the BBB. In vitro data were further corroborated by detailed inspection of the compounds' plausible binding modes in the active sites of hAChE and hBuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.
ESTHER : Kohelova_2019_Molecules_24_
PubMedSearch : Kohelova_2019_Molecules_24_
PubMedID: 30987121

Title : A Systematic Review on Donepezil-based Derivatives as Potential Cholinesterase Inhibitors for Alzheimer's Disease - Korabecny_2019_Curr.Med.Chem_26_5625
Author(s) : Korabecny J , Spilovska K , Mezeiova E , Benek O , Juza R , Kaping D , Soukup O
Ref : Curr Med Chem , 26 :5625 , 2019
Abstract : Alzheimer's Disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by memory loss, disorientation, and gradual deterioration of intellectual capacity. Its etiology has not been elucidated yet. To date, only one therapeutic approach has been approved for the treatment of AD. The pharmacotherapy of AD has relied on noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist - memantine, and acetylcholinesterase (AChE) inhibitors (AChEIs) - tacrine, donepezil, rivastigmine and galantamine. Donepezil was able to ameliorate the symptoms related to AD mainly via AChE, but also through reduction of beta-amyloid burden. This review presents the overview of donepezilrelated compounds as potential anti-AD drugs developed on the basis of cholinergic hypothesis to act as solely AChE and butyrylcholinesterase (BChE) inhibitors.
ESTHER : Korabecny_2019_Curr.Med.Chem_26_5625
PubMedSearch : Korabecny_2019_Curr.Med.Chem_26_5625
PubMedID: 29768996

Title : Orexin supplementation in narcolepsy treatment: A review - Nepovimova_2019_Med.Res.Rev_39_961
Author(s) : Nepovimova E , Janockova J , Misik J , Kubik S , Stuchlik A , Vales K , Korabecny J , Mezeiova E , Dolezal R , Soukup O , Kobrlova T , Pham NL , Nguyen TD , Konecny J , Kuca K
Ref : Med Res Rev , 39 :961 , 2019
Abstract : Narcolepsy is a rare, chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, vivid hallucinations, and sleep paralysis. Narcolepsy occurs in approximately 1 of 3000 people, affecting mainly adolescents aged 15 to 30 years. Recently, people with narcolepsy were shown to exhibit extensive orexin/hypocretin neuronal loss. The orexin system regulates sleep/wake control via complex interactions with monoaminergic, cholinergic and GABA-ergic neuronal systems. Currently, no cure for narcolepsy exists, but some symptoms can be controlled with medication (eg, stimulants, antidepressants, etc). Orexin supplementation represents a more sophisticated way to treat narcolepsy because it addresses the underlying cause of the disease and not just the symptoms. Research on orexin supplementation in the treatment of sleep disorders has strongly increased over the past two decades. This review focuses on a brief description of narcolepsy, the mechanisms by which the orexin system regulates sleep/wake cycles, and finally, possible therapeutic options based on orexin supplementation in animal models and patients with narcolepsy.
ESTHER : Nepovimova_2019_Med.Res.Rev_39_961
PubMedSearch : Nepovimova_2019_Med.Res.Rev_39_961
PubMedID: 30426515

Title : Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors - Svobodova_2019_Biomolecules_9_
Author(s) : Svobodova B , Mezeiova E , Hepnarova V , Hrabinova M , Muckova L , Kobrlova T , Jun D , Soukup O , Jimeno ML , Marco-Contelles J , Korabecny J
Ref : Biomolecules , 9 : , 2019
Abstract : Tacrine was the first drug to be approved for Alzheimer's disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes.
ESTHER : Svobodova_2019_Biomolecules_9_
PubMedSearch : Svobodova_2019_Biomolecules_9_
PubMedID: 31430943

Title : Isoquinoline Alkaloids from Berberis vulgaris as Potential Lead Compounds for the Treatment of Alzheimer's Disease - Hostalkova_2019_J.Nat.Prod_82_239
Author(s) : Hostalkova A , Marikova J , Opletal L , Korabecny J , Hulcova D , Kunes J , Novakova L , Perez DI , Jun D , Kucera T , Andrisano V , Siatka T , Cahlikova L
Ref : Journal of Natural Products , 82 :239 , 2019
Abstract : Three new alkaloids, bersavine (3), muraricine (4), and berbostrejdine (8), together with seven known isoquinoline alkaloids (1-2, 5-7, 9, and 10) were isolated from an alkaloidal extract of the root bark of Berberis vulgaris. The structures of the isolated compounds were determined by spectroscopic methods, including 1D and 2D NMR techniques, HRMS, and optical rotation, and by comparison of the obtained data with those in the literature. The NMR data of berbamine (5), aromoline (6), and obamegine (7) were completely assigned employing 2D NMR experiments. Alkaloids isolated in sufficient amounts were evaluated for their in vitro acetylcholinesterase, butyrylcholinesterase (BuChE), prolyl oligopeptidase, and glycogen synthase kinase-3beta inhibitory activities. Selected compounds were studied for their ability to permeate through the blood-brain barrier. Significant human BuChE ( hBuChE) inhibitory activity was demonstrated by 6 (IC50 = 0.82 +/- 0.10 muM). The in vitro data were further supported by computational analysis that showed the accommodation of 6 in the active site of hBuChE.
ESTHER : Hostalkova_2019_J.Nat.Prod_82_239
PubMedSearch : Hostalkova_2019_J.Nat.Prod_82_239
PubMedID: 30701972

Title : N-alkylated Tacrine Derivatives as Potential Agents in Alzheimer's Disease Therapy - Nepovimova_2019_Curr.Alzheimer.Res_16_333
Author(s) : Nepovimova E , Korabecny J , Hepnarova V , Jun D , Dolezal R , Muckova L , Jost P , Soukup O , Janockova J , Pham NL , Nguyen TD , Valis M , Kuca K
Ref : Curr Alzheimer Res , 16 :333 , 2019
Abstract : BACKGROUND: Based on the prevalence studies, the number of people suffering from dementia will almost double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050, assuming no changes in mortality, effective preventative measures, definitive diagnostic guidelines or curative treatment. From the abovementioned epidemiological data, it is obvious that dementia constitutes a major public health problem not only at present, but unfortunately also in the future. OBJECTIVES AND METHODS: Several N-alkylated tacrine (THA) derivatives have already been synthesized by Pomponi et al., in 1997. However, these compounds were tested for their anti-AChE activity using enzyme isolated from Electrophorus electricus. For this reason, we have decided to extend the previously reported series of THA derivatives and consequently test them in the battery of experiments, the results of which have served to more relevant evaluation of these compounds from the perspective of Alzeimer s disease compared to that published by Pomponi. RESULTS AND CONCLUSION: In summary, all compounds of interest effectively inhibited ChEs in vitro. One of the most promising derivatives 8 bearing an N-octyl chain showed 2.5-fold higher AChE inhibitory activity in relation to tacrine. With respect to blood-brain barrier (BBB) penetration, it can be claimed that synthesized analogues are presumably able to cross the BBB. From the point of view of hepatotoxicity, selected Nalkylated tacrine derivatives exerted worse results compared to tacrine. However, in vitro results are only illustrative, therefore, only in vivo experiments could determine the real value of selected N-alkylated THA derivatives.
ESTHER : Nepovimova_2019_Curr.Alzheimer.Res_16_333
PubMedSearch : Nepovimova_2019_Curr.Alzheimer.Res_16_333
PubMedID: 30873921

Title : Donepezil Derivatives Targeting Amyloid-beta Cascade in Alzheimer's Disease - Mezeiova_2019_Curr.Alzheimer.Res_16_772
Author(s) : Mezeiova E , Chalupova K , Nepovimova E , Gorecki L , Prchal L , Malinak D , Kuca K , Soukup O , Korabecny J
Ref : Curr Alzheimer Res , 16 :772 , 2019
Abstract : Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge number of novel compounds are developed every year exploiting knowledge of the various aspects of AD pathophysiology. To better address the pathological complexity of AD, one of the most extensively pursued strategies by medicinal chemists is based on Multi-target-directed Ligands (MTDLs). Donepezil is one of the currently approved drugs for AD therapy acting as an acetylcholinesterase inhibitor. In this review, we have made an extensive literature survey focusing on donepezil-derived MTDL hybrids primarily targeting on different levels cholinesterases and amyloid beta (Abeta) peptide. The targeting includes direct interaction of the compounds with Abeta, AChE-induced Abeta aggregation, inhibition of BACE-1 enzyme, and modulation of biometal balance thus impeding Abeta assembly.
ESTHER : Mezeiova_2019_Curr.Alzheimer.Res_16_772
PubMedSearch : Mezeiova_2019_Curr.Alzheimer.Res_16_772
PubMedID: 30819078

Title : UHPLC-HRMS study of anti-Alzheimer's drug candidates: metabolism of 7-MEOTA-tryptophan hybrids hampers their passage into brain - Mzik_2019_J.Pharm.Biomed.Anal_174_134
Author(s) : Mzik M , Zdarova-Karasova J , Chalupova K , Korabecny J , Palicka V , Sestak V
Ref : J Pharm Biomed Anal , 174 :134 , 2019
Abstract : Being among the top five causes of death in the developed world, Alzheimer's disease represents a major socio-economic issue. We administered a single intramuscular dose of two new hybrid anti-Alzheimer's compounds, with 7-methoxytacrine (7-MEOTA; acetylcholinesterase inhibitor) and tryptophan (inhibitor of amyloid accumulation) in their structure, to rats. Using validated ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) methods, we uncovered their inability to enter the site of action - the brain. We discuss four possible explanations: i) physico-chemical properties, ii) lack of active/facilitated transport, iii) effective efflux and/or iv) extensive metabolism. High-resolution mass spectrometric analyses proved that the compounds are easily hydrolysed at amide bond between tryptophan and the linker both in vitro and in vivo. Contrary to the parent compounds these metabolites - analogues of 7-MEOTA - can enter the brain in significant amounts.
ESTHER : Mzik_2019_J.Pharm.Biomed.Anal_174_134
PubMedSearch : Mzik_2019_J.Pharm.Biomed.Anal_174_134
PubMedID: 31167157

Title : Amaryllidaceae alkaloids from Narcissus pseudonarcissus L. cv. Dutch Master as potential drugs in treatment of Alzheimer's disease - Hulcova_2019_Phytochemistry_165_112055
Author(s) : Hulcova D , Marikova J , Korabecny J , Hostalkova A , Jun D , Kunes J , Chlebek J , Opletal L , De Simone A , Novakova L , Andrisano V , Ruzicka A , Cahlikova L
Ref : Phytochemistry , 165 :112055 , 2019
Abstract : Twenty-one known Amaryllidaceae alkaloids of various structural types and one undescribed alkaloid, named narcimatuline, have been isolated from fresh bulbs of Narcissus pseudonarcissus L. cv. Dutch Master. The chemical structures were elucidated by combination of MS, HRMS, 1D and 2D NMR spectroscopic techniques, and by comparison with literature data. Narcimatuline amalgamates two basic scaffolds of Amaryllidaceae alkaloids in its core, namely galanthamine and galanthindole. All isolated compounds were evaluated for their in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), prolyl oligopeptidase (POP), and glycogen synthase kinase-3beta (GSK-3beta) inhibitory activities. The most interesting biological profile was demonstrated by newly isolated alkaloid narcimatuline.
ESTHER : Hulcova_2019_Phytochemistry_165_112055
PubMedSearch : Hulcova_2019_Phytochemistry_165_112055
PubMedID: 31261031

Title : Current approaches to enhancing oxime reactivator delivery into the brain - Kobrlova_2019_Toxicology_423_75
Author(s) : Kobrlova T , Korabecny J , Soukup O
Ref : Toxicology , 423 :75 , 2019
Abstract : The misuse of organophosphate compounds still represents a current threat worldwide. Treatment of poisoning with organophosphates (OPs) remains unsatisfactorily resolved despite the extensive investment in research in academia. There are no universal, effective and centrally-active acetylcholinesterase (AChE) reactivators to countermeasure OP intoxication. One major obstacle is to overcome the blood-brain barrier (BBB). The central compartment is readily accessible by the OPs which are lipophilic bullets that can easily cross the BBB, whereas first-line therapeutics, namely oxime-based AChE reactivators and atropine, do not cross or do so rather slowly. The limitation of oxime-based AChE reactivators can be ascribed to their chemical nature, bearing a positive charge which is essential either for their AChE affinity or their reactivating potency. The aim of this article is to review the methods for targeting the brain by oxime reactivators that have been developed so far. Approaches using prodrugs, lipophilicity enhancement, or sugar-based oximes have been rather unsuccessful. However, other strategies have been more promising, such as the use of nanoparticles or co-administration of the reactivator with efflux transporter inhibitors. Encouraging results have also been associated with intranasal delivery, but research in this field is still at the beginning. Further research of auspicious approaches is inevitable.
ESTHER : Kobrlova_2019_Toxicology_423_75
PubMedSearch : Kobrlova_2019_Toxicology_423_75
PubMedID: 31112674

Title : Cholinesterase inhibitor 6-chlorotacrine - in vivo toxicological profile and behavioural effects - Misik_2018_Curr.Alzheimer.Res_15_552
Author(s) : Misik J , Nepovimova E , Pejchal J , Kassa J , Korabecny J , Soukup O
Ref : Curr Alzheimer Res , 15 :552 , 2018
Abstract : BACKGROUND: 6-chlorotacrine is a cholinesterase inhibitor showing good inhibitory potential, even better than parent compound tacrine, in vitro. Despite tacrine scaffold is broadly used for design and synthesis of novel compounds with anti-Alzheimer's potential, no in vivo effects have been investigated so far. Thus, basic toxicological and behavioural evaluation has been carried out throughout this study. METHODS: Maximum tolerated dose (MTD) and median lethal dose (LD50) were assessed in BALB/c mice and Wistar rats. Behavioural effects were observed in rats performing the multiple T-maze test, the water maze test and the step-through passive avoidance test. All outcomes were compared with the effects of parent compound - tacrine. RESULTS: The toxicity of 6-chlorotacrine was increased compared to tacrine with MTD 6.0/5.0 mg.kg-1 (i.m., male/female mice), 6.0/5.0 mg.kg-1 (i.p., male/female rats) and LD50 9.0 mg.kg-1 (male rats). At MTD doses, no histopathological changes and blood biochemistry abnormalities were observed except decreased plasma creatinine levels. 6-chlorotacrine showed good effects in the reversal of quinuclidinyl benzilate-induced amnesia. Best results were achieved at the dose of 1.8 mg.kg-1 (20% LD50) in the water maze test; the pro-cognitive effect was stronger than that of tacrine (5.2 mg.kg-1, 20% LD50). Other doses tested (0.9 mg.kg-1 and 2.7 mg.kg-1) showed similar effects as tacrine in the water maze, multiple T-maze and passive avoidance test. CONCLUSION: Observed effects predetermine 6-chlorotacrine as a potent parent compound for synthesis of novel multifactorial drugs intended to treatment of Alzheimer's disease. Even though 6-chlorotacrine showed in vivo beneficial effect with no signs of toxicity, further tests on the field of biochemistry and pharmacology are essential to disclose exact mechanism of action, safety evaluation and the metabolic fate of the compound after the repeated administration.
ESTHER : Misik_2018_Curr.Alzheimer.Res_15_552
PubMedSearch : Misik_2018_Curr.Alzheimer.Res_15_552
PubMedID: 29231138

Title : Newly Developed Drugs for Alzheimer's Disease in Relation to Energy Metabolism, Cholinergic and Monoaminergic Neurotransmission - Korabecny_2018_Neurosci_370_191
Author(s) : Korabecny J , Nepovimova E , Cikankova T , Spilovska K , Vaskova L , Mezeiova E , Kuca K , Hroudova J
Ref : Neuroscience , 370 :191 , 2018
Abstract : Current options for Alzheimer's disease (AD) treatment are based on administration of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or memantine, acting as an N-methyl-D-aspartate (NMDA). Therapeutic approaches vary and include novel cholinesterase inhibitors, modulators of NMDA receptors, monoamine oxidase (MAO) inhibitors, immunotherapeutics, modulators of mitochondrial permeability transition pores (mPTP), amyloid-beta binding alcohol dehydrogenase (ABAD) modulators, antioxidant agents, etc. The novel trends of AD therapy are focused on multiple targeted ligands, where mostly ChE inhibition is combined with additional biological properties, positively affecting neuronal energy metabolism as well as mitochondrial functions, and possessing antioxidant properties. The present review summarizes newly developed drugs targeting cholinesterase and MAO, as well as drugs affecting mitochondrial functions.
ESTHER : Korabecny_2018_Neurosci_370_191
PubMedSearch : Korabecny_2018_Neurosci_370_191
PubMedID: 28673719

Title : The New Acetylcholinesterase Inhibitors PC-37 and PC-48 (7-Methoxytacrine-Donepezil-Like Compounds): Characterization of Their Metabolites in Human Liver Microsomes, Pharmacokinetics and In Vivo Formation of the Major Metabolites in Rats - Zdarova Karasova_2018_Basic.Clin.Pharmacol.Toxicol_122_373
Author(s) : Karasova JZ , Mzik M , Hroch M , Korabecny J , Nepovimova E , Vorisek V , Palicka V , Kuca K
Ref : Basic Clin Pharmacol Toxicol , 122 :373 , 2018
Abstract : The objective of this study was to elucidate the pharmacokinetics and metabolite formation of newly developed non-selective AChE/BChE 7-MEOTA-donepezil-like inhibitors for potential therapeutic use in Alzheimer's disease (AD) patients. The chemical structures of metabolites were defined during incubation with human liver microsomes, and subsequently, the metabolization was verified in in vivo study. In vitro metabolic profiling revealed the formation of nine major metabolites in the case of PC-37 and eight metabolites of PC-48. Hydroxylation and the enzymatic hydrolysis of bonds close to the piperazine ring appeared to be the principal metabolic pathways in vitro. Of these metabolites, M1-M7 of PC-37 and M1-M6 of PC-48 were confirmed under in vivo conditions. Pilot pharmacokinetic experiments in rats were focused on the absorption, distribution and elimination of these compounds. Absorption after i.m. application was relatively fast; the bioavailability expressed as AUCtotal was 28179 +/- 4691 min.ng/mL for PC-37 and 23374 +/- 4045 min.ng/mL for PC-48. Both compounds showed ability to target the central nervous system, with brain concentrations exceeding those in plasma. The maximal brain concentrations are approximately two times higher than the plasma concentrations. The relatively high brain concentrations persisted throughout the experiment until 24 hr after application. Elimination via the kidneys (urine) significantly exceeded elimination via the liver (bile). All these characteristics are crucial for new candidates intended for AD treatment. The principle metabolic pathways that were verified in the in vivo study do not show any evidence for formation of extremely toxic metabolites, but this needs to be confirmed by further studies.
ESTHER : Zdarova Karasova_2018_Basic.Clin.Pharmacol.Toxicol_122_373
PubMedSearch : Zdarova Karasova_2018_Basic.Clin.Pharmacol.Toxicol_122_373
PubMedID: 29067789

Title : The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer's disease - Hepnarova_2018_Eur.J.Med.Chem_150_292
Author(s) : Hepnarova V , Korabecny J , Matouskova L , Jost P , Muckova L , Hrabinova M , Vykoukalova N , Kerhartova M , Kucera T , Dolezal R , Nepovimova E , Spilovska K , Mezeiova E , Pham NL , Jun D , Staud F , Kaping D , Kuca K , Soukup O
Ref : Eur Journal of Medicinal Chemistry , 150 :292 , 2018
Abstract : Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line. All the novel tacrine-BQCA hybrids were able to block the action of hAChE and hBChE in micromolar to nanomolar range. The hAChE kinetic profile of 5p was found to be mixed-type which is consistent with our docking experiments. Moreover, selected ligands were assessed for their potential hepatotoxicity on HepG2 cell line and presumable permeation through the blood-brain barrier by PAMPA assay. Expected agonistic profile towards M1 mAChRs delivered by BQCA moiety was not confirmed. From all the hybrids, 5o can be highlighted as non-selective cholinesterase inhibitor (hAChE IC50=74.5nM; hBChE IC50=83.3nM) with micromolar antagonistic activity towards M1 mAChR (IC50=4.23muM). A non-selective pattern of cholinesterase inhibition is likely to be valuable during the onset as well as later stages of AD.
ESTHER : Hepnarova_2018_Eur.J.Med.Chem_150_292
PubMedSearch : Hepnarova_2018_Eur.J.Med.Chem_150_292
PubMedID: 29533874

Title : Pro-cognitive effect of bis(7)-tacrine as potential therapeutic agent against neurodegenerative disorders - Korabecny_2018_Mil.Med.Sci.Lett_87_34
Author(s) : Korabecny J
Ref : Military Medical Science Letters , 87 :34 , 2018
Abstract : The acetylcholinesterase (AChE) structure elucidation has significantly contributed to the development of both novel homo- and heterodimer molecules that are capable of simultaneous binding to both anionic sites of the enzyme. This mostly resulted into improved AChE inhibition potency concurrently affecting other pathological hallmarks of the disease. In this regard, bis(7)-tacrine can be considered as the pioneering molecule. It consists of two tacrine moieties connected via alkylene tether of seven carbon atoms. In in vitro and in vivo, bis(7)-tacrine revealed interesting multipotent profile capable to affect several enzymes and receptors which are implicated in the pathogenesis of AD. It also became a key structural template in the development of other more potent compounds intended for the therapy of neurodegenerative disorders.
ESTHER : Korabecny_2018_Mil.Med.Sci.Lett_87_34
PubMedSearch : Korabecny_2018_Mil.Med.Sci.Lett_87_34
PubMedID:

Title : Investigation of New Orexin 2 Receptor Modulators Using In Silico and In Vitro Methods - Janockova_2018_Molecules_23_
Author(s) : Janockova J , Dolezal R , Nepovimova E , Kobrlova T , Benkova M , Kuca K , Konecny J , Mezeiova E , Melikova M , Hepnarova V , Ring A , Soukup O , Korabecny J
Ref : Molecules , 23 : , 2018
Abstract : The neuropeptides, orexin A and orexin B (also known as hypocretins), are produced in hypothalamic neurons and belong to ligands for orphan G protein-coupled receptors. Generally, the primary role of orexins is to act as excitatory neurotransmitters and regulate the sleep process. Lack of orexins may lead to sleep disorder narcolepsy in mice, dogs, and humans. Narcolepsy is a neurological disorder of alertness characterized by a decrease of ability to manage sleep-wake cycles, excessive daytime sleepiness, and other symptoms, such as cataplexy, vivid hallucinations, and paralysis. Thus, the discovery of orexin receptors, modulators, and their causal implication in narcolepsy is the most important advance in sleep-research. The presented work is focused on the evaluation of compounds L1L11 selected by structure-based virtual screening for their ability to modulate orexin receptor type 2 (OX2R) in comparison with standard agonist orexin-A together with their blood-brain barrier permeability and cytotoxicity. We can conclude that the studied compounds possess an affinity towards the OX2R. However, the compounds do not have intrinsic activity and act as the antagonists of this receptor. It was shown that L4 was the most potent antagonistic ligand to orexin A and displayed an IC(50) of 2.2 microM, offering some promise mainly for the treatment of insomnia.
ESTHER : Janockova_2018_Molecules_23_
PubMedSearch : Janockova_2018_Molecules_23_
PubMedID: 30423961

Title : In vitro and in silico Evaluation of Non-Quaternary Reactivators of AChE as Antidotes of Organophosphorus Poisoning - a New Hope or a Blind Alley? - Soukup_2018_Med.Chem_14_281
Author(s) : Soukup O , Korabecny J , Malinak D , Nepovimova E , Pham NL , Musilek K , Hrabinova M , Hepnarova V , Dolezal R , Pavek P , Jost P , Kobrlova T , Jankockova J , Gorecki L , Psotka M , Nguyen TD , Box K , Outhwaite B , Ceckova M , Sorf A , Jun D , Kuca K
Ref : Med Chem , 14 :281 , 2018
Abstract : BACKGROUND: In the last decade, the concept of uncharged reactivators potentially able to penetrate the CNS has been introduced as an alternative to the classic charged oxime reactivators. However, this concept brings with it several associated drawbacks such as higher lipophilicity, difficulty in administration, lower affinity to cholinesterases, and higher toxicity risk. OBJECTIVE: In this study, we compare data obtained for a set of five classic charged reactivators and a set of three recently published uncharged oximes supplemented by two novel ones. METHODS: This time, we used only in silico prediction and in vitro approaches. RESULTS: Our data showed that tested uncharged oximes have low affinity for cholinesterases, do not possess high reactivation potency, and certainly represent a greater toxicity risk due to higher lipophilicity. We assume that balanced physicochemical properties will be required for the successful treatment of OP poisoning. Nevertheless, the compound meeting such criteria and pinpointed in silico (K1280) failed in this particular case. CONCLUSION: From the presented data, it seems that the concept of uncharged reactivators will have to be modified, at least to improve the bioavailability and to satisfy requirements for in vivo administration.
ESTHER : Soukup_2018_Med.Chem_14_281
PubMedSearch : Soukup_2018_Med.Chem_14_281
PubMedID: 29332594

Title : Profiling donepezil template into multipotent hybrids with antioxidant properties - Mezeiova_2018_J.Enzyme.Inhib.Med.Chem_33_583
Author(s) : Mezeiova E , Spilovska K , Nepovimova E , Gorecki L , Soukup O , Dolezal R , Malinak D , Janockova J , Jun D , Kuca K , Korabecny J
Ref : J Enzyme Inhib Med Chem , 33 :583 , 2018
Abstract : Alzheimer's disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer's disease.
ESTHER : Mezeiova_2018_J.Enzyme.Inhib.Med.Chem_33_583
PubMedSearch : Mezeiova_2018_J.Enzyme.Inhib.Med.Chem_33_583
PubMedID: 29529892

Title : Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer's Disease - Wieckowska_2018_ACS.Chem.Neurosci_9_1195
Author(s) : Wieckowska A , Wichur T , Godyn J , Bucki A , Marcinkowska M , Siwek A , Wieckowski K , Zareba P , Knez D , Gluch-Lutwin M , Kazek G , Latacz G , Mika K , Kolaczkowski M , Korabecny J , Soukup O , Benkova M , Kiec-Kononowicz K , Gobec S , Malawska B
Ref : ACS Chem Neurosci , 9 :1195 , 2018
Abstract : Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, and amyloid beta antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT6 receptors ( Ki = 18 nM) and noncompetitive inhibitor of cholinesterases (IC50 hAChE = 14 nM, IC50 eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid beta antiaggregation activity (IC50 = 1.27 muM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.
ESTHER : Wieckowska_2018_ACS.Chem.Neurosci_9_1195
PubMedSearch : Wieckowska_2018_ACS.Chem.Neurosci_9_1195
PubMedID: 29384656

Title : Melatonin as a structural template in the development of novel drugs for neurodegenerative disorders - Korabecny_2018_Ceska.Slov.Farm_67_51
Author(s) : Korabecny J
Ref : Ceska a Slovenska Farmacie , 67 :51 , 2018
Abstract : Melatonin is a key regulatory hormone produced mainly in the pineal gland. In the recent years, melatonin contribution to neurodegenerative disorders has dramatically increased when inspecting its favorable pharmacological profile. Its levels were found to be decreased during aging. Data from clinical studies point out to its positive outcome not only in improving the quality of sleep but it also exerts anti-inflammatory and antioxidant profile. Moreover, it was found as an effective neuroprotective agent. Current study summarizes the experimental data from basic research of medicinal chemistry field devoted to melatonin. Particular emphasis is directed toward melatonin derivatives with multipotent profile affecting concomitantly several pathological hallmarks of the neurodegenerative disorders. Key words: acetylcholinesterase * Alzheimer's disease * antioxidant * butyrylcholinesterase * melatonin * neurodegenerative disorders.
ESTHER : Korabecny_2018_Ceska.Slov.Farm_67_51
PubMedSearch : Korabecny_2018_Ceska.Slov.Farm_67_51
PubMedID: 30189733

Title : A Review of the Synthesis of Quaternary Acetylcholinesterase Reactivators - Tsai_2021_J.Food.Drug.Anal_29_153
Author(s) : Malinak D , Korabecny J , Soukup O , Gorecki L , Nepovimova E , Psotka M , Dolezal R , Nguyen TD , Mezeiova E , Musilek K , Kuca K
Ref : Current Organic Chemistry , 22\ :1619 , 2018
Abstract : Acetylcholinesterase (AChE) is well-known enzyme studied in many fields of research, e.g. in Alzheimer's disease, Parkinson's disease, or in eco-toxicology as a biological marker. Many inhibitors of AChE have been identified in nature as well as prepared in chemical labs as a result of systematic synthetic efforts. The organophosphorus (OP) inhibitors of AChE are one of the oldest artificial inhibitors being purposely developed as military nerve agents (e.g. sarin, soman, tabun, VX, RVX). Some of the compounds with decreased toxicity are currently used in agriculture as pesticides (e.g. parathion, chlorpyrifos, paraoxon) or in the industry as softening agents and flame retardants. The common mechanism of action of all organophosphate compounds is the irreversible inhibition of AChE via a binding to the hydroxyl group of the serine residue within the active site of the enzyme. Subsequently, AChE loses its ability to fulfill its physiological role in cholinergic transmission, which leads to the cholinergic crisis with the possibility of respiratory failure and death. The reactivators of AChE are classified as strong nucleophilic agents capable to cleave the non-aged organophosphate- serine adduct and thereby restoring the activity of the enzyme. This work provides a unique overview of the most potent oximes reactivators of inhibited AChE since 1955 to the present. In this review article, we have reviewed different synthetic approaches of known and widely used oxime reactivators of AChE such as pralidoxime, methoxime, trimedoxime, obidoxime, asoxime (HI-6), HS-6, HLo-7, K027, K048, K203, K075 and BI-6. The review covers the original articles as well as patented research.
ESTHER : Tsai_2021_J.Food.Drug.Anal_29_153
PubMedSearch : Tsai_2021_J.Food.Drug.Anal_29_153
PubMedID:

Title : Design, Synthesis, and Biological Evaluation of 1-Benzylamino-2-hydroxyalkyl Derivatives as New Potential Disease-Modifying Multifunctional Anti-Alzheimer's Agents - Panek_2018_ACS.Chem.Neurosci_9_1074
Author(s) : Panek D , Wieckowska A , Jonczyk J , Godyn J , Bajda M , Wichur T , Pasieka A , Knez D , Pislar A , Korabecny J , Soukup O , Sepsova V , Sabate R , Kos J , Gobec S , Malawska B
Ref : ACS Chem Neurosci , 9 :1074 , 2018
Abstract : The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer's disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, beta-secretase, beta-amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer's disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of beta-secretase (IC50 hBACE-1 = 41.60 muM), inhibition of amyloid beta aggregation (IC50 Abeta = 3.09 muM), inhibition of tau aggregation (55% at 10 muM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50 hBuChE = 7.22 muM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer's agents.
ESTHER : Panek_2018_ACS.Chem.Neurosci_9_1074
PubMedSearch : Panek_2018_ACS.Chem.Neurosci_9_1074
PubMedID: 29345897

Title : Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer's Agents: Design, Synthesis and Biological Evaluation - Spilovska_2017_Molecules_22_
Author(s) : Spilovska K , Korabecny J , Sepsova V , Jun D , Hrabinova M , Jost P , Muckova L , Soukup O , Janockova J , Kucera T , Dolezal R , Mezeiova E , Kaping D , Kuca K
Ref : Molecules , 22 : , 2017
Abstract : A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer's agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383, bearing two methylene tether between two basic scaffolds, was found to be very potent hAChE inhibitor (IC50 = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50 >/= 500 muM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on hAChE with the most active compound in the study, K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.
ESTHER : Spilovska_2017_Molecules_22_
PubMedSearch : Spilovska_2017_Molecules_22_
PubMedID: 28621747

Title : Development of 2-Methoxyhuprine as Novel Lead for Alzheimer's Disease Therapy - Mezeiova_2017_Molecules_22_
Author(s) : Mezeiova E , Korabecny J , Sepsova V , Hrabinova M , Jost P , Muckova L , Kucera T , Dolezal R , Misik J , Spilovska K , Pham NL , Pokrievkova L , Roh J , Jun D , Soukup O , Kaping D , Kuca K
Ref : Molecules , 22 : , 2017
Abstract : Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer's disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors-THA and (-)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.
ESTHER : Mezeiova_2017_Molecules_22_
PubMedSearch : Mezeiova_2017_Molecules_22_
PubMedID: 28788095

Title : Dose Dependent Prophylactic Efficacy of 6-Chlorotacrine in Soman-Poisoned Mice - Kassa_2017_Acta.Medica.(Hradec.Kralove)_60_140
Author(s) : Kassa J , Korabecny J
Ref : Acta Medica (Hradec Kralove) , 60 :140 , 2017
Abstract : AIM: The influence of the dose on the ability of promising newly prepared reversible inhibitor of acetylcholinesterase (6-chlorotacrine) to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated. METHODS: The evaluation of the effect of pharmacological pretreatment is based on the identification of changes of soman-induced toxicity that was evaluated by the assessment of its LD50 value and its 95% confidence limit using probit-logarithmical analysis of death occurring within 24 hrs after administration of soman. RESULTS: The dose of 6-chlorotacrine significantly influences the prophylactic efficacy of 6-chlorotacrine. Its highest dose was only able to significantly protect mice against acute toxicity of soman and increase the efficacy of antidotal treatment (atropine in combination with the oxime HI-6) of soman-poisoned mice. In addition, the highest dose of 6-chlorotacrine was significantly more effective to protect mice from soman poisoning than its lowest dose. CONCLUSION: These findings demonstrate the important influence of the dose of 6-chlorotacine on its prophylactic efficacy in the case of pharmacological pretreatment of soman poisoning in mice.
ESTHER : Kassa_2017_Acta.Medica.(Hradec.Kralove)_60_140
PubMedSearch : Kassa_2017_Acta.Medica.(Hradec.Kralove)_60_140
PubMedID: 29716679

Title : The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice - Kassa_2017_Acta.Medica.(Hradec.Kralove)_60_37
Author(s) : Kassa J , Korabecny J , Nepovimova E
Ref : Acta Medica (Hradec Kralove) , 60 :37 , 2017
Abstract : AIM: The ability of four newly prepared reversible inhibitors of acetylcholinesterase (6-chlorotacrine, 7-phenoxytacrine, compounds 1 and 2) and currently used carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated.
METHODS: The evaluation of the effect of pharmacological pretreatment is based on the identification of changes of soman-induced toxicity that was evaluated by the assessment of its LD50 value and its 95% confidence limit using probitlogarithmical analysis of death occurring within 24 h after administration of soman.
RESULTS: 6-chlorotacrine was only able to markedly protect mice against acute toxicity of soman. In addition, the pharmacological pretreatment with 6-chlorotacrine or compound 2 was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. The other newly prepared reversible inhibitors of acetylcholinesterase (7-phenoxytacrine, compound 1) as well as commonly used pyridostigmine did not influence the efficacy of antidotal treatment. CONCLUSION: These findings demonstrate that pharmacological pretreatment of somanpoisoned mice can be promising and useful in the case of administration of 6-chlorotacrine and partly compound 2.
ESTHER : Kassa_2017_Acta.Medica.(Hradec.Kralove)_60_37
PubMedSearch : Kassa_2017_Acta.Medica.(Hradec.Kralove)_60_37
PubMedID: 28418831

Title : Multitarget Tacrine Hybrids with Neuroprotective Properties to Confront Alzheimer's Disease - Spilovska_2017_Curr.Top.Med.Chem_17_1006
Author(s) : Spilovska K , Korabecny J , Nepovimova E , Dolezal R , Mezeiova E , Soukup O , Kuca K
Ref : Curr Top Med Chem , 17 :1006 , 2017
Abstract : Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Several hallmarks such as beta-amyloid (Abeta) aggregation underlying amyloid plaque formation, tau-hyperphosphorylation leading to production of neurofibrillary tangles, and decline in the number of cholinergic neurons appear to be fundamental in the pathophysiology of the disease. Other evidence points also to the involvement of oxidative stress, biometal dyshomeostasis, inflammation, and cell cycle regulatory failure. Taking into account such premises, many attractive targets for the development of anti-AD drugs have emerged. Specifically, the multifactorial nature of AD calls for multi-target-directed ligands (MTDLs) which can be beneficial by providing interactions with multiple targets. Tacrine (THA), the first clinically effective acetylcholinesterase inhibitor, was approved for the treatment of mild to moderate AD. Unfortunately, frequent adverse effects including peripheral cholinergic effects and hepatotoxicity limited its therapeutic potential. Based on the numerous biological systems involved in AD progression, this review covers THA-incorporated hybrids possessing a neuroprotective profile. In particular, it focuses on THA hybrids capable of scavenging reactive oxygen species (ROS), and derivatives which reduce the formation of Abeta-plaques either directly by confronting the Abeta1-42 selfaggregation process or indirectly by inhibiting the BACE-1 enzyme or AChE-induced Abeta1-40 aggregation. Particular interest is also addressed to THA hybrids with suppressed hepatotoxicity.
ESTHER : Spilovska_2017_Curr.Top.Med.Chem_17_1006
PubMedSearch : Spilovska_2017_Curr.Top.Med.Chem_17_1006
PubMedID: 27697055

Title : HLo-7 - A review of acetylcholinesterase reactivator against organophosphorus intoxication - Psotka_2017_Mil.Med.Sci.Lett_86_70
Author(s) : Psotka M , Malinak D , Gorecki L , Nguyen TD , Soukup O , Jun D , Kuca K , Musilek K , Korabecny J
Ref : Military Medical Science Letters , 86 :70 , 2017
Abstract : The treatment of organophosphate (OP) poisoning consists of the administration of a parasympatholytic agent, an anticonvulsant and an acetylcholinesterase (AChE) reactivator. Since there is no broad AChE reactivator available, a post-treatment strategy currently exploits administration of different types of oximes depending on the exposure of OP. In this contribution, we summarize all the available data about AChE reactivator HL-7 including its synthesis, physico-chemical properties, pharmacokinetic and pharmacodynamics profile, and its efficacy in vitro and in vitro.
ESTHER : Psotka_2017_Mil.Med.Sci.Lett_86_70
PubMedSearch : Psotka_2017_Mil.Med.Sci.Lett_86_70
PubMedID:

Title : Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment - Gazova_2017_Biochim.Biophys.Acta.Mol.Basis.Dis_1863_607
Author(s) : Gazova Z , Soukup O , Sepsova V , Siposova K , Drtinova L , Jost P , Spilovska K , Korabecny J , Nepovimova E , Fedunova D , Horak M , Kaniakova M , Wang ZJ , Hamouda AK , Kuca K
Ref : Biochimica & Biophysica Acta Mol Basis Dis , 1863 :607 , 2017
Abstract : Alzheimer's disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the "one-molecule-one-target" paradigm was found to be ineffective in the case of multifactorial diseases like AD. A novel multi-target-directed ligand strategy based on the assumption that a single compound consisting of two or more distinct pharmacophores is able to hit multiple targets has been proposed as promising. Herein, we investigated 7-methoxytacrine - memantine heterodimers developed with respect to the multi-target-directed ligand theory. The spectroscopic, microscopic and cell culture methods were used for systematic investigation of the interference of the heterodimers with beta-secretase (BACE1) activity, Abeta peptide amyloid fibrillization (amyloid theory) and interaction with M1 subtype of muscarinic (mAChRs), nicotinic (nAChRs) acetylcholine receptors (cholinergic theory) and N-methyl-d-aspartate receptors (NMDA) (glutamatergic theory). The drug-like properties of selected compounds have been evaluated from the point of view of blood-brain barrier penetration and cell proliferation. We have confirmed the multipotent effect of novel series of compounds. They inhibited effectively Abeta peptide amyloid fibrillization and affected the BACE1 activity. Moreover, they have AChE inhibitory potency but they could not potentiate cholinergic transmission via direct interaction with cholinergic receptors. All compounds were reported to act as an antagonist of both M1 muscarinic and muscle-type nicotinic receptors. We have found that 7-methoxytacrine - memantine heterodimers are able to hit multiple targets associated with Alzheimer's disease and thus, have a potential clinical impact for slowing or blocking the neurodegenerative process related to this disease.
ESTHER : Gazova_2017_Biochim.Biophys.Acta.Mol.Basis.Dis_1863_607
PubMedSearch : Gazova_2017_Biochim.Biophys.Acta.Mol.Basis.Dis_1863_607
PubMedID: 27865910

Title : Prolyl oligopeptidase and its role in the organism: attention to the most promising and clinically relevant inhibitors - Babkova_2017_Future.Med.Chem_9_1015
Author(s) : Babkova K , Korabecny J , Soukup O , Nepovimova E , Jun D , Kuca K
Ref : Future Med Chem , 9 :1015 , 2017
Abstract : Prolyl oligopeptidase (POP), also called prolyl endopeptidase, is a cytosolic enzyme investigated by several research groups. It has been proposed to play an important role in physiological processes such as modulation of the levels of several neuronal peptides and hormones containing a proline residue. Due to its proteolytic activity and physiological role in cell signaling pathways, inhibition of POP offers an emerging approach for the treatment of Alzheimer's and Parkinson's diseases as well as other diseases related to cognitive impairment. Furthermore, it may also represent an interesting target for treatment of neuropsychiatric disorders, and as an antiangiogenesis or antineoplastic agent. In this review paper, we summarized naturally occurring POP inhibitors together with peptide-like inhibitors and their biological effects. Some of them have shown promising results and interesting pharmacological profiles. However, to date, there is no POP inhibitor available on the market although several clinical trials have been undertaken.
ESTHER : Babkova_2017_Future.Med.Chem_9_1015
PubMedSearch : Babkova_2017_Future.Med.Chem_9_1015
PubMedID: 28632451

Title : The pharmacology of tacrine at N-methyl-d-aspartate receptors - Horak_2017_Prog.Neuropsychopharmacol.Biol.Psychiatry_75_54
Author(s) : Horak M , Holubova K , Nepovimova E , Krusek J , Kaniakova M , Korabecny J , Vyklicky L , Kuca K , Stuchlik A , Ricny J , Vales K , Soukup O
Ref : Prog Neuropsychopharmacol Biological Psychiatry , 75 :54 , 2017
Abstract : The mechanism of tacrine as a precognitive drug has been considered to be complex and not fully understood. It has been reported to involve a wide spectrum of targets involving cholinergic, gabaergic, nitrinergic and glutamatergic pathways. Here, we review the effect of tacrine and its derivatives on the NMDA receptors (NMDAR) with a focus on the mechanism of action and biological consequences related to the Alzheimer's disease treatment. Our findings indicate that effect of tacrine on glutamatergic neurons is both direct and indirect. Direct NMDAR antagonistic effect is often reported by in vitro studies; however, it is achieved by high tacrine concentrations which are not likely to occur under clinical conditions. The impact on memory and behavioral testing can be ascribed to indirect effects of tacrine caused by influencing the NMDAR-mediated currents via M1 receptor activation, which leads to inhibition of Ca2+-activated potassium channels. Such inhibition prevents membrane repolarization leading to prolonged NMDAR activation and subsequently to long term potentiation. Considering these findings, we can conclude that tacrine-derivatives with dual cholinesterase and NMDARs modulating activity may represent a promising approach in the drug development for diseases associated with cognitive dysfunction, such as the Alzheimer disease.
ESTHER : Horak_2017_Prog.Neuropsychopharmacol.Biol.Psychiatry_75_54
PubMedSearch : Horak_2017_Prog.Neuropsychopharmacol.Biol.Psychiatry_75_54
PubMedID: 28089695

Title : Progress in acetylcholinesterase reactivators and in the treatment of organophosphorus intoxication: a patent review (2006-2016) - Gorecki_2017_Expert.Opin.Ther.Pat_27_971
Author(s) : Gorecki L , Korabecny J , Musilek K , Nepovimova E , Malinak D , Kucera T , Dolezal R , Jun D , Soukup O , Kuca K
Ref : Expert Opin Ther Pat , 27 :971 , 2017
Abstract : INTRODUCTION: organophosphorus compounds act as irreversible inhibitors of the vital enzyme acetylcholinesterase (AChE). this leads in the accumulation of acetylcholine (ACh) leading to cholinergic crisis and death. The main therapeutic approach is based on immediate administration of an ache reactivator as an antidote enabling recovery of the ache function. Areas covered: This review covers the development of AChE reactivators in order to introduce a new efficient drug that will overcome significant failures of common antidotes. Further options together with methods of detection are also discussed in order to assure a complete insight into the treatment of intoxication. Expert opinion: Since organophosphates belong to the most toxic chemical warfare agents, efficient antidotes are a matter of importance. The solution of how to limit the basic drawbacks of clinically used reactivators remained a spotlight for many researches worldwide. Recent strategies of the treatment of OP exposure bring us new possibilities which may overcome classic antidotes. The importance of detection of OP also has to be taken into consideration. Especially, with the fast spreading toxic effect when death can occur within minutes.
ESTHER : Gorecki_2017_Expert.Opin.Ther.Pat_27_971
PubMedSearch : Gorecki_2017_Expert.Opin.Ther.Pat_27_971
PubMedID: 28569609

Title : A 7-methoxytacrine-4-pyridinealdoxime hybrid as a novel prophylactic agent with reactivation properties in organophosphate intoxication - Nepovimova_2016_Toxicol.Res.(Camb)_5_1012
Author(s) : Nepovimova E , Korabecny J , Dolezal R , Nguyen TD , Jun D , Soukup O , Pasdiorova M , Jost P , Muckova L , Malinak D , Gorecki L , Musilek K , Kuca K
Ref : Toxicol Res (Camb) , 5 :1012 , 2016
Abstract : Chemical warfare agents constitute an increasing threat to both military and civilian populations. Therefore, effective prophylactic approaches are urgently needed. Herein, we present a novel hybrid compound which is able not only to keep acetylcholinesterase resistant to organophosphate (OP) inhibitors, but also to serve as an enzyme reactivator in the case of OP intoxication.
ESTHER : Nepovimova_2016_Toxicol.Res.(Camb)_5_1012
PubMedSearch : Nepovimova_2016_Toxicol.Res.(Camb)_5_1012
PubMedID: 30090408

Title : Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation - Panek_2016_Eur.J.Med.Chem_125_676
Author(s) : Panek D , Wieckowska A , Wichur T , Bajda M , Godyn J , Jonczyk J , Mika K , Janockova J , Soukup O , Knez D , Korabecny J , Gobec S , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 125 :676 , 2016
Abstract : The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, beta-secretase and beta-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50 values ranging from 0.83 muM to 19.18 muM. The target compounds displayed inhibition of human beta-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 muM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50 = 0.83 muM) and inhibitory activity against hBACE1 (33.61% at 50 muM). Compound 52 is a selective AChE inhibitor (IC50 AChE = 6.47 muM) with BACE1 inhibitory activity (26.3% at 50 muM) and it displays the most significant Abeta anti-aggregating properties among all the obtained compounds (39% at 10 muM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.
ESTHER : Panek_2016_Eur.J.Med.Chem_125_676
PubMedSearch : Panek_2016_Eur.J.Med.Chem_125_676
PubMedID: 27721153

Title : Novel 8-Hydroxyquinoline Derivatives as Multitarget Compounds for the Treatment of Alzheimer's Disease - Prati_2016_ChemMedChem_11_1284
Author(s) : Prati F , Bergamini C , Fato R , Soukup O , Korabecny J , Andrisano V , Bartolini M , Bolognesi ML
Ref : ChemMedChem , 11 :1284 , 2016
Abstract : We discovered a small series of hit compounds that show multitargeting activities against key targets in Alzheimer's disease (AD). The compounds were designed by combining the structural features of the anti-AD drug donepezil with clioquinol, which is able to chelate redox-active metals, thus decreasing metal-driven oxidative phenomena and beta-amyloid (Abeta)-mediated neurotoxicity. The majority of the new hybrid compounds selectively target human butyrylcholinesterase at micromolar concentrations and effectively inhibit Abeta self-aggregation. In addition, compounds 5-chloro-7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (1 b), 7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (2 b), and 7-(((1-benzylpiperidin-4-yl)amino)methyl)-5-chloro-8-hydroxyquinoline (3 a) are able to chelate copper(II) and zinc(II) and exert antioxidant activity in vitro. Importantly, in the case of 2 b, the multitarget profile is accompanied by high predicted blood-brain barrier permeability, low cytotoxicity in T67 cells, and acceptable toxicity in HUVEC primary cells.
ESTHER : Prati_2016_ChemMedChem_11_1284
PubMedSearch : Prati_2016_ChemMedChem_11_1284
PubMedID: 26880501

Title : Towards understanding the mechanism of action of antibacterial N-alkyl-3-hydroxypyridinium salts: Biological activities, molecular modeling and QSAR studies - Dolezal_2016_Eur.J.Med.Chem_121_699
Author(s) : Dolezal R , Soukup O , Malinak D , Savedra RML , Marek J , Dolezalova M , Pasdiorova M , Salajkova S , Korabecny J , Honegr J , Ramalho TC , Kuca K
Ref : Eur Journal of Medicinal Chemistry , 121 :699 , 2016
Abstract : In this study, we have carried out a combined experimental and computational investigation to elucidate several bred-in-the-bone ideas standing out in rational design of novel cationic surfactants as antibacterial agents. Five 3-hydroxypyridinium salts differing in the length of N-alkyl side chain have been synthesized, analyzed by high performance liquid chromatography, tested for in vitro activity against a panel of pathogenic bacterial and fungal strains, computationally modeled in water by a SCRF B3LYP/6-311++G(d,p) method, and evaluated by a systematic QSAR analysis. Given the results of this work, the hypothesis suggesting that higher positive charge of the quaternary nitrogen should increase antimicrobial efficacy can be rejected since 3-hydroxyl group does increase the positive charge on the nitrogen but, simultaneously, it significantly derogates the antimicrobial activity by lowering the lipophilicity and by escalating the desolvation energy of the compounds in comparison with non-hydroxylated analogues. Herein, the majority of the prepared 3-hydroxylated substances showed notably lower potency than the parent pyridinium structures, although compound 8 with C12 alkyl chain proved a distinctly better antimicrobial activity in submicromolar range. Focusing on this anomaly, we have made an effort to reveal the reason of the observed activity through a molecular dynamics simulation of the interaction between the bacterial membrane and compound 8 in GROMACS software.
ESTHER : Dolezal_2016_Eur.J.Med.Chem_121_699
PubMedSearch : Dolezal_2016_Eur.J.Med.Chem_121_699
PubMedID: 27341309

Title : Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer's disease - Jerabek_2016_Eur.J.Med.Chem_127_250
Author(s) : Jerabek J , Uliassi E , Guidotti L , Korabecny J , Soukup O , Sepsova V , Hrabinova M , Kuca K , Bartolini M , Pena-Altamira LE , Petralla S , Monti B , Roberti M , Bolognesi ML
Ref : Eur Journal of Medicinal Chemistry , 127 :250 , 2016
Abstract : Multi-target drug discovery is one of the most followed approaches in the active central nervous system (CNS) therapeutic area, especially in the search for new drugs against Alzheimer's disease (AD). This is because innovative multi-target-directed ligands (MTDLs) could more adequately address the complexity of this pathological condition. In a continuation of our efforts aimed at a new series of anti-AD MTDLs, we combined the structural features of the cholinesterase inhibitor drug tacrine with that of resveratrol, which is known for its purported antioxidant and anti-neuroinflammatory activities. The most interesting hybrid compounds (5, 8, 9 and 12) inhibited human acetylcholinesterase at micromolar concentrations and effectively modulated Abeta self-aggregation in vitro. In addition, 12 showed intriguing anti-inflammatory and immuno-modulatory properties in neuronal and glial AD cell models. Importantly, the MTDL profile is accompanied by high-predicted blood-brain barrier permeability, and low cytotoxicity on primary neurons.
ESTHER : Jerabek_2016_Eur.J.Med.Chem_127_250
PubMedSearch : Jerabek_2016_Eur.J.Med.Chem_127_250
PubMedID: 28064079

Title : An HPLC-MS method for the quantification of new acetylcholinesterase inhibitor PC 48 (7-MEOTA-donepezil like compound) in rat plasma: Application to a pharmacokinetic study - Mzik_2016_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1020_85
Author(s) : Mzik M , Korabecny J , Nepovimova E , Vorisek V , Palicka V , Kuca K , Karasova JZ
Ref : Journal of Chromatography B Analyt Technol Biomed Life Sciences , 1020 :85 , 2016
Abstract : A simple, rapid and sensitive method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and validated for the quantitative determination in rat plasma of a new candidate for AD treatment, namely PC 48 (a 7-MEOTA-donepezil like compound) in rat plasma. Sample preparation involved pH adjustment with sodium hydroxide followed by solvent extraction with ethyl acetate:dichloromethane (80:20, v/v). The chromatographic separation was achieved on an Ascentis Express RP-Amide column (75mmx2.1mm, 2.7mum) with a gradient mobile phase consisting of 0.05M aqueous formic acid and acetonitrile. Detection was carried out using positive-ion electrospray tandem mass spectrometry on an LTQ XL system using the MS/MS CID (collision-induced dissociation) mode. The method was linear in the range 0.1-1000ng/ml (r2=0.999) with a lower limit of quantitation of 0.1ng/mL. Extraction recovery was in the range 63.5-72.1% for PC 48 and 70.5% for reserpine (internal standard, IS). Intra- and inter-day precisions measured as relative standard deviation were below 10.8% and accuracy was from -7.2% to 7.4%. The method was successfully applied to a pharmacokinetic study involving intramuscular application of 3.86mg/kg PC 48 to rats for the first time. Pharmacokinetic parameters for PC 48 include Cmax 39.09+/-4.45ng/mL,Tmax 5.00+/-3.08min, AUC0-t 23374+/-4045minng/mL and t1/2 1065+/-246min.
ESTHER : Mzik_2016_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1020_85
PubMedSearch : Mzik_2016_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1020_85
PubMedID: 27030895

Title : SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides - Gorecki_2016_Arch.Toxicol_90_2831
Author(s) : Gorecki L , Korabecny J , Musilek K , Malinak D , Nepovimova E , Dolezal R , Jun D , Soukup O , Kuca K
Ref : Archives of Toxicology , 90 :2831 , 2016
Abstract : Irreversible inhibition of acetylcholinesterase (AChE) by organophosphates leads to many failures in living organism and ultimately in death. Organophosphorus compounds developed as nerve agents such as tabun, sarin, soman, VX and others belong to the most toxic chemical warfare agents and are one of the biggest threats to the modern civilization. Moreover, misuse of nerve agents together with organophosphorus pesticides (e.g. malathion, paraoxon, chlorpyrifos, etc.) which are annually implicated in millions of intoxications and hundreds of thousand deaths reminds us of insufficient protection against these compounds. Basic treatments for these intoxications are based on immediate administration of atropine and acetylcholinesterase reactivators which are currently represented by mono- or bis-pyridinium aldoximes. However, these antidotes are not sufficient to ensure 100 % treatment efficacy even they are administered immediately after intoxication, and in general, they possess several drawbacks. Herein, we have reviewed new efforts leading to the development of novel reactivators and proposition of new promising strategies to design novel and effective antidotes. Structure-activity relationships and biological activities of recently proposed acetylcholinesterase reactivators are discussed and summarized. Among further modifications of known oximes, the main attention has been paid to dual binding site ligands of AChE as the current mainstream strategy. We have also discussed new chemical entities as potential replacement of oxime functional group.
ESTHER : Gorecki_2016_Arch.Toxicol_90_2831
PubMedSearch : Gorecki_2016_Arch.Toxicol_90_2831
PubMedID: 27582056

Title : Effects of novel tacrine-related cholinesterase inhibitors in the reversal of 3-quinuclidinyl benzilate-induced cognitive deficit in rats-Is there a potential for Alzheimer's disease treatment? - Misik_2016_Neurosci.Lett_612_261
Author(s) : Misik J , Korabecny J , Nepovimova E , Kracmarova A , Kassa J
Ref : Neuroscience Letters , 612 :261 , 2016
Abstract : Inhibitors of cholinesterase are important drugs for therapy of Alzheimer's disease and the search for new modifications is extensive, including dual inhibitors or multi-target hybrid compounds. The aim of the present study was a preliminary evaluation of pro-cognitive effects of newly-developed 7-MEOTA-donepezil like hybrids (compounds no. 1 and 2) and N-alkylated tacrine derivatives (compounds no. 3 and 4) using an animal model of pharmacologically-induced cognitive deficit. Male Wistar rats were subjected to tests of learning and memory in a water maze and step-through passive avoidance task. Cognitive impairment was induced by 3-quinuclidinyl benzilate (QNB, 2mgkg(-1)), administered intraperitoneally 1h before training sessions. Cholinesterase inhibitors were administered as a single therapeutic dose following the QNB at 30min at the following dose rates; 1 (25.6mgkg(-1)), 2 (12.3mgkg(-1)), 3 (5.7mgkg(-1)), 4 (5.2mgkg(-1)). The decrease in total path within the 10-swim session (water maze), the preference for target quadrant (water maze) and the entrance latency (passive avoidance) were taken as indicators of learning ability in rats. The effects of novel compounds were compared to that of standards tacrine (5.2mgkg(-1)) and donepezil (2.65mgkg(-1)). QNB significantly impaired spatial navigation as well as fear learning. Generally, the performance of rats was improved when treated with novel inhibitors and this effect reached efficiency of standard donepezil at selected doses. There was a significant improvement in the groups treated with compounds 2 and 3 in all behavioral tasks. The rest of the novel compounds succeed in the passive avoidance test. In summary, the potential of novel inhibitors (especially compounds 2 and 3) was proved and further detailed evaluation of these compounds as potential drugs for Alzheimer's disease treatment is proposed.
ESTHER : Misik_2016_Neurosci.Lett_612_261
PubMedSearch : Misik_2016_Neurosci.Lett_612_261
PubMedID: 26708634

Title : Inhibitors of Acetylcholinesterase Derived from 7-Methoxytacrine and Their Effects on the Choline Transporter CHT1 - Kristofikova_2016_Dement.Geriatr.Cogn.Disord_43_45
Author(s) : Kristofikova Z , Ricny J , Soukup O , Korabecny J , Nepovimova E , Kuca K , Ripova D
Ref : Dementia & Geriatric Cognitive Disorders , 43 :45 , 2016
Abstract : BACKGROUND: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic.
METHODS: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C4-C5 chains and 5 N-alkylated C4-C8 side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1.
RESULTS: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA. All derivatives were able to inhibit CHT1, probably via quaternary ammonium, and this interaction could be involved in the enhancement of their detrimental side effects and/or in the attenuation of their promising effects. Under conditions of disrupted lipid rafts, the unfavorable effects of some derivatives were weakened. Only tacrine was probably able to stereospecifically interact with the naturally occurring amyloid-beta isoform and to simultaneously stimulate CHT1. Some derivatives, when coincubated with amyloid beta, did not influence CHT1. All derivatives also increased the fluidity of the cortical membranes. CONCLUSION: The N-alkylated derivative of 7-MEOTA bearing from C4 side chains appears to be the most promising compound and should be evaluated in future in vivo research.
ESTHER : Kristofikova_2016_Dement.Geriatr.Cogn.Disord_43_45
PubMedSearch : Kristofikova_2016_Dement.Geriatr.Cogn.Disord_43_45
PubMedID: 27988521

Title : 7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment - Korabecny_2015_Molecules_20_22084
Author(s) : Korabecny J , Andrs M , Nepovimova E , Dolezal R , Babkova K , Horova A , Malinak D , Mezeiova E , Gorecki L , Sepsova V , Hrabinova M , Soukup O , Jun D , Kuca K
Ref : Molecules , 20 :22084 , 2015
Abstract : Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient's death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds' behavior was confirmed in the subsequent molecular modeling studies.
ESTHER : Korabecny_2015_Molecules_20_22084
PubMedSearch : Korabecny_2015_Molecules_20_22084
PubMedID: 26690394

Title : Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity - Nepovimova_2015_J.Med.Chem_58_8985
Author(s) : Nepovimova E , Korabecny J , Dolezal R , Babkova K , Ondrejicek A , Jun D , Sepsova V , Horova A , Hrabinova M , Soukup O , Bukum N , Jost P , Muckova L , Kassa J , Malinak D , Andrs M , Kuca K
Ref : Journal of Medicinal Chemistry , 58 :8985 , 2015
Abstract : Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation.
ESTHER : Nepovimova_2015_J.Med.Chem_58_8985
PubMedSearch : Nepovimova_2015_J.Med.Chem_58_8985
PubMedID: 26503905

Title : Cardanol-derived AChE inhibitors: Towards the development of dual binding derivatives for Alzheimer's disease - Lemes_2015_Eur.J.Med.Chem_108_687
Author(s) : Lemes LF , de Andrade Ramos G , de Oliveira AS , da Silva FM , de Castro Couto G , da Silva Boni M , Guimaraes MJ , Souza IN , Bartolini M , Andrisano V , do Nascimento Nogueira PC , Silveira ER , Brand GD , Soukup O , Korabecny J , Romeiro NC , Castro NG , Bolognesi ML , Romeiro LA
Ref : Eur Journal of Medicinal Chemistry , 108 :687 , 2015
Abstract : Cardanol is a phenolic lipid component of cashew nut shell liquid (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the production of high-value chemicals, including drugs. On the basis of these findings and in connection with our previous studies on cardanol derivatives as acetylcholinesterase (AChE) inhibitors, we designed a novel series of analogues by including a protonable amino moiety belonging to different systems. Properly addressed docking studies suggested that the proposed structural modifications would allow the new molecules to interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, thus being able to act as dual binding inhibitors. To disclose whether the new molecules showed the desired profile, they were first tested for their cholinesterase inhibitory activity towards EeAChE and eqBuChE. Compound 26, bearing an N-ethyl-N-(2-methoxybenzyl)amine moiety, showed the highest inhibitory activity against EeAChE, with a promising IC50 of 6.6 muM, and a similar inhibition profile of the human isoform (IC50 = 5.7 muM). As another positive feature, most of the derivatives did not show appreciable toxicity against HT-29 cells, up to a concentration of 100 muM, which indicates drug-conform behavior. Also, compound 26 is capable of crossing the blood-brain barrier (BBB), as predicted by a PAMPA-BBB assay. Collectively, the data suggest that the approach to obtain potential anti-Alzheimer drugs from CNSL is worth of further pursuit and development.
ESTHER : Lemes_2015_Eur.J.Med.Chem_108_687
PubMedSearch : Lemes_2015_Eur.J.Med.Chem_108_687
PubMedID: 26735910

Title : Ligand-based 3D QSAR analysis of reactivation potency of mono- and bis-pyridinium aldoximes toward VX-inhibited rat acetylcholinesterase - Dolezal_2015_J.Mol.Graph.Model_56_113
Author(s) : Dolezal R , Korabecny J , Malinak D , Honegr J , Musilek K , Kuca K
Ref : J Mol Graph Model , 56 :113 , 2015
Abstract : To predict unknown reactivation potencies of 12 mono- and bis-pyridinium aldoximes for VX-inhibited rat acetylcholinesterase (rAChE), three-dimensional quantitative structure-activity relationship (3D QSAR) analysis has been carried out. Utilizing molecular interaction fields (MIFs) calculated by molecular mechanical (MMFF94) and quantum chemical (B3LYP/6-31G*) methods, two satisfactory ligand-based CoMFA models have been developed: 1. R2=0.9989, QLOO2=0.9090, QLTO2=0.8921, QLMO(20%)2=0.8853, Rext2=0.9259, SDEPext=6.8938; 2. R2=0.9962, QLOO2=0.9368, QLTO2=0.9298, QLMO(20%)2=0.9248, Rext2=0.8905, SDEPext=6.6756. High statistical significance of the 3D QSAR models has been achieved through the application of several data noise reduction techniques (i.e. smart region definition SRD, fractional factor design FFD, uninformative/iterative variable elimination UVE/IVE) on the original MIFs. Besides the ligand-based CoMFA models, an alignment molecular set constructed by flexible molecular docking has been also studied. The contour maps as well as the predicted reactivation potencies resulting from 3D QSAR analyses help better understand which structural features are associated with increased reactivation potency of studied compounds.
ESTHER : Dolezal_2015_J.Mol.Graph.Model_56_113
PubMedSearch : Dolezal_2015_J.Mol.Graph.Model_56_113
PubMedID: 25588616

Title : Cholinergic properties of new 7-methoxytacrine-donepezil derivatives - Sepsova_2015_Gen.Physiol.Biophys_34_189
Author(s) : Sepsova V , Karasova JZ , Tobin G , Jun D , Korabecny J , Cabelova P , Janska K , Krusek J , Skrenkova K , Kuca K , Soukup O
Ref : Gen Physiol Biophys , 34 :189 , 2015
Abstract : Organophosphorus nerve agents inhibit acetylcholinesterase (AChE) which causes the breakdown of the transmitter acetylcholine (ACh) in the synaptic cleft. Overstimulation of cholinergic receptors (muscarinic and nicotinic) by excessive amounts of ACh causes several health problems and may even cause death. Reversible AChE inhibitors play an important role in prophylaxis against nerve agents. The presented study investigated whether 7-methoxytacrine (7-MEOTA) and 7-MEOTA-donepezil derivatives can act as central and peripheral reversible AChE inhibitors and simultaneously antagonize muscarinic and nicotinic receptors. The possible mechanism of action was studied on cell cultures (patch clamp technique, calcium mobilization assay) and on isolated smooth muscle tissue (contraction study). Furthermore, the kinetics of the compounds were also examined. CNS availability was predicted by determining the passive blood-brain barrier penetration estimated via a modified PAMPA assay. In conclusion, this study provides promising evidence that the new synthesized 7-MEOTA-donepezil derivatives have the desired anticholinergic effect; they can inhibit AChE, and nicotinic and muscarinic receptors in the micromolar range. Furthermore, they seem to penetrate readily into the CNS. However, their real potency and benefit must be verified by in vivo experiments.
ESTHER : Sepsova_2015_Gen.Physiol.Biophys_34_189
PubMedSearch : Sepsova_2015_Gen.Physiol.Biophys_34_189
PubMedID: 25504063

Title : The effects of novel 7-MEOTA-donepezil like hybrids and N-alkylated tacrine analogues in the treatment of quinuclidinyl benzilate-induced behavioural deficits in rats performing the multiple T-maze test - Misik_2015_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_159_547
Author(s) : Misik J , Korabecny J , Nepovimova E , Cabelova P , Kassa J
Ref : Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub , 159 :547 , 2015
Abstract : AIMS: The number of approved drugs for the clinical treatment of Alzheimer disease remains limited. For this reason, there is extensive search for novel therapies. Of these, cholinesterase inhibitors have some proven benefit in slowing the disease progression and still remain the first-line therapeutic approach. In this study, the pro-cognitive effect of four novel tacrine-related inhibitors was evaluated and compared with the standards, tacrine and donepezil.
METHODS: Wistar rats trained to perform the multiple T-maze were treated intra-peritoneally with the anticholinergic agent 3-quinuclidinyl benzilate (QNB, 2.0 mg/kg), followed 30 min later by another injection containing a therapeutic dose of standard or novel cholinesterase inhibitor. The rats were repeatedly subjected to the multiple T-maze task at several time points following QNB administration (1, 24, 48 and 72 h). The passage time and number of errors were recorded. The inhibitory potential of selected therapeutic doses was assessed in a separate in vivo experiment using a spectrophotometric method.
RESULTS: QNB significantly impaired the performance of the rats within 48 h. The four novel cholinesterase inhibitors attenuated the effect of QNB at 1 h, 24 h and 48 h test intervals. The novel compounds resulted in brain cholinesterase inhibition ranging from 5.4 to 11.3 %, and their effect on the QNB-induced deficit recorded in the T-maze performance was comparable to that of the standards or higher at some time points. CONCLUSION: The best result was achieved with derivative 4, followed by derivatives 2 and 3, suggesting that these compounds could be candidates for the treatment of Alzheimer disease.
ESTHER : Misik_2015_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_159_547
PubMedSearch : Misik_2015_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_159_547
PubMedID: 25690521

Title : Synthesis and biological evaluation of novel tacrine derivatives and tacrine-coumarin hybrids as cholinesterase inhibitors - Hamulakova_2014_J.Med.Chem_57_7073
Author(s) : Hamulakova S , Janovec L , Hrabinova M , Spilovska K , Korabecny J , Kristian P , Kuca K , Imrich J
Ref : Journal of Medicinal Chemistry , 57 :7073 , 2014
Abstract : A series of novel tacrine derivatives and tacrine-coumarin heterodimers were designed, synthesized, and biologically evaluated for their potential inhibitory effect on both acetylcholinesterase (AChE) and butyrylcholinesterase (BCHE). Of these compounds, tacrine-coumarin heterodimer 7c and tacrine derivative 6b were found to be the most potent inhibitors of human AChE (hAChE), demonstrating IC50 values of 0.0154 and 0.0263 muM. Ligands 6b, 6c, and 7c exhibited the highest levels of inhibitory activity against human BCHE (hBCHE), demonstrating IC50 values that range from 0.228 to 0.328 muM. Docking studies were performed in order to predict the binding modes of compounds 6b and 7c with hAChE/hBCHE.
ESTHER : Hamulakova_2014_J.Med.Chem_57_7073
PubMedSearch : Hamulakova_2014_J.Med.Chem_57_7073
PubMedID: 25089370

Title : The Evaluation of Prophylactic Efficacy of Newly Developed Reversible Inhibitors of Acetylcholinesterase in Soman-Poisoned Mice - A Comparison with Commonly Used Pyridostigmine - Kassa_2014_Basic.Clin.Pharmacol.Toxicol_115_571
Author(s) : Kassa J , Korabecny J , Sepsova V , Tumova M
Ref : Basic Clin Pharmacol Toxicol , 115 :571 , 2014
Abstract : The ability of four newly developed reversible inhibitors of acetylcholinesterase (PC-37, PC-48, JaKo 39, JaKo 40) and currently available carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated and compared. No reversible inhibitor of acetylcholinesterase studied was able to decrease the LD50 value of soman in mice. Thus, the pharmacological pre-treatment with pyridostigmine or newly synthesized inhibitors of acetylcholinesterase was not able to significantly protect mice against soman-induced lethal acute toxicity. In addition, neither pyridostigmine nor new reversible inhibitors of acetylcholinesterase was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. These findings demonstrate that pharmacological pre-treatment of soman-poisoned mice with tested reversible inhibitors of acetylcholinesterase is not promising.
ESTHER : Kassa_2014_Basic.Clin.Pharmacol.Toxicol_115_571
PubMedSearch : Kassa_2014_Basic.Clin.Pharmacol.Toxicol_115_571
PubMedID: 24842281

Title : Outcomes of Alzheimer's disease therapy with acetylcholinesterase inhibitors and memantine - Zemek_2014_Expert.Opin.Drug.Saf_13_759
Author(s) : Zemek F , Drtinova L , Nepovimova E , Sepsova V , Korabecny J , Klimes J , Kuca K
Ref : Expert Opin Drug Safety , 13 :759 , 2014
Abstract : Introduction: Alzheimer's disease (AD) is a world-wide health problem with implications for an increasing number of people and countries. Populations suffering from AD financially strain the healthcare budgets of rich and poor countries alike. Moreover, no effective treatment is available and current drugs merely slow the progression of cognitive function deterioration and overall health status toward an inevitable end point. An increasing number of novel approaches have been tested in numerous clinical trials, but none of them has proved safe and effective for treating AD. Areas covered: This review summarizes all currently available compounds (donepezil, rivastigmine, galantamine, memantine) for the management of AD, concentrating on clinical aspects such as the mechanisms of action, pharmacokinetics, pharmacodynamics and clinical trials. This review also considers the mechanisms and side effects to provide perspective on current treatment options. Expert opinion: Novel approaches in the treatment of AD are being intensively tested, but so far without any major success. Patients diagnosed with AD still mostly benefit from four compounds to significantly improve cognition functions and overall health and help manage other symptoms or even prolong the symptom-free period.
ESTHER : Zemek_2014_Expert.Opin.Drug.Saf_13_759
PubMedSearch : Zemek_2014_Expert.Opin.Drug.Saf_13_759
PubMedID: 24845946

Title : 7-MEOTA-donepezil like compounds as cholinesterase inhibitors: Synthesis, pharmacological evaluation, molecular modeling and QSAR studies - Korabecny_2014_Eur.J.Med.Chem_82C_426
Author(s) : Korabecny J , Dolezal R , Cabelova P , Horova A , Hruba E , Ricny J , Sedlacek L , Nepovimova E , Spilovska K , Andrs M , Musilek K , Opletalova V , Sepsova V , Ripova D , Kuca K
Ref : Eur Journal of Medicinal Chemistry , 82C :426 , 2014
Abstract : A novel series of 7-methoxytacrine (7-MEOTA)-donepezil like compounds was synthesized and tested for their ability to inhibit electric eel acetylcholinesterase (EeAChE), human recombinant AChE (hAChE), equine serum butyrylcholinesterase (eqBChE) and human plasmatic BChE (hBChE). New hybrids consist of a 7-MEOTA unit, representing less toxic tacrine (THA) derivative, connected with analogues of N-benzylpiperazine moieties mimicking N-benzylpiperidine fragment from donepezil. 7-MEOTA-donepezil like compounds exerted mostly non-selective profile in inhibiting cholinesterases of different origin with IC50 ranging from micromolar to sub-micromolar concentration scale. Kinetic analysis confirmed mixed-type inhibition presuming that these inhibitors are capable to simultaneously bind peripheral anionic site (PAS) as well as catalytic anionic site (CAS) of AChE. Molecular modeling studies and QSAR studies were performed to rationalize studies from in vitro. Overall, 7-MEOTA-donepezil like derivatives can be considered as interesting candidates for Alzheimer's disease treatment.
ESTHER : Korabecny_2014_Eur.J.Med.Chem_82C_426
PubMedSearch : Korabecny_2014_Eur.J.Med.Chem_82C_426
PubMedID: 24929293

Title : Multitarget Drug Design Strategy: Quinone-Tacrine Hybrids Designed To Block Amyloid-beta Aggregation and To Exert Anticholinesterase and Antioxidant Effects - Nepovimova_2014_J.Med.Chem_57_8576
Author(s) : Nepovimova E , Uliassi E , Korabecny J , Pena-Altamira LE , Samez S , Pesaresi A , Garcia GE , Bartolini M , Andrisano V , Bergamini C , Fato R , Lamba D , Roberti M , Kuca K , Monti B , Bolognesi ML
Ref : Journal of Medicinal Chemistry , 57 :8576 , 2014
Abstract : We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-beta (Abeta) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by Abeta. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit.
ESTHER : Nepovimova_2014_J.Med.Chem_57_8576
PubMedSearch : Nepovimova_2014_J.Med.Chem_57_8576
PubMedID: 25259726
Gene_locus related to this paper: torca-ACHE

Title : From Pyridinium-based to Centrally Active Acetylcholinesterase Reactivators - Korabecny_2014_Mini.Rev.Med.Chem_14_215
Author(s) : Korabecny J , Soukup O , Dolezal R , Spilovska K , Nepovimova E , Andrs M , Nguyen TD , Jun D , Musilek K , Kucerova-Chlupacova M , Kuca K
Ref : Mini Rev Med Chem , 14 :215 , 2014
Abstract : Organophosphates are used as pesticides or misused as warfare nerve agents. Exposure to them can be fatal and death is usually caused by respiratory arrest. For almost six decades, pyridinium oximes represent a therapeutic tool used for the management of poisoning with organophosphorus (OP) compounds. However, these compounds possess several drawbacks. Firstly, they are inefficient in the restoration of brain acetylcholinesterase (AChE) activity due to a hard blood-brain barrier penetration. Secondly, there is no broad-spectrum AChE reactivator. Lastly, none of the oximes can reactivate "aged" AChE. In this context, uncharged reactivators represent a new hope in a way of increased bioavailability in the central compartment and better therapeutic management of the OP poisoning.
ESTHER : Korabecny_2014_Mini.Rev.Med.Chem_14_215
PubMedSearch : Korabecny_2014_Mini.Rev.Med.Chem_14_215
PubMedID: 24552265

Title : 7-methoxytacrine-adamantylamine heterodimers as cholinesterase inhibitors in alzheimer's disease treatment, synthesis, biological evaluation and molecular modeling studies - Spilovska_2013_Molecules_18_2397
Author(s) : Spilovska K , Korabecny J , Kral J , Horova A , Musilek K , Soukup O , Drtinova L , Gazova Z , Siposova K , Kuca K
Ref : Molecules , 18 :2397 , 2013
Abstract : A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC(50) value of 0.47 microM for hAChE and an IC(50) value of 0.11 microM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.
ESTHER : Spilovska_2013_Molecules_18_2397
PubMedSearch : Spilovska_2013_Molecules_18_2397
PubMedID: 23429378

Title : Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study - Sepsova_2013_Int.J.Mol.Sci_14_16882
Author(s) : Sepsova V , Karasova JZ , Korabecny J , Dolezal R , Zemek F , Bennion BJ , Kuca K
Ref : Int J Mol Sci , 14 :16882 , 2013
Abstract : Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring.
ESTHER : Sepsova_2013_Int.J.Mol.Sci_14_16882
PubMedSearch : Sepsova_2013_Int.J.Mol.Sci_14_16882
PubMedID: 23959117

Title : A Resurrection of 7-MEOTA: A Comparison with Tacrine - Soukup_2013_Curr.Alzheimer.Res_10_893
Author(s) : Soukup O , Jun D , Karasova JZ , Patocka J , Musilek K , Korabecny J , Krusek J , Kaniakova M , Sepsova V , Mandikova J , Trejtnar F , Pohanka M , Drtinova L , Pavlik M , Tobin G , Kuca K
Ref : Curr Alzheimer Res , 10 :893 , 2013
Abstract : Alzheimer s disease (AD) is a progressive neurodegenerative dementia which currently represents one of the biggest threats for the human kind. The cure is still unknown and various hypotheses (cholinergic, amyloidal, oxidative, vascular etc.) are investigated in order to understand the pathophysiology of the disease and on this basis find an effective treatment. Tacrine, the first approved drug for the AD disease treatment, has been reported to be a multitargeted drug, however it was withdrawn from the market particularly due to its hepatotoxicity. Its derivative 7-methoxytacrine (7- MEOTA) probably due to the different metabolization does not exert this side effect. The aim of our study was to compare these two cholinesterase inhibitors from various, mainly cholinergic, points of view relevant for a potential AD drug. We found that 7-MEOTA does not fall behind its more well-known parent compound - tacrine. Furthermore, we found, that 7-MEOTA exerts better properties in most of the tests related to a possible AD treatment. Only the pharmacokinetics and a higher acetylcholinesterase and butyrylcholinesterase inhibitory potency would slightly give advantages to tacrine over 7-MEOTA, but concerning its lower toxicity, better antioxidant properties, interaction with muscarinic and nicotinic receptors and "safer" metabolization provide strong evidence for reconsider 7-MEOTA and its derivatives as candidate molecules for the treatment of AD.
ESTHER : Soukup_2013_Curr.Alzheimer.Res_10_893
PubMedSearch : Soukup_2013_Curr.Alzheimer.Res_10_893
PubMedID: 24093535

Title : [Tacrine and its derivatives in the therapy of Alzheimers disease] - Korabecny_2012_Ceska.Slov.Farm_61_210
Author(s) : Korabecny J , Spilovska K , Benek O , Musilek K , Soukup O , Kuca K
Ref : Ceska a Slovenska Farmacie , 61 :210 , 2012
Abstract : Cholinesterase inhibitors have beneficial effects on the cognitive, functional, and behavioural symptoms of Alzheimers disease (AD). Up to date, they represent almost the only drugs approved by the U.S. Food and Drug Administration agency for AD treatment. The group involves donepezil, rivastigmine and galantamine. Apart from the above mentioned cholinesterase inhibitors, memantine is used for AD treatment as well acting as Nmethyl-D-aspartate (NMDA) non-competitive antagonist. Tacrine (9-amino-1,2,3,4-tetrahydroacridine) was the first cholinesterase inhibitor approved for symptomatic AD treatment. However, its several side effects (hepatotoxicity and gastrointestinal discomfort) limited tacrine further use. Recently, novel tacrine analogues are extensively investigated in endeavour to find less toxic compounds with the "multi-target directed ligand" profile affecting more AD pathological mechanisms. The following study summarizes the knowledge of up to date published tacrine analogues, their structural aspects and biological properties. According to structural aspects, tacrine derivatives are divided into three groups, where they are discussed. Keywords: Alzheimers disease tacrine and its derivatives acetylcholinesterase inhibitor.
ESTHER : Korabecny_2012_Ceska.Slov.Farm_61_210
PubMedSearch : Korabecny_2012_Ceska.Slov.Farm_61_210
PubMedID: 23256654

Title : Synthesis and in vitro evaluation of 7-methoxy-N-(pent-4-enyl)-1,2,3,4-tetrahydroacridin-9-amine-new tacrine derivate with cholinergic properties - Korabecny_2011_Bioorg.Med.Chem.Lett_21_6563
Author(s) : Korabecny J , Musilek K , Zemek F , Horova A , Holas O , Nepovimova E , Opletalova V , Hroudova J , Fisar Z , Jung YS , Kuca K
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :6563 , 2011
Abstract : Cholinesterase inhibitors are, so far, the only successful strategy for the symptomatic treatment of Alzheimer's disease. Tacrine (THA) is a potent acetylcholinesterase inhibitor that was used in the treatment of Alzheimer's disease for a long time. However, the clinical use of THA was hampered by its low therapeutic index, short half-life and liver toxicity. 7-Methoxytacrine (7-MEOTA) is equally pharmacological active compound with lower toxicity compared to THA. In this Letter, the synthesis, biological activity and molecular modelling of elimination by-product isolated during synthesis of 7-MEOTA based bis-alkylene linked compound is described.
ESTHER : Korabecny_2011_Bioorg.Med.Chem.Lett_21_6563
PubMedSearch : Korabecny_2011_Bioorg.Med.Chem.Lett_21_6563
PubMedID: 21920739

Title : Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease - Korabecny_2010_Bioorg.Med.Chem.Lett_20_6093
Author(s) : Korabecny J , Musilek K , Holas O , Binder J , Zemek F , Marek J , Pohanka M , Opletalova V , Dohnal V , Kuca K
Ref : Bioorganic & Medicinal Chemistry Lett , 20 :6093 , 2010
Abstract : All approved drugs for Alzheimer disease (AD) in clinical practice ameliorate the symptoms of the disease. Among them, acetylcholinesterase inhibitors (AChEIs) are used to increase the cholinergic activity. Among new AChEI, tacrine compounds were found to be more toxic compared to 7-MEOTA (9-amino-7-methoxy-1,2,3,4-tetrahydroacridine). In this Letter, series of 7-MEOTA analogues (N-alkyl-7-methoxytacrine) were synthesized. Their inhibitory ability was evaluated on recombinant human acetylcholinesterase (AChE) and plasmatic human butyrylcholinesterase (BChE). Three novel compounds showed promising results towards hAChE better to THA or 7-MEOTA. Three compounds resulted as potent inhibitors of hBChE. The SAR findings highlighted the C(6)-C(7)N-alkyl chains for cholinesterase inhibition.
ESTHER : Korabecny_2010_Bioorg.Med.Chem.Lett_20_6093
PubMedSearch : Korabecny_2010_Bioorg.Med.Chem.Lett_20_6093
PubMedID: 20817518

Title : Colorimetric dipstick for assay of organophosphate pesticides and nerve agents represented by paraoxon, sarin and VX - Pohanka_2010_Talanta_81_621
Author(s) : Pohanka M , Karasova JZ , Kuca K , Pikula J , Holas O , Korabecny J , Cabal J
Ref : Talanta , 81 :621 , 2010
Abstract : A dipstick for fast assay of nerve agents and organophosphate pesticides was developed. Indicator pH papers were used as detectors. The principle of the assay is based on enzymatic hydrolysis of acetylcholine into acetic acid and choline by acetylcholinesterase. Acidification of the reaction medium due to accumulation of acetic acid was visible. The colour changed from dark red to yellow as the pH indicator recognized pH shift. Presence of an organophosphate pesticide or a nerve agent results in irreversible inhibition of acetylcholinesterase intercepted on the dipstick. The inhibition stops the enzymatic reaction. The inhibition appears as no change of the medium pH. Three compounds were assayed: paraoxon-ethyl as representative organophosphate pesticides and nerve agents sarin and VX. The achieved limit of detection was 5 x 10(-8)M for paraoxon-ethyl and 5 x 10(-9)M for sarin and VX. Dipsticks were found stable for at least one month. Suitability of these dipsticks for routine assay is discussed.
ESTHER : Pohanka_2010_Talanta_81_621
PubMedSearch : Pohanka_2010_Talanta_81_621
PubMedID: 20188972

Title : Synthesis and in vitro evaluation of N-(Bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine as a cholinesterase inhibitor with regard to Alzheimer's disease treatment - Korabecny_2010_Molecules_15_8804
Author(s) : Korabecny J , Musilek K , Holas O , Nepovimova E , Jun D , Zemek F , Opletalova V , Patocka J , Dohnal V , Nachon F , Hroudova J , Fisar Z , Kuca K
Ref : Molecules , 15 :8804 , 2010
Abstract : A new tacrine based cholinesterase inhibitor, N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine (1), was designed and synthesized to interact with specific regions of human acetylcholinesterase and human butyrylcholinesterase. Its inhibitory ability towards cholinesterases was determined and compared to tacrine (THA) and 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine (7-MEOTA). The assessment of IC50 values revealed 1 as a weak inhibitor of both tested enzymes.
ESTHER : Korabecny_2010_Molecules_15_8804
PubMedSearch : Korabecny_2010_Molecules_15_8804
PubMedID: 21127466