Hrabinova M

General

Full name : Hrabinova Martina

First name : Martina

Mail : University of Defence\; Faculty of Military Health Sciences, Department of Toxicology and Military Pharmacy,Trebeska 1575, 50001, Hradec Kralove

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Country : Czech Republic

Email : martina.hrabinova@unob.cz

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References (79)

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 : Carltonine-Derived Compounds for Targeted Butyrylcholinesterase Inhibition - Pidany_2024_RSC.Med.Chem_15_1601
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 , 15 :1601 , 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_15_1601
PubMedSearch : Pidany_2024_RSC.Med.Chem_15_1601
PubMedID: 38784455
Gene_locus related to this paper: human-BCHE

Title : A-series agent A-234: initial in vitro and in vivo characterization - Hrabinova_2024_Arch.Toxicol__
Author(s) : Hrabinova M , Pejchal J , Hepnarova V , Muckova L , Junova L , Opravil J , Zdarova Karasova J , Rozsypal T , Dlabkova A , Rehulkova H , Kucera T , Vecera Z , Caisberger F , Schmidt M , Soukup O , Jun D
Ref : Archives of Toxicology , : , 2024
Abstract : A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC(50) = 0.101 +/- 0.003 microM and HssBChE IC(50) = 0.036 +/- 0.002 microM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.
ESTHER : Hrabinova_2024_Arch.Toxicol__
PubMedSearch : Hrabinova_2024_Arch.Toxicol__
PubMedID: 38446233

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 : 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 : 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 : 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 : 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 : 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 : 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 : 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 : 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 : 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 : 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 : Donepezil and Rivastigmine: Pharmacokinetic Profile and Brain-targeting After Intramuscular Administration in Rats - Karasova_2020_Iran.J.Pharm.Res_19_95
Author(s) : Karasova JZ , Hrabinova M , Krejciova M , Jun D , Kuca K
Ref : Iran J Pharm Res , 19 :95 , 2020
Abstract : Current palliative pharmacotherapy of Alzheimer's disease based on the cholinergic hypothesis led to the development of four cholinesterase inhibitors. These compounds can bring prolongation of the symptom-free period in some patients. This is the first report directly comparing donepezil and rivastigmine plasma and brain levels in in-vivo study. Donepezil and rivastigmine were applied i.m. to rats; the dose was calculated from clinical recommendations. The samples were analysed on an Agilent 1260 Series LC with UV/VIS detector. An analytical column (Waters Spherisorb S5 W (250 mm x 4.6 i.d.; 5 microm particle size)) with guard column (Waters Spherisorb S5 W (30 mm x 4.6 mm i.d.)) was used. The mobile phase contained acetonitrile and 50 mM sodium dihydrogen phosphate (17:83; v/v); pH 3.1. The LLOQ in rat plasma was 0.5 ng/mL for donepezil and 0.8 ng/mL for rivastigmine, and the LLOQ in rat brain was 1.0 ng/mL for donepezil and 1.1 ng/mL for rivastigmine. Both compounds showed ability to target the central nervous system, with brain concentrations exceeding those in plasma. Maximum brain concentration after i.m. administration was reached in the 36 (8.34 +/- 0.34 ng/mL) and 17 minute (6.18 +/- 0.40 ng/mL), respectively for donepezil and rivastigmine. The differences in brain profile can be most easily expressed by plasma/brain AUC(total) ratios: donepezil ratio in the brain was nine-times higher than in plasma and rivastigmine ratio was less than two-times higher than in plasma.
ESTHER : Karasova_2020_Iran.J.Pharm.Res_19_95
PubMedSearch : Karasova_2020_Iran.J.Pharm.Res_19_95
PubMedID: 33680013

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 : 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 : 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 : 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 : 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 : Pharmacological and toxicological in vitro and in vivo effect of higher doses of oxime reactivators - Hepnarova_2019_Toxicol.Appl.Pharmacol__114776
Author(s) : Hepnarova V , Muckova L , Ring A , Pejchal J , Herman D , Misik J , Hrabinova M , Jun D , Soukup O
Ref : Toxicol Appl Pharmacol , :114776 , 2019
Abstract : The major function of compounds with an oxime moiety attached to a quarternary nitrogen pyridinium ring is to reactivate acetylcholinesterase inhibited by organophosphorus agent (OP). However, other oxime mechanisms (e.g. modulation of cholinergic or glutamatergic receptor) may be involved in the recovery. The main disadvantage of positively charged reactivators is their low ability to penetrate into the brain although crossing the blood brain barrier could be supported via increasing the dose of administered oxime. Thus, this study presents maximal tolerated doses (MTD) for marketed oximes (TMB-4, MMB-4, LuH-6, HI-6, 2-PAM) and the most promising K-oximes (K027, K048, K203) which can be used in OP therapy in the future. No signs of sarin intoxication were observed in mice treated with 100% MTD of HI-6 in contrast to those treated with atropine and only 5% LD50 of HI-6. 100% MTD of HI-6 resulted in levels of 500muM and 12muM in plasma and brain, respectively. This concentration is by a far margin safe with respect to direct effects on neuronal cell viability and, on the other hand, does not have any effects on central NMDA receptors or central nACh receptors. However, a weak antimuscarinic activity in case of LuH-6 and a weak peripheral antinicotinic action in case of TMB-4 and 2-PAM could be observed at their respective 100% MTD dose. These high doses, represented by MTD, are, however, irrelevant to clinical practice since they led to mild to moderate toxic side effects. Therefore, we conclude that clinically used doses of marketed oxime reactivators have no significant direct pharmacological effect on the tested receptors.
ESTHER : Hepnarova_2019_Toxicol.Appl.Pharmacol__114776
PubMedSearch : Hepnarova_2019_Toxicol.Appl.Pharmacol__114776
PubMedID: 31629733

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 : 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 : 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 : 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 : A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase - Kuca_2018_BMC.Pharmacol.Toxicol_19_8
Author(s) : Kuca K , Musilek K , Jun D , Karasova JZ , Nepovimova E , Soukup O , Hrabinova M , Mikler J , Franca TCC , da Cunha EFF , de Castro AA , Valis M , Ramalho TC
Ref : BMC Pharmacol Toxicol , 19 :8 , 2018
Abstract : BACKGROUND: Based on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes. METHODS: To determine if this reactivating efficacy would extend to humans, studies were conducted in vitro using human brain homogenate as the source of AChE. The efficacy of K203 was compared with commercially available oximes; pralidoxime, obidoxime and asoxime (HI-6). RESULTS: Reactivation studies showed that K203 was the most effective reactivator with a second order kinetic constant (kr) of 2142 min(- 1). M(- 1), which was 51 times higher than that obtained for obidoxime (kr = 42 min(- 1). M(- 1)). Both pralidoxime and asoxime (HI-6) failed to significantly reactivate tabun-inhibited human AChE. DISCUSSION: According to these results and previous studies, using K203, it appears that oxime K203 is the most effective reactivator of tabun-inhibited cholinesterase in several species including humans and should be considered as a possible medical countermeasure to tabun exposure.
ESTHER : Kuca_2018_BMC.Pharmacol.Toxicol_19_8
PubMedSearch : Kuca_2018_BMC.Pharmacol.Toxicol_19_8
PubMedID: 29467029

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 : Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings - Kuca_2018_Drug.Des.Devel.Ther_12_505
Author(s) : Kuca K , Karasova JZ , Soukup O , Kassa J , Novotna E , Sepsova V , Horova A , Pejchal J , Hrabinova M , Vodakova E , Jun D , Nepovimova E , Valis M , Musilek K
Ref : Drug Des Devel Ther , 12 :505 , 2018
Abstract : Background: Intoxication by nerve agents could be prevented by using small acetylcholinesterase inhibitors (eg, pyridostigmine) for potentially exposed personnel. However, the serious side effects of currently used drugs led to research of novel potent molecules for prophylaxis of organophosphorus intoxication. Methods: The molecular design, molecular docking, chemical synthesis, in vitro methods (enzyme inhibition, cytotoxicity, and nicotinic receptors modulation), and in vivo methods (acute toxicity and prophylactic effect) were used to study bispyridinium, bisquinolinium, bisisoquinolinium, and pyridinium-quinolinium/isoquinolinium molecules presented in this study. Results: The studied molecules showed non-competitive inhibitory ability towards human acetylcholinesterase in vitro that was further confirmed by molecular modelling studies. Several compounds were selected for further studies. First, their cytotoxicity, nicotinic receptors modulation, and acute toxicity (lethal dose for 50% of laboratory animals [LD50]; mice and rats) were tested to evaluate their safety with promising results. Furthermore, their blood levels were measured to select the appropriate time for prophylactic administration. Finally, the protective ratio of selected compounds against soman-induced toxicity was determined when selected compounds were found similarly potent or only slightly better to standard pyridostigmine. Conclusion: The presented small bisquaternary molecules did not show overall benefit in prophylaxis of soman-induced in vivo toxicity.
ESTHER : Kuca_2018_Drug.Des.Devel.Ther_12_505
PubMedSearch : Kuca_2018_Drug.Des.Devel.Ther_12_505
PubMedID: 29563775

Title : Alkaloids from Narcissus poeticus cv. Pink Parasol of various structural types and their biological activity - Safratova_2018_Arch.Pharm.Res_41_208
Author(s) : Safratova M , Hostalkova A , Hulcova D , Breiterova K , Hrabcova V , Machado M , Fontinha D , Prudencio M , Kunes J , Chlebek J , Jun D , Hrabinova M , Novakova L , Havelek R , Seifrtova M , Opletal L , Cahlikova L
Ref : Arch Pharm Res , 41 :208 , 2018
Abstract : Fifteen Amaryllidaceae alkaloids (1-15) of various structural types were isolated by standard chromatographic methods from fresh bulbs of Narcissus poeticus cv. Pink Parasol. The chemical structures were elucidated by MS, and 1D and 2D NMR spectroscopic analyses, and by comparison with literature data. Narcipavline (5) and narcikachnine (6) are reported here for the first time. In their structure are combined two basic structural types of Amaryllidaceae alkaloids (galanthamine- and galanthindole-structural types), which represent a new structural type of these compounds. Alkaloids isolated in sufficient amounts were evaluated for their human erythrocytic acetylcholinesterase, and human serum butyrylcholinesterase (HuBuChE) inhibition activity using Ellman's method. Z-Gly-Pro-p-nitroanilide was used as substrate in the prolyl oligopeptidase (POP) assay. Untested alkaloids were also screened for their cytotoxic activity against a small panel of human cancer cells, which spanned cell lines from different tissue types. In parallel, MRC-5 human fibroblasts were employed to determine overall toxicity against noncancerous cells. Some compounds were evaluated for their antiprotozoal activity. The newly isolated alkaloid narcipavline (5) showed interesting HuBuChE inhibition activity (IC50 = 24.4 +/- 1.2 microM), and norlycoramine (11) demonstrated promising POP inhibition (IC50 = 0.21 +/- 0.01 mM).
ESTHER : Safratova_2018_Arch.Pharm.Res_41_208
PubMedSearch : Safratova_2018_Arch.Pharm.Res_41_208
PubMedID: 29243039

Title : Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon - Kuca_2018_Molecules_23_
Author(s) : Kuca K , Jun D , Junova L , Musilek K , Hrabinova M , da Silva JAV , Ramalho TC , Valko M , Wu Q , Nepovimova E , Franca TCC
Ref : Molecules , 23 : , 2018
Abstract : Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8), and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6) are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called “oximes”) depends on their chemical structure and also the type of organophosphorus inhibitor. Three novel oximes (K131, K142, K153) with an oxime group in position four of the pyridinium ring were designed and then tested for their potency to reactivate human (Homo sapiens sapiens) AChE (HssACHE) and BChE (HssBChE) inhibited by the pesticide paraoxon (diethyl 4-nitrophenyl phosphate). According to the obtained results, none of the prepared oximes were able to satisfactorily reactivate paraoxon-inhibited cholinesterases. On the contrary, extraordinary activity of obidoxime in the case of paraoxon-inhibited HssAChE reactivation was confirmed. Additional docking studies pointed to possible explanations for these results.
ESTHER : Kuca_2018_Molecules_23_
PubMedSearch : Kuca_2018_Molecules_23_
PubMedID: 29735900

Title : Tacrine-coumarin and Tacrine-7-chloroquinoline Hybrids with Thiourea Linkers: Cholinesterase Inhibition Properties, Kinetic Study, Molecular Docking and Permeability Assay for Blood-brain Barrier - Hamulakova_2018_Curr.Alzheimer.Res_15_1096
Author(s) : Hamulakova S , Janovec L , Soukup O , Jun D , Janockova J , Hrabinova M , Sepsova V , Kuca K
Ref : Curr Alzheimer Res , 15 :1096 , 2018
Abstract : BACKGROUND: The design of new heterodimeric dual binding site acetylcholinesterase inhibitors constitutes the main goal-directed to the development of new anticholinesterase agents with the expanded pharmacological profile. Multi-target compounds are usually designed by combining in a hybrid molecule with two or more pharmacophoric moieties that are known to enable interaction with the selected molecular targets. METHODS: All compounds were tested for their inhibitory activity on human AChE/BChE. The Ellman s method was used to determine inhibition kinetics and IC50 values. In order to predict passive bloodbrain penetration of novel compounds, modification of the parallel artificial membrane permeation assay has been used. Docking studies were performed in order to predict the binding modes of new hybrids with hAChE/ hBChE respectively. RESULTS: In this study, we described the design, synthesis, and evaluation of series tacrine-coumarin and tacrine-quinoline compounds which were found to show potential inhibition of ChEs and penetration of the blood-brain barrier. CONCLUSION: Tacrine-quinoline hybrids 7a exhibited the highest activity towards hBChE (IC50 = 0.97 micromol) and 7d towards hAChE (IC50 = 0.32 micromol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (Ki = 1.69 micromol) and 7a was a mixed-type BChE inhibitor (Ki = 1.09 micromol). Moreover, hybrid 5d and 7c could penetrate the CNS.
ESTHER : Hamulakova_2018_Curr.Alzheimer.Res_15_1096
PubMedSearch : Hamulakova_2018_Curr.Alzheimer.Res_15_1096
PubMedID: 29992880

Title : Cholinesterase and Prolyl Oligopeptidase Inhibitory Activities of Alkaloids from Argemone platyceras (Papaveraceae) - Siatka_2017_Molecules_22_
Author(s) : Siatka T , Adamcova M , Opletal L , Cahlikova L , Jun D , Hrabinova M , Kunes J , Chlebek J
Ref : Molecules , 22 : , 2017
Abstract : Alzheimer's disease is an age-related, neurodegenerative disorder, characterized by cognitive impairment and restrictions in activities of daily living. This disease is the most common form of dementia with complex multifactorial pathological mechanisms. Many therapeutic approaches have been proposed. Among them, inhibition of acetylcholinesterase, butyrylcholinesterase, and prolyl oligopeptidase can be beneficial targets in the treatment of Alzheimer's disease. Roots, along with aerial parts of Argemone platyceras, were extracted with ethanol and fractionated on an alumina column using light petrol, chloroform and ethanol. Subsequently, repeated preparative thin-layer chromatography led to the isolation of (+)-laudanosine, protopine, (-)-argemonine, allocryptopine, (-)-platycerine, (-)-munitagine, and (-)-norargemonine belonging to pavine, protopine and benzyltetrahydroisoquinoline structural types. Chemical structures of the isolated alkaloids were elucidated by optical rotation, spectroscopic and spectrometric analysis (NMR, MS), and comparison with literature data. (+)-Laudanosine was isolated from A. platyceras for the first time. Isolated compounds were tested for human blood acetylcholinesterase, human plasma butyrylcholinesterase and recombinant prolyl oligopeptidase inhibitory activity. The alkaloids inhibited the enzymes in a dose-dependent manner. The most active compound (-)-munitagine, a pavine alkaloid, inhibited both acetylcholinesterase and prolyl oligopeptidase with IC50 values of 62.3 +/- 5.8 microM and 277.0 +/- 31.3 microM, respectively.
ESTHER : Siatka_2017_Molecules_22_
PubMedSearch : Siatka_2017_Molecules_22_
PubMedID: 28708094

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 : 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 : Targeting copper(II)-induced oxidative stress and the acetylcholinesterase system in Alzheimer's disease using multifunctional tacrine-coumarin hybrid molecules - Hamulakova_2016_J.Inorg.Biochem_161_52
Author(s) : Hamulakova S , Poprac P , Jomova K , Brezova V , Lauro P , Drostinova L , Jun D , Sepsova V , Hrabinova M , Soukup O , Kristian P , Gazova Z , Bednarikova Z , Kuca K , Valko M
Ref : J Inorg Biochem , 161 :52 , 2016
Abstract : Alzheimer's disease is a multifactorial disease that is characterized mainly by Amyloid-beta (A-beta) deposits, cholinergic deficit and extensive metal (copper, iron)-induced oxidative stress. In this work we present details of the synthesis, antioxidant and copper-chelating properties, DNA protection study, cholinergic activity and amyloid-antiaggregation properties of new multifunctional tacrine-7-hydroxycoumarin hybrids. The mode of interaction between copper(II) and hybrids and interestingly, the reduction of Cu(II) to Cu(I) species (for complexes Cu-5e-g) were confirmed by EPR measurements. EPR spin trapping on the model Fenton reaction, using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, demonstrated a significantly suppressed formation of hydroxyl radicals for the Cu-5e complex in comparison with free copper(II). This suggests that compound 5e upon coordination to free copper ion prevents the Cu(II)-catalyzed decomposition of hydrogen peroxide, which in turn may alleviate oxidative stress-induced damage. Protective activity of hybrids 5c and 5e against DNA damage in a Fenton system (copper catalyzed) was found to be in excellent agreement with the EPR spin trapping study. Compound 5g was the most effective in the inhibition of acetylcholinesterase (hAChE, IC50=38nM) and compound 5b was the most potent inhibitor of butyrylcholinesterase (hBuChE, IC50=63nM). Compound 5c was the strongest inhibitor of A-beta1-40 aggregation, although a significant inhibition (>50%) was detected for compounds 5b, 5d, 5e and 5g. Collectively, these results suggest that the design and investigation of multifunctional agents containing along with the acetylcholinesterase inhibitory segment also an antioxidant moiety capable of alleviating metal (copper)-induced oxidative stress, may be of importance in the treatment of Alzheimer's disease.
ESTHER : Hamulakova_2016_J.Inorg.Biochem_161_52
PubMedSearch : Hamulakova_2016_J.Inorg.Biochem_161_52
PubMedID: 27230386

Title : Isoquinoline Alkaloids from Fumaria officinalis L. and Their Biological Activities Related to Alzheimer's Disease - Chlebek_2016_Chem.Biodivers_13_91
Author(s) : Chlebek J , Novak Z , Kassemova D , Safratova M , Kostelnik J , Maly L , Locarek M , Opletal L , Host'alkova A , Hrabinova M , Kunes J , Novotna P , Urbanova M , Novakova L , Macakova K , Hulcova D , Solich P , Perez Martin C , Jun D , Cahlikova L
Ref : Chem Biodivers , 13 :91 , 2016
Abstract : Two new isoquinoline alkaloids, named fumaranine (2) and fumarostrejdine (10), along with 18 known alkaloids were isolated from aerial parts of Fumaria officinalis. The structures of the isolated compounds were elucidated on the basis of spectroscopic analyses and by comparison with literature data. The absolute configuration of the new compound 2 was determined by comparing its circular dichroism spectra with those of known analogs. Compounds isolated in sufficient amounts were evaluated for their acetylcholinesterase, butyrylcholinesterase, prolyl oligopeptidase (POP), and glycogen synthase kinase-3beta inhibitory activities. Parfumidine (8) and sinactine (15) exhibited potent POP inhibition activities (IC50 99+/-5 and 53+/-2 muM, resp.).
ESTHER : Chlebek_2016_Chem.Biodivers_13_91
PubMedSearch : Chlebek_2016_Chem.Biodivers_13_91
PubMedID: 26765356

Title : Design, Synthesis and in vitro Evaluation of Indolotacrine Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease - Benek_2016_ChemMedChem_11_1264
Author(s) : Benek O , Soukup O , Pasdiorova M , Hroch L , Sepsova V , Jost P , Hrabinova M , Jun D , Kuca K , Zala D , Ramsay RR , Marco-Contelles J , Musilek K
Ref : ChemMedChem , 11 :1264 , 2016
Abstract : Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget-directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9 b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50 : 1.5 mum), butyrylcholinesterase (BChE IC50 : 2.4 mum) and MAO A (IC50 : 0.49 mum), and it is also a weak inhibitor of MAO B (IC50 : 53.9 mum). Although its cytotoxic (IC50 : 5.5+/-0.4 mum) and hepatotoxic (IC50 : 1.22+/-0.11 mum) profiles are not as good as those of the standard 7-methoxytacrine (IC50 : 63+/-4 and 11.50+/-0.77 mum, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation.
ESTHER : Benek_2016_ChemMedChem_11_1264
PubMedSearch : Benek_2016_ChemMedChem_11_1264
PubMedID: 26427608

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 : Impact of tacrine and 7-methoxytacrine on gastric myoelectrical activity assessed using electrogastrography in experimental pigs - Bures_2015_Neuro.Endocrinol.Lett_36_
Author(s) : Bures J , Jun D , Hrabinova M , Tacheci I , Kvetina J , Pavlik M , Rejchrt S , Douda T , Kunes M , Kuca K , Kopacova M
Ref : Neuro Endocrinol Lett , 36 : , 2015
Abstract : OBJECTIVES: Tacrine was the first acetylcholinesterase inhibitor approved for therapy of Alzheimer's disease. It has currently been withdrawn in some countries mostly due to the risk of hepatotoxicity and might be replaced by its derivate 7-methoxytacrine (7-MEOTA). The aim of this study was to assess the impact of these two compounds on gastric myoelectrical activity by means of surface cutaneous electrogastrography (EGG).
METHODS: Twelve pigs (Sus scrofa f. domestica, weighing 30-35 kg) entered the study. A single dose of tacrine (200 mg i.m., n=6) or 7-MEOTA (200 mg i.m., n=6) was administrated. All EGG recordings were performed under general anaesthesia in the morning after 24 hours of fasting. Basal (30 minutes) and study recordings (150 minutes) were accomplished using an EGG stand (MMS, Enschede, the Netherlands). Results were expressed as dominant frequency of gastric slow waves, power analysis (areas of amplitudes) and power ratio assessment (ratio of the areas of amplitudes after and before study drug administration).
RESULTS: Tacrine decreased EGG dominant frequency 10 minutes after its administration (from basal 3.1+/-0.6 to 2.8+/-0.6 cycles per minute; p=0.014). Tacrine induced a non-significant 60-minute increase of the power (with maximal value 493+/-533 muV2 at 20 minutes) and power ratio (with maximal value 2.04+/-3.4 at 10 minutes). Tacrine caused substantial gastric arrhythmia. 7-MEOTA did not influence dominant frequency of gastric slow waves significantly. 7-MEOTA caused a short-term late increase of the power ratio at 60 minutes (6.3+/-11.2; p=0.003). Blood cholinesterase activity did not correlate with any EGG parameter either after tacrine or 7-MEOTA at any time.
CONCLUSIONS: Tacrine and 7-MEOTA have different impacts on EGG. Tacrine decreased dominant frequency and induced long-lasting gastric arrhythmia. 7-MEOTA caused a short-term late increase of the EGG power in experimental pigs.
ESTHER : Bures_2015_Neuro.Endocrinol.Lett_36_
PubMedSearch : Bures_2015_Neuro.Endocrinol.Lett_36_
PubMedID: 26757120

Title : Universality of Oxime K203 for Reactivation of Nerve Agent-Inhibited AChE - Kuca_2015_Med.Chem_11_683
Author(s) : Kuca K , Hrabinova M , Jun D , Musilek K , Penhaker M , Krejcar O , Soukup O
Ref : Med Chem , 11 :683 , 2015
Abstract : Oxime K203 seems to be the most promising oxime in case of reactivation of tabuninhibited acetylcholinesterase (AChE). Although it was originally developed for treatment of tabun intoxications, it is able to reactivate cholinesterases inhibited by other nerve agents. This study is aimed at the evaluation of its potency in vitro against other nerve agents. For this purpose, sarin, tabun, cyclosarin, soman, VX, Russian VX and DFP were selected as members of the nerve agent family to check its universality. At high concentrations (10(-3) M), oxime K203 reached promising reactivation activity. At low concentrations, relevant for human use (10(-5) M), promising reactivation potency was obtained only with tabun. In conclusion, oxime K203 reactivates other nerve agents-inhibited cholinesterases, however its broad-spectrum reactivation is limited at high, for human not attainable, concentrations only.
ESTHER : Kuca_2015_Med.Chem_11_683
PubMedSearch : Kuca_2015_Med.Chem_11_683
PubMedID: 25845909

Title : Alkaloids from Peumus boldus and their acetylcholinesterase, butyrylcholinesterase and prolyl oligopeptidase inhibition activity - Host'alkova_2015_Nat.Prod.Commun_10_577
Author(s) : Host'alkova A , Opletal L , Kunes J , Novak Z , Hrabinova M , Chlebek J , Cegan L , Cahlikova L
Ref : Nat Prod Commun , 10 :577 , 2015
Abstract : Eleven isoquinoline alkaloids (1-11) were isolated from dried leaves of Peumus boldus Mol. by standard chromatographic methods. The chemical structures were elucidated by MS, and 1D and 2D NMR spectroscopic analysis, and by comparison with literature data. Compounds isolated in sufficient amount were evaluated for their acetylcholinesterase, and butyrylcholinesterase inhibition activity using Ellman's method. In the prolyl oligopeptidase assay, Z-Gly-Pro-p-nitroanilide was used as substrate. Promising butyrylcholinesterase inhibition activities were demonstrated by two benzylisoquinoline alkaloids, reticuline (8) and N-methylcoclaurine (9), with IC50 values of 33.6 +/- 3.0 microM and 15.0 +/- 1.4 microM, respectively. Important prolyl oligopeptidase inhibition activities were shown by N-methyllaurotetanine (6) and sinoacutine (4) with IC50 values of 135.4 +/- 23.2 microM and 143.1 +/- 25.4 microM, respectively. Other tested compounds were considered inactive.
ESTHER : Host'alkova_2015_Nat.Prod.Commun_10_577
PubMedSearch : Host'alkova_2015_Nat.Prod.Commun_10_577
PubMedID: 25973480

Title : Alkaloids from hydrastidis canadensis and their cholinesterase and prolyl oligopeptidase inhibitory -
Author(s) : Hostalkova A , Kunes J , Macakova K , Hrabinova M , Opletal L
Ref : Ceska a Slovenska Farmacie , 64 :41 , 2015
PubMedID: 26084651

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 : (+)-Chenabinol (Revised NMR Data) and Two New Alkaloids from Berberis vulgaris and their Biological Activity - Novak_2015_Nat.Prod.Commun_10_1695
Author(s) : Novak Z , Host'alkova A , Opletal L , Novakova L , Hrabinova M , Kunes J , Cahlikova L
Ref : Nat Prod Commun , 10 :1695 , 2015
Abstract : A known alkaloid (+)-chenabinol (1) and two new secobisbenzylisoquinoline alkaloids were isolated by standard chromatographic methods from the root bark of Berberis vulgaris L. The structures of the new alkaloids, named berkristine (2) and verfilline (3), were established by spectroscopic (including 2D NMR), and HRMS (ESI) methods. The alkaloids were tested for their inhibition activity of human cholinesterases and prolyl oligopeptidase. Compound 1 inhibited human butyrylcholinesterase with an IC50 value of 44.8 +/- 5.4 muM.
ESTHER : Novak_2015_Nat.Prod.Commun_10_1695
PubMedSearch : Novak_2015_Nat.Prod.Commun_10_1695
PubMedID: 26669104

Title : Revised NMR data for 9-O-demethylgalanthine: an alkaloid from Zephyranthes robusta (Amaryllidaceae) and its biological activity - Safratova_2014_Nat.Prod.Commun_9_787
Author(s) : Safratova M , Novak Z , Kulhankova A , Kunes J , Hrabinova M , Jun D , Macakova K , Opletal L , Cahlikova L
Ref : Nat Prod Commun , 9 :787 , 2014
Abstract : Ongoing studies of Zephyranthes robusta resulted in the isolation of the lycorine-type alkaloid previously called carinatine and 10-O-demethylgalanthine. The NMR data given previously for this compound were revised and completed by two-dimensional 1H-1H and 1H-13C chemical shift correlation experiments. The name of the isolated compound was corrected to 9-O-demethylgalanthine in accordance with the currently used system of numbering of lycorine-type alkaloids. 9-O-Demethylgalanthine and galanthine, a previously isolated alkaloid from Z robusta, were inactive in acetylcholinesterase/butyrylcholinesterase assays (IC50 > 500 microM), but showed important prolyl oligopeptidase inhibition activity.
ESTHER : Safratova_2014_Nat.Prod.Commun_9_787
PubMedSearch : Safratova_2014_Nat.Prod.Commun_9_787
PubMedID: 25115079

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 : Chemical composition of bioactive alkaloid extracts from some Narcissus species and varieties and their biological activity - Havlasova_2014_Nat.Prod.Commun_9_1151
Author(s) : Havlasova J , Safratova M , Siatka T , Stepankova S , Novak Z , Locarek M , Opletal L , Hrabinova M , Jun D , Benesova N , Kunes J , Cahlikova L
Ref : Nat Prod Commun , 9 :1151 , 2014
Abstract : Alkaloid extracts of eight Narcissus (Amaryllidaceae) species and varieties were studied with respect to their acetylcholinesterase (HuAChE) and butyrylcholinesterase (HuBCHE) inhibitory activity and alkaloid patterns. Thirty alkaloids were determined by GC/MS, and twenty-five of them identified from their mass spectra, retention times and retention indexes. Promising HuAChE inhibition activity was demonstrated by six Narcissus taxa and HuBCHE inhibition by N. jonquila cv. Double Campernelle and N. nanus cv. Elka with IC50 values of 24.1 +/- 1.9 microg/mL and 25.1 +/- 1.8 microg/mL, respectively. Two alkaloids were isolated in pure form using preparative TLC and identified as the galanthamine type alkaloid narwedine and the lycorine type alkaloid incartine. Both compounds were tested for their biological activity. They were considered inactive in HuAChE/HuBCHE assays, but showed promising prolyl oligopeptidase inhibition activities with IC50 values of 0.95 +/- 0.12 mM and 0.91 g 0.09 mM, respectively.
ESTHER : Havlasova_2014_Nat.Prod.Commun_9_1151
PubMedSearch : Havlasova_2014_Nat.Prod.Commun_9_1151
PubMedID: 25233595

Title : Structure-activity relationship for the reactivators of acetylcholinesterase inhibited by nerve agent VX - Kuca_2013_Med.Chem_9_689
Author(s) : Kuca K , Musilek K , Jun D , Karasova J , Soukup O , Pejchal J , Hrabinova M
Ref : Med Chem , 9 :689 , 2013
Abstract : Nerve agents such as sarin, VX and tabun are organophosphorus compounds able to inhibit an enzyme acetylcholinesterase (AChE). AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication with these agents. None from the known AChE reactivators is able to reactivate AChE inhibited by all kinds of nerve agents. In this work, reactivation potency of seventeen structurally different AChE reactivators was tested in vitro and subsequently, relationship between their chemical structure and biological activity was outlined. VX was chosen as appropriate member of the nerve agent family.
ESTHER : Kuca_2013_Med.Chem_9_689
PubMedSearch : Kuca_2013_Med.Chem_9_689
PubMedID: 22779796

Title : Alkaloids from Chlidanthus fragrans and their acetylcholinesterase, butyrylcholinesterase and prolyl oligopeptidase activities - Cahlikova_2013_Nat.Prod.Commun_8_1541
Author(s) : Cahlikova L , Hrabinova M , Kulhankova A , Benesova N , Chlebek J , Jun D , Novak Z , Macakova K , Kunes J , Kuca K , Opletal L
Ref : Nat Prod Commun , 8 :1541 , 2013
Abstract : Eleven Amaryllidaceae alkaloids (1-11) were isolated from fresh bulbs of Chlidanthus fragrans Herb. The chemical structures were elucidated by MS, and 1D and 2D NMR spectroscopic experiments. Complete NMR assignments were achieved for deoxypretazzetine (1). All compounds were evaluated for their erythrocytic acetylcholinesterase and serum butyrylcholinesterase inhibition activity using Ellman's method. In the prolyl oligopeptidase assay, Z-Gly-Pro-p-nitroanilide was used as substrate. In biological assays, only the crinine type Amaryllidaceae alkaloid undulatine showed promising acetylcholinesterase and prolyl oligopeptidase inhibition activity with IC50 values of 23.0 +/- 1.0 microM and 1.96 +/- 0.12 mM, respectively. Other isolated compounds were considered inactive.
ESTHER : Cahlikova_2013_Nat.Prod.Commun_8_1541
PubMedSearch : Cahlikova_2013_Nat.Prod.Commun_8_1541
PubMedID: 24427936

Title : Preparation, in vitro evaluation and molecular modelling of pyridinium-quinolinium\/isoquinolinium non-symmetrical bisquaternary cholinesterase inhibitors - Komloova_2013_Bioorg.Med.Chem.Lett_23_6663
Author(s) : Komloova M , Horova A , Hrabinova M , Jun D , Dolezal M , Vinsova J , Kuca K , Musilek K
Ref : Bioorganic & Medicinal Chemistry Lett , 23 :6663 , 2013
Abstract : Two series of non-symmetrical bisquaternary pyridinium-quinolinium and pyridinium-isoquinolinium compounds were prepared as molecules potentially applicable in myasthenia gravis treatment. Their inhibitory ability towards human recombinant acetylcholinesterase and human plasmatic butyrylcholinesterase was determined and the results were compared to the known effective inhibitors such as ambenonium dichloride, edrophonium bromide and experimental compound BW284C51. Two compounds, 1-(10-(pyridinium-1-yl)decyl)quinolinium dibromide and 1-(12-(pyridinium-1-yl)dodecyl)quinolinium dibromide, showed very promising affinity for acetylcholinesterase with their IC50 values reaching nM inhibition of acetylcholinesterase. These most active compounds also showed satisfactory selectivity towards acetylcholinesterase and they seem to be very promising as leading structures for further modifications and optimization. Two of the most promising compounds were examined in the molecular modelling study in order to find the possible interactions between the ligand and tested enzyme.
ESTHER : Komloova_2013_Bioorg.Med.Chem.Lett_23_6663
PubMedSearch : Komloova_2013_Bioorg.Med.Chem.Lett_23_6663
PubMedID: 24220173

Title : Impact of paraoxon followed by acetylcholinesterase reactivator HI-6 on gastric myoelectric activity in experimental pigs - Bures_2013_Neuro.Endocrinol.Lett_34_79
Author(s) : Bures J , Kvetina J , Pavlik M , Kunes M , Kopacova M , Rejchrt S , Jun D , Hrabinova M , Kuca K , Tacheci I
Ref : Neuro Endocrinol Lett , 34 :79 , 2013
Abstract : OBJECTIVES: Organophosphorus compounds represent nerve agents, pesticides and several industrial compounds. Treatment after exposure to organophosphates involves the use of parasympatolytics, acetylcholinesterase (AChE) reactivators/modulators and anticonvulsive drugs. Wider clinical use of several AChE reactivators/modulators might be limited because of possible side effects, including gastrointestinal toxicity. In this study we evaluated the effect of paraoxon and an AChE reactivator (HI-6) on the gastric myoelectric activity in experimental pigs.
METHODS: Six female experimental pigs (mean weight 33 kg) entered the study. Intramuscular paraoxon (1.5 g) was administrated after the baseline gastric electrogastrography (EGG) recording, followed by HI-6 dimethansulphonate (1.5 g i.m.) 10 min. later. A further ten 15-minute-interval EGG recordings were performed. Running spectral analysis was used for the elemental evaluation of the EGG. The results were expressed as dominant frequency of slow waves at all intervals of EGG recordings. EGG power analysis was performed in all animals.
RESULTS: Paraoxon induced a non-significant decrease of dominant frequency (2.8+/-0.6 vs. 2.6+/-0.5 cycles per min.; p=0.092). Subsequent administration of HI-6 normalised dominant frequency to basal values and increased it significantly within the subsequent 30 minutes (3.0+/-0.4; p<0.001). Paraoxon administration did not influence the power (within a 10-minute exposure). However, the amplitudes increased significantly 90 minutes after administration of HI-6 (819+/-109 vs. 5054+/-732 muV2; p<0.001).
CONCLUSIONS: AChE reactivator HI-6 blocked the gastric effect of paraoxon significantly. Subsequent myoelectric changes in the dominant frequency and power were executed by HI-6. The effect of paraoxon was non-significant.
ESTHER : Bures_2013_Neuro.Endocrinol.Lett_34_79
PubMedSearch : Bures_2013_Neuro.Endocrinol.Lett_34_79
PubMedID: 24362097

Title : Synthesis, design and biological evaluation of novel highly potent tacrine congeners for the treatment of Alzheimer's disease - Hamulakova_2012_Eur.J.Med.Chem_55_23
Author(s) : Hamulakova S , Janovec L , Hrabinova M , Kristian P , Kuca K , Banasova M , Imrich J
Ref : Eur Journal of Medicinal Chemistry , 55 :23 , 2012
Abstract : New tacrine derivatives 5a-d 6a-d with piperazino-ethyl spacer linked with corresponding secondary amines and tacrine homodimer 8 were synthesized and tested as cholinesterase inhibitors on human acetylcholinesterase hAChE and human plasmatic butyrylcholinesterase hBChE In most cases the majority of synthesized derivatives exhibit a high AChE and BChE inhibitory activity with IC(50 values in the low-nanomolar range being clearly more potent than the reference standard tacrine 9-amino-1,2,3,4-tetrahydroacridine 1 and 7-MEOTA 7-methoxy-9-amino-1,2,3,4-tetrahydroacridine Among them inhibitors 8 and 5c showed a strong inhibitory activity against hAChE with an IC(50 value of 4.49 nM and 4.97 nM resp and a high selectivity to hAChE The compound 5d acted as the most potent inhibitor against hBChE with an IC(50 value of 33.7 nM and exhibited also a good selectivity towards hBChE The dissociation constants K(i of the selected inhibitors were compared with their IC(50 values Molecular modeling studies were performed to predict the binding modes between individual derivatives and hAChE/hBChE.
ESTHER : Hamulakova_2012_Eur.J.Med.Chem_55_23
PubMedSearch : Hamulakova_2012_Eur.J.Med.Chem_55_23
PubMedID: 22818849

Title : Preparation, in vitro screening and molecular modelling of symmetrical 4-tert-butylpyridinium cholinesterase inhibitors--analogues of SAD-128 - Musilek_2011_Bioorg.Med.Chem.Lett_21_150
Author(s) : Musilek K , Roder J , Komloova M , Holas O , Hrabinova M , Pohanka M , Dohnal V , Opletalova V , Kuca K , Jung YS
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :150 , 2011
Abstract : Carbamate inhibitors (e.g., pyridostimine bromide) are used as a pre-exposure treatment for the prevention of organophosphorus poisoning. They work by blocking acetylcholinesterase's (AChE) native function and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for many undesirable side-effects related to the carbamylation of AChE. In this Letter, 19 analogues of SAD-128 were prepared and evaluated as cholinesterase inhibitors. The screening results showed promising inhibitory ability of four compounds better to used standards (pralidoxime, obidoxime, BW284c51, ethopropazine, SAD-128). Four most promising compounds were selected for further molecular docking studies. The SAR was stated from obtained data. The former receptor studies were reported and discussed. The further in vivo studies were recommended in the view of OP pre-exposure treatment.
ESTHER : Musilek_2011_Bioorg.Med.Chem.Lett_21_150
PubMedSearch : Musilek_2011_Bioorg.Med.Chem.Lett_21_150
PubMedID: 21144749

Title : On the universality of oxime Hl-7 - antidote for case of the nerve agent poisoning - Kuca_2011_Mil.Med.Sci.Lett_80_80
Author(s) : Kuca K , Musilek K , Karasova J , Jun D , Soukup O , Pohanka M , Ghosh KK , Hrabinova M
Ref : Military Medical Science Letters , 80 :80 , 2011
Abstract : Searching for the universal oxime, which could be able to reactivate acetylcholinesterase inhibited by various nerve agents is still topic of high interest. In this contribution, oxime HL-7, that was thoroughly discussed in the last decade, is evaluated . Its universality was tested in vitro using the rat brain homogenate as a source of the cholinesterases. The main members of the nerve agent family (tabun, sarin, soman, cyclosarin and VX) were used for this purpose. As shown, oxime HL-7 was able to reactivate cholinesterases inhibited by all tested nerve agents with the exception of tabun. Hence, it could not be designated as the broad-spectrum reactivator.
ESTHER : Kuca_2011_Mil.Med.Sci.Lett_80_80
PubMedSearch : Kuca_2011_Mil.Med.Sci.Lett_80_80
PubMedID:

Title : Assessment of acetylcholinesterase activity using indoxylacetate and comparison with the standard Ellman's method - Pohanka_2011_Int.J.Mol.Sci_12_2631
Author(s) : Pohanka M , Hrabinova M , Kuca K , Simonato JP
Ref : Int J Mol Sci , 12 :2631 , 2011
Abstract : Assay of acetylcholinesterase (AChE) activity plays an important role in diagnostic, detection of pesticides and nerve agents, in vitro characterization of toxins and drugs including potential treatments for Alzheimer's disease. These experiments were done in order to determine whether indoxylacetate could be an adequate chromogenic reactant for AChE assay evaluation. Moreover, the results were compared to the standard Ellman's method. We calculated Michaelis constant Km (2.06 x 10(-4) mol/L for acetylthiocholine and 3.21 x 10(-3) mol/L for indoxylacetate) maximum reaction velocity V(max) (4.97 x 10(-7) kat for acetylcholine and 7.71 x 10(-8) kat for indoxylacetate) for electric eel AChE. In a second part, inhibition values were plotted for paraoxon, and reactivation efficacy was measured for some standard oxime reactivators: obidoxime, pralidoxime (2-PAM) and HI-6. Though indoxylacetate is split with lower turnover rate, this compound appears as a very attractive reactant since it does not show any chemical reactivity with oxime antidots and thiol used for the Ellman's method. Thus it can be advantageously used for accurate measurement of AChE activity. Suitability of assay for butyrylcholinesterase activity assessment is also discussed.
ESTHER : Pohanka_2011_Int.J.Mol.Sci_12_2631
PubMedSearch : Pohanka_2011_Int.J.Mol.Sci_12_2631
PubMedID: 21731462

Title : Preparation and in vitro screening of symmetrical bis-isoquinolinium cholinesterase inhibitors bearing various connecting linkage--implications for early Myasthenia gravis treatment - Musilek_2011_Eur.J.Med.Chem_46_811
Author(s) : Musilek K , Komloova M , Holas O , Hrabinova M , Pohanka M , Dohnal V , Nachon F , Dolezal M , Kuca K
Ref : Eur Journal of Medicinal Chemistry , 46 :811 , 2011
Abstract : Inhibitors of acetylcholinesterase are compounds widely used in the treatment of various diseases, such as Alzheimer's disease, glaucoma and Myasthenia gravis (MG). Compounds used in the therapy of MG posses a positive charge in the molecule to ensure peripheral effect of action and minimal blood-brain barrier penetration. The most prescribed carbamate inhibitors are however known for many severe side effects related to the carbamylation of AChE. This paper describes preparation and in vitro evaluation of 20 newly prepared bis-isoquinolinium inhibitors of potential concern for MG. The newly prepared compounds were evaluated in vitro on human recombinant AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC50 and compared to chosen standards ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. Three novel compounds presented promising inhibition (in nM range) of both enzymes in vitro better or similar to edrophonium and BW284c51, but worse to ambenonium. The novel inhibitors did not present higher selectivity toward AChE or BChE. The kinetic assay confirmed non-competitive inhibition of hAChE by two selected promising novel compounds. Two newly prepared compounds were also chosen for docking studies that confirmed apparent pi-pi or pi-cationic interactions aside the cholinesterases catalytic sites. The SAR findings were discussed.
ESTHER : Musilek_2011_Eur.J.Med.Chem_46_811
PubMedSearch : Musilek_2011_Eur.J.Med.Chem_46_811
PubMedID: 21236521

Title : The preparation, in vitro screening and molecular docking of symmetrical bisquaternary cholinesterase inhibitors containing a but-(2E)-en-1,4-diyl connecting linkage - Musilek_2011_J.Enzyme.Inhib.Med.Chem_26_245
Author(s) : Musilek K , Pavlikova R , Marek J , Komloova M , Holas O , Hrabinova M , Pohanka M , Dohnal V , Dolezal M , Gunn-Moore F , Kuca K
Ref : J Enzyme Inhib Med Chem , 26 :245 , 2011
Abstract : Carbamate inhibitors (e.g. pyridostigmine bromide) are used as a pre-treatment for the prevention of organophosphorus poisoning. They work by blocking the native function of acetylcholinesterases (AChE) and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for their many undesirable side effects related to the carbamylation of AChE. In this paper, we describe 17 novel bisquaternary compounds and have analysed their effect on AChE inhibition. The newly prepared compounds were evaluated in vitro using both human erythrocyte AChE and human plasmatic butyrylcholinesterase. Their inhibitory ability was expressed as the half maximal inhibitory concentration (IC(5)(0)) and then compared to the standard carbamate drugs and two AChE reactivators. One of these novel compounds showed promising AChE inhibition in vitro (nM range) and was better than the currently used standards. Additionally, a kinetic assay confirmed the non-competitive inhibition of hAChE by this novel compound. Consequently, the docking results confirmed the apparent pi-pi or pi-cationic interactions with the key amino acid residues of hAChE and the binding of the chosen compound at the enzyme catalytic site.
ESTHER : Musilek_2011_J.Enzyme.Inhib.Med.Chem_26_245
PubMedSearch : Musilek_2011_J.Enzyme.Inhib.Med.Chem_26_245
PubMedID: 21406034

Title : Preparation and in vitro screening of symmetrical bispyridinium cholinesterase inhibitors bearing different connecting linkage-initial study for Myasthenia gravis implications - Musilek_2010_Bioorg.Med.Chem.Lett_20_1763
Author(s) : Musilek K , Komloova M , Zavadova V , Holas O , Hrabinova M , Pohanka M , Dohnal V , Nachon F , Dolezal M , Kuca K , Jung YS
Ref : Bioorganic & Medicinal Chemistry Lett , 20 :1763 , 2010
Abstract : Reversible inhibitors (e.g., pyridostigmine bromide, neostigmine bromide) of carbamate origin are used in the early treatment of Myasthenia gravis (MG) to block acetylcholinesterase (AChE) native function and conserve efficient amount of acetylcholine for decreasing number of nicotinic receptors. Carbamate inhibitors are known for many undesirable side effects related to the reversible inhibition of AChE. In contrast, this paper describes 20 newly prepared bispyridinium inhibitors of potential concern for MG. Although some compounds from this series have been known before, they were not assayed for cholinesterase inhibition yet. The newly prepared compounds were evaluated in vitro on human erythrocyte AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC(50) and compared to standard carbamate drugs. Three compounds presented promising inhibition (in muM range) of both enzymes in vitro similar to the used standards. The novel inhibitors did not present selectivity between AChE and BChE. Two newly prepared compounds were chosen for docking studies and confirmed apparent pi-pi or pi-cationic interactions aside enzyme's catalytic sites. The kinetics assay confirmed non-competitive inhibition of AChE by two best newly prepared compounds.
ESTHER : Musilek_2010_Bioorg.Med.Chem.Lett_20_1763
PubMedSearch : Musilek_2010_Bioorg.Med.Chem.Lett_20_1763
PubMedID: 20138518

Title : Oxime K027: novel low-toxic candidate for the universal reactivator of nerve agent- and pesticide-inhibited acetylcholinesterase - Kuca_2010_J.Enzyme.Inhib.Med.Chem_25_509
Author(s) : Kuca K , Musilek K , Jun D , Pohanka M , Ghosh KK , Hrabinova M
Ref : J Enzyme Inhib Med Chem , 25 :509 , 2010
Abstract : Oxime K027 is a low-toxic bisquaternary compound originally developed as a reactivator of acetylcholinesterase (AChE) inhibited by nerve agents. The reactivation potency of K027 has been tested as a potential reactivator of AChE inhibited by tabun, sarin, cyclosarin, soman, VX, Russian VX, paraoxon, methylchlorpyrifos, and DDVP. The results show that oxime K027 reactivated AChE inhibited by almost all tested inhibitors to more than 10%, which is believed to be enough for saving the lives of intoxicated organisms. In the case of cyclosarin- and soman-inhibited AChE, oxime K027 did not reach sufficient reactivation potency.
ESTHER : Kuca_2010_J.Enzyme.Inhib.Med.Chem_25_509
PubMedSearch : Kuca_2010_J.Enzyme.Inhib.Med.Chem_25_509
PubMedID: 20192902

Title : Pralidoxime--the gold standard of acetylcholinesterase reactivators--reactivation in vitro efficacy - Kuca_2010_Bratisl.Lek.Listy_111_502
Author(s) : Kuca K , Hrabinova M , Soukup O , Tobin G , Karasova J , Pohanka M
Ref : Bratislavske Lekarske Listy , 111 :502 , 2010
Abstract : OBJECTIVE: In this work, we aim to summarize the universality of this compound, its reactivation potential when different cholinesterase inhibitors are used. BACKGROUND: Pralidoxime is considered as a gold standard of acetylcholinesterase reactivators--antidotes used in case of nerve agent poisonings. It has been commercially available for many years. However, several studies deem this oxime an old-fashion antidote. METHODS: Pralidoxime was synthesized at our department. The reactivating efficacy was tested on 10% (w/v) rat brain homogenate that had been incubated with appropriate inhibitor for 30 minutes to reach 96% inhibition of AChE. Then, pralidoxime was added for 10 minutes. Measurements were performed at 25 degrees C, pH 8, and 10(-3) and 10(-5) M concentrations of AChE reactivators. The activities of brain AChE were measured by a potentiostatic method. RESULTS: No sufficient reactivation was achieved at the concentration of 10(-5) M, which is a concentration that can be reached after administration of therapeutic doses. At a higher dose (10(-3) M), pralidoxime reactivated AChE inhibited by paraoxon, chlorpyrifos, Russian VX, VX and sarin. CONCLUSION: From the obtained results, it is clear that pralidoxime seems to be a poor reactivator of AChE inhibited by organophosphorous AChE inhibitors and thus cannot be labeled as a universal reactivator (Tab. 1, Fig. 3, Ref. 31).
ESTHER : Kuca_2010_Bratisl.Lek.Listy_111_502
PubMedSearch : Kuca_2010_Bratisl.Lek.Listy_111_502
PubMedID: 21180265

Title : Testing of a Referential Method Based on Indoxylacetate as a Acetylcholinesterase Substrate for Identification of Reactivation Efficacy. - Pohanka_2010_Mil.Med.Sci.Lett_79_111
Author(s) : Pohanka M , Hrabinova M , Karasova JZ , Holas O , Kuca K , Cabal J
Ref : Military Medical Science Letters , 79 :111 , 2010
Abstract : Biochemical evaluation of acetylcholinesterase activity is an important factor for selection and evaluation of drugs, such as oxime reactivators, which modulate acetylcholinesterase activity. A spontaneous reaction between an Ellman reagent and an oxime reactivator is the main disadvantage of currently available Ellman's method used for identification of cholinesterase activity. In this study, an alternative chromogen, substrate indoxylacetate is used. It is suitable for evaluation of acetylcholinesterase reactivation efficacy without oxime interference in vitro. The method was successfully examined for five standard oxime reactivators (HI-6, methoxime, trimedoxime, obidoxime, and 2-PAM) and three organophosphate inhibitors: paraoxon-methyl, sarin and tabun.
ESTHER : Pohanka_2010_Mil.Med.Sci.Lett_79_111
PubMedSearch : Pohanka_2010_Mil.Med.Sci.Lett_79_111
PubMedID:

Title : Reactivation of human brain homogenate cholinesterases inhibited by Tabun using newly developed oximes K117 and K127 - Kuca_2009_Basic.Clin.Pharmacol.Toxicol_105_207
Author(s) : Kuca K , Cabal J , Jung YS , Musilek K , Soukup O , Jun D , Pohanka M , Musilova L , Karasova J , Novotny L , Hrabinova M
Ref : Basic Clin Pharmacol Toxicol , 105 :207 , 2009
Abstract : Newly developed acetylcholinesterase reactivators K117 [1,5-bis(4-hydroxyiminomethylpyridinium)-3-oxapentane dichloride] and K127 [(1-(4-hydroxyiminomethylpyridinium)-5-(4-carbamoylpyridinium)-3-oxapentane dibromide)] were tested for their potency to reactivate tabun-inhibited human brain cholinesterases. Pralidoxime and trimedoxime were chosen as standard reference reactivators. Human tissue was used, as that was closer on the real treatment of human beings. As a result, oxime K127 was found as the best tested reactivator according to the constant k(r), characterizing the overall reactivation process. On the contrary, the maximal reactivation ability expressed as percentage of reactivation was the best for trimedoxime. This differences were caused as a result of using the enzyme from different species. Due to this, experiments on human tissue should be conducted after in vitro and in vivo tests on animals to eliminate such important failures of promising oximes.
ESTHER : Kuca_2009_Basic.Clin.Pharmacol.Toxicol_105_207
PubMedSearch : Kuca_2009_Basic.Clin.Pharmacol.Toxicol_105_207
PubMedID: 19473310

Title : Novel bisquaternary oximes--reactivation of acetylcholinesterase and butyrylcholinesterase inhibited by paraoxon - Kuca_2009_Molecules_14_4915
Author(s) : Kuca K , Musilova L , Palecek J , Cirkva V , Paar M , Musilek K , Hrabinova M , Pohanka M , Karasova JZ , Jun D
Ref : Molecules , 14 :4915 , 2009
Abstract : Four novel bisquaternary aldoxime cholinesterase reactivators differing in their chemical structure were prepared. Afterwards, their biological activity was evaluated for their ability to reactivate acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BuChE; EC 3.1.1.8) inhibited by paraoxon. Their reactivation activity was compared with standard reactivators--pralidoxime, obidoxime and HI-6--which are clinically used at present. As it resulted, none of the prepared compounds surpassed obidoxime, which is considered to be the most potent compound if used for reactivation of AChE inhibited by paraoxon. In case of BuChE reactivation, two compounds (K053 and K068) achieved similar results as obidoxime.
ESTHER : Kuca_2009_Molecules_14_4915
PubMedSearch : Kuca_2009_Molecules_14_4915
PubMedID: 20032868

Title : Diagnosis of Intoxication by the Organophosphate VX: Comparison Between an Electrochemical Sensor and Ellman s Photometric Method - Pohanka_2008_Sensors.(Basel)_8_5229
Author(s) : Pohanka M , Hrabinova M , Kuca K
Ref : Sensors (Basel) , 8 :5229 , 2008
Abstract : An electrochemical sensor is introduced as a tool applicable for diagnosis of intoxication by cholinesterase inhibitors caused by the well-known nerve agent VX. The traditional Ellman method was chosen for comparison with the sensor's analytical parameters. Both methods are based on estimation of blood cholinesterase inhibition as a marker of intoxication. While Ellman s method provided a limit of detection of 5.2 10-7 M for blood containing VX, the electrochemical sensor was able to detect 4.0 10-7 M. Good correlation between both methods was observed (R = 0.92). The electrochemical sensor could be considered a convenient tool for a fast yet accurate method, easily available for field as well as laboratory use. Time and cost savings are key features of the sensor-based assay.
ESTHER : Pohanka_2008_Sensors.(Basel)_8_5229
PubMedSearch : Pohanka_2008_Sensors.(Basel)_8_5229
PubMedID: 27873811

Title : Targeted synthesis of 1-(4-hydroxyiminomethylpyridinium)-3-pyridiniumpropane dibromide--a new nerve agent reactivator - Kuca_2007_Molecules_12_1964
Author(s) : Kuca K , Musilek K , Paar M , Jun D , Stodulka P , Hrabinova M , Marek J
Ref : Molecules , 12 :1964 , 2007
Abstract : Preparation of 1-(4-hydroxy-iminomethylpyridinium)-3-pyridiniumpropane dibromide is described. This compound represents a new acetylcholinesterase (AChE) reactivator, which has no substituents on the second pyridinium ring as found in other commonly used AChE reactivators. The reactivation ability of this reactivator was tested on tabun- and cyclosarin-inhibited AChE. According to the results obtained, the new compound (without substitution and with decreased molecule size) showed increased reactivation potency in case of cyclosarin inhibited AChE. A potent oxime for treatment of tabun and cyclosarin-caused intoxications was thus obtained via slight modification of the reactivator structure (compared to trimedoxime and K027).
ESTHER : Kuca_2007_Molecules_12_1964
PubMedSearch : Kuca_2007_Molecules_12_1964
PubMedID: 17960099

Title : Potency of five structurally different acetylcholinesterase reactivators to reactivate human brain cholinesterases inhibited by cyclosarin - Kuca_2007_Clin.Toxicol.(Phila)_45_512
Author(s) : Kuca K , Cabal J , Jun D , Hrabinova M
Ref : Clinical Toxicology (Phila) , 45 :512 , 2007
Abstract : Acetylcholinesterase (AChE; EC 3.1.1.7) reactivators are used as a part of the antidotal therapy of organophosphorus pesticide and nerve agent intoxications. Cyclosarin is one member of the nerve agent family. In this article, we compared the reactivation potency of five structurally different AChE reactivators (pralidoxime, trimedoxime, methoxime, HS-6, and BI-6) to reactivate cyclosarin-inhibited cholinesterases of human brain. The results demonstrate that the bisquaternary monooxime reactivator BI-6 seems to be the most potent reactivator of cyclosarin-inhibited cholinesterases. Moreover, according to the results, we can describe basic structural requirements, which are necessary for the efficacious reactivation process.
ESTHER : Kuca_2007_Clin.Toxicol.(Phila)_45_512
PubMedSearch : Kuca_2007_Clin.Toxicol.(Phila)_45_512
PubMedID: 17503257

Title : Substituted monoquaternary oximes as reactivators of cyclosarin--and chlorpyrifos--inhibited acetylcholinesterase - Racakova_2006_Arh.Hig.Rada.Toksikol_57_387
Author(s) : Racakova V , Hrabinova M , Jun D , Kuca K
Ref : Arh Hig Rada Toksikol , 57 :387 , 2006
Abstract : This paper describes an in vitro study of three potential acetylcholinesterase (AChE; EC 3.1.1.7) reactivators derived from a monoquaternary reactivator pralidoxime. Compounds used were pyridinium-2-aldoxime-4-carbamoyl-N-methyl iodide (TO231), pyridinium-2-aldoxime-4-ethoxycarbonyl-N-methyl iodide (TO237), and pyridinium-2-aldoxime-5-ethoxycarbonyl-N-methyl iodide (TO238). Pralidoxime and obidoxime were used for comparison. Nerve agent cyclosarin and pesticide chlorpyrifos were used as organophosphorus cholinesterase inhibitors. The source of AChE was rat brain homogenate. None of the tested oximes was able to reactivate cyclosarin-inhibited AChE (at 1.0 mmol L(-1) oxime concentration). In case of chlorpyrifos, TO231 was the most potent AChE reactivator with an 82 % reactivation at 1.0 mmol L(-1) oxime concentration. This reactivating potency equals that of pralidoxime and obidoxime. TO238 was less effective, and TO237 did not reactivate chlorpyrifos-inhibited AChE at all. None of the tested AChE reactivators, reference compounds included, could be considered universal for both chlorpyrifos- and cyclosarin-inhibited AChE.
ESTHER : Racakova_2006_Arh.Hig.Rada.Toksikol_57_387
PubMedSearch : Racakova_2006_Arh.Hig.Rada.Toksikol_57_387
PubMedID: 17265677

Title : New group of xylene linker-containing acetylcholinesterase reactivators as antidotes against the nerve agent cyclosarin - Hrabinova_2006_J.Enzyme.Inhib.Med.Chem_21_515
Author(s) : Hrabinova M , Musilek K , Jun D , Kuca K
Ref : J Enzyme Inhib Med Chem , 21 :515 , 2006
Abstract : Nerve agents such as sarin, cyclosarin and tabun are organophosphorus substances able to inhibit the enzyme acetylcholinesterase (AChE; EC 3.1.1.7). AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication with these agents. None of the known AChE reactivators is able to reactivate AChE inhibited by all nerve agents used. In this work, reactivation potency of nine newly developed AChE reactivators with an incorporated xylene ring in their structure was measured in vitro. Cyclosarin was chosen as an appropriate member of the nerve agent family. Reactivation potency of the tested AChE reactivators was compared with the gold standard of AChE reactivators--pralidoxime. Two oximes (K107 and K108) surpassed the reactivation potency of pralidoxime. Moreover, from the obtained results it could be deduced that AChE reactivators with a functional oxime group in position-2 are the most potent AChE reactivators in the case of cyclosarin intoxications.
ESTHER : Hrabinova_2006_J.Enzyme.Inhib.Med.Chem_21_515
PubMedSearch : Hrabinova_2006_J.Enzyme.Inhib.Med.Chem_21_515
PubMedID: 17194020

Title : Russian VX: inhibition and reactivation of acetylcholinesterase compared with VX agent - Kuca_2006_Basic.Clin.Pharmacol.Toxicol_98_389
Author(s) : Kuca K , Jun D , Cabal J , Hrabinova M , Bartosova L , Opletalova V
Ref : Basic Clin Pharmacol Toxicol , 98 :389 , 2006
Abstract : Organophosphorus compounds such as nerve agents inhibit, practically irreversibly, cholinesterases by their phosphorylation in the active site of these enzymes. Current antidotal treatment used in the case of acute nerve agent intoxications consists of combined administration of anticholinergic drug (usually atropine) and acetylcholinesterase (AChE, EC 3.1.1.7) reactivator (HI-6, obidoxime, pralidoxime), which from a chemical view is a derivative from the group of pyridinium or bispyridinium aldoximes (commonly called "oxime"). Oximes counteract acetylcholine increase, resulting from AChE inhibition. In the human body environment these compounds are powerful nucleophiles and are able to break down the bond between AChE and nerve agent molecule. This process leads to renewal of enzyme functionality -- to its reactivation. The usefulness of oxime in the reactivation process depends on its chemical structure and on the nerve agent whereby AChE is inhibited. Due to this fact, selection of suitable reactivator in the treatment of intoxications is very important. In our work, we have compared differences in the in vitro inhibition potency of VX and Russian VX on rat, pig and human brain, and subsequently we have tested reactivation of rat brain cholinesterase inhibited by these agents using oxime HI-6, obidoxime, pralidoxime, trimedoxime and methoxime. The results showed that no major differences in the reactivation process of both VX and Russian VX-inhibited cholinesterase. The similarity in reactivation was caused by analogous chemical structure of either nerve agent; and that oxime HI-6 seems to be the most effective reactivator tested, which confirms that HI-6 is currently the most potent reactivator of AChE inhibited by nerve agents. The results obtained in our study should be considered in the future development of new AChE reactivators.
ESTHER : Kuca_2006_Basic.Clin.Pharmacol.Toxicol_98_389
PubMedSearch : Kuca_2006_Basic.Clin.Pharmacol.Toxicol_98_389
PubMedID: 16623863

Title : In vitro evaluation of acetylcholinesterase reactivators as potential antidotes against tabun nerve agent poisonings - Kuca_2006_Drug.Chem.Toxicol_29_443
Author(s) : Kuca K , Cabal J , Jun D , Hrabinova M
Ref : Drug & Chemical Toxicology , 29 :443 , 2006
Abstract : Searching for new potent acetylcholinesterase (AChE; E.C. 3.1.1.7) reactivators (oximes) is a very time-consuming process. At our department, we are able to synthesize more than 50 new AChE reactivators per year. Owing to this fact, we have to select promising reactivators using our in vitro method (potentiometric titration, pH 8 and temperature 25 degrees C; source of cholinesterases, rat brain homogenate; time of inhibition by nerve agents, 30 min; time of reactivation, 10 min) prior to in vivo experiments. For this purpose, we are using two-phase in vitro evaluation of reactivator potency. In the first phase, reactivation potency of all newly synthesized AChE reactivators is tested at two concentrations: 10(-3) M and 10(-5) M. Afterwards, all reactivators achieving reactivation potency over 15% (especially at the concentration 10(-5) M) are tested. The second phase consists of the measurement of the relationship between concentration of the oxime and its reactivation ability. In most cases, the reactivation bell-shaped curve is obtained. The most potent AChE reactivators are selected and provided for further experiments during our development process.
ESTHER : Kuca_2006_Drug.Chem.Toxicol_29_443
PubMedSearch : Kuca_2006_Drug.Chem.Toxicol_29_443
PubMedID: 16931445

Title : Potency of new structurally different oximes to reactivate cyclosarin-inhibited human brain acetylcholinesterases - Kuca_2006_J.Enzyme.Inhib.Med.Chem_21_663
Author(s) : Kuca K , Cabal J , Jun D , Bajgar J , Hrabinova M
Ref : J Enzyme Inhib Med Chem , 21 :663 , 2006
Abstract : Antidotes currently used for organophosphorus pesticide and nerve agent intoxications consist of anticholinergics (atropine mainly) and acetylcholinesterase (AChE, EC 3.1.1.7) reactivators called oximes. Owing to the wide-spread of these toxic compounds worldwide, development of antidotes in the case of first aid is needed. To select the most promising AChE reactivators is a very time consuming process, which is necessary before approval of these compounds to be used as human antidotes. Because of ethical reasons, many developing experiments have been conducted on laboratory animals. However, these results often could not be transferred directly to human. Here, we have tested five newly developed AChE reactivators--K027, K033, K048, K074 and K075, which showed promising reactivation activity on rodents, as reactivators of inhibited human brain cholinesterases. For this purpose, cyclosarin was used as member of the nerve agent family. Oxime HI-6 and pralidoxime were used as AChE reactivator standards. Two AChE reactivators, K027 and K033, achieved comparable reactivation potency as HI-6. Moreover, oxime K033 reached its maximal reactivation potency at the lowest concentration which could be attained in humans.
ESTHER : Kuca_2006_J.Enzyme.Inhib.Med.Chem_21_663
PubMedSearch : Kuca_2006_J.Enzyme.Inhib.Med.Chem_21_663
PubMedID: 17252938

Title : In vitro potency of H oximes (HI-6, HLo-7), the oxime BI-6, and currently used oximes (pralidoxime, obidoxime, trimedoxime) to reactivate nerve agent-inhibited rat brain acetylcholinesterase - Kuca_2006_J.Toxicol.Environ.Health.A_69_1431
Author(s) : Kuca K , Cabal J , Kassa J , Jun D , Hrabinova M
Ref : J Toxicol Environ Health A , 69 :1431 , 2006
Abstract : The efficacy of H oximes (HI-6, HLo-7), the oxime BI-6, and currently used oximes (pralidoxime, obidoxime, trimedoxime) to reactivate acetylcholinesterase inhibited by two nerve agents (tabun, VX agent) was tested in vitro. Both H oximes (HI-6, HLo-7) and the oxime BI-6 were found to be more efficacious reactivators of VX-inhibited acetylcholinesterase than pralidoxime and obidoxime. On the other hand, their potency to reactivate tabun-inhibited acetylcholinesterase was low and did not reach the reactivating efficacy of trimedoxime and obidoxime. Thus, none of these compounds can be considered to be a broad-spectrum reactivator of nerve agent-inhibited acetylcholinesterase in spite of high potency to reactivate acetylcholinesterase inhibited by some nerve agents. More than one oxime may be necessary for the antidotal treatment of nerve agent-exposed individuals.
ESTHER : Kuca_2006_J.Toxicol.Environ.Health.A_69_1431
PubMedSearch : Kuca_2006_J.Toxicol.Environ.Health.A_69_1431
PubMedID: 16766478

Title : A comparison of the potency of the oxime HLo-7 and currently used oximes (HI-6, pralidoxime, obidoxime) to reactivate nerve agent-inhibited rat brain acetylcholinesterase by in vitro methods - Kuca_2005_Acta.Medica.(Hradec.Kralove)_48_81
Author(s) : Kuca K , Cabal J , Kassa J , Jun D , Hrabinova M
Ref : Acta Medica (Hradec Kralove) , 48 :81 , 2005
Abstract : (1) The efficacy of the oxime HLo7 and currently used oximes (pralidoxime, obidoxime, HI-6) to reactivate acetylcholinesterase inhibited by various nerve agents (sarin, tabun, cyclosarin, VX) was tested by in vitro methods. (2) Both H oximes (HLo-7, HI-6) were found to be more efficacious reactivators of sarin and VX-inhibited acetylcholinesterase than pralidoxime and obidoxime. On the other hand, their potency to reactivate tabun-inhibited acetylcholinesterase is very low and does not reach the reactivating efficacy of obidoxime. In the case of cyclosarin, the oxime HI-6 was only found to be able to sufficiently reactivate cyclosarin-inhibited acetylcholinesterase in vitro. (3) Thus, the oxime HLo-7 does not seem to be more efficacious reactivator of nerve agent-inhibited acetylcholinesterase than HI-6 according to in vitro evaluation of their reactivation potency and, therefore, it is not more suitable to be introduced for antidotal treatment of nerve agent-exposed people than HI-6.
ESTHER : Kuca_2005_Acta.Medica.(Hradec.Kralove)_48_81
PubMedSearch : Kuca_2005_Acta.Medica.(Hradec.Kralove)_48_81
PubMedID: 16259317

Title : [A comparison of the efficacy of the reactivators of acetylcholinesterase inhibited with tabun] - Cabal_2005_Ceska.Slov.Farm_54_192
Author(s) : Cabal J , Kuca K , Jun D , Bajgar J , Hrabinova M
Ref : Ceska a Slovenska Farmacie , 54 :192 , 2005
Abstract : The nerve agent tabun inhibits acetylcholinesterase (AChE; EC 3.1.1.7) by the formation of a covalent bond with the enzyme. Afterwards, AChE is not able to fulfil its role in the organism and subsequently cholinergic crisis occurs. AChE reactivators (pralidoxime, obidoxime and HI-6) as causal antidotes are used for the cleavage of the bond between the enzyme and nerve agent. Unfortunately, their potency for reactivation of tabun-inhibited AChE is poor. The aim of the study was to choose the most potent reactivator of tabun-inhibited AChE. We have tested eight AChE reactivators--pralidoxime, obidoxime, trimedoxime, HI-6, methoxime, Hlo-7 and our newly synthesized oximes K027 and K048. All reactivators were tested using our standard in vitro reactivation test (pH 8, 25 degrees C, time of inhibition by the nerve agent 30 minutes, time of reactivation by AChE reactivator 10 minutes). According to our results, only trimedoxime was able to achieve 50% reactivation potency. However, this relatively high potency was achieved at high oxime concentration (10(-2) M). At a lower concentration of 10(-4) M (the probably attainable concentration in vivo), four AChE reactivators (trimedoxime, obidoxime, K027, and K048) were able to reactivate AChE inhibited by tabun reaching from 10 to 18%.
ESTHER : Cabal_2005_Ceska.Slov.Farm_54_192
PubMedSearch : Cabal_2005_Ceska.Slov.Farm_54_192
PubMedID: 16124202

Title : Comparison of in vitro potency of oximes (pralidoxime, obidoxime, HI-6) to reactivate sarin-inhibited acetylcholinesterase in various parts of pig brain - Kuca_2005_J.Appl.Toxicol_25_271
Author(s) : Kuca K , Cabal J , Kassa J , Jun D , Hrabinova M
Ref : J Appl Toxicol , 25 :271 , 2005
Abstract : The potency of currently used oximes to reactivate sarin-inhibited acetylcholinesterase (AChE) in various parts of pig brain and whole pig brain was evaluated using in vitro methods. Significant differences in reactivation potency among all tested oximes were observed. At concentrations (10(-4) M) corresponding to recommended doses in vivo, the oxime HI-6 seems to be a more efficacious reactivator of sarin-inhibited AChE in whole pig brain as well as in cerebral hemispheres and cerebellum compared with the other oximes studied. Nevertheless, there are not any differences in the potency of oximes tested to reactivate sarin-inhibited AChE in medulla oblongata. Thus, the oxime HI-6 appears to be the most promising oxime among currently available oximes for the antidotal treatment of acute sarin poisoning, although it is not more efficacious than other currently used oximes in medulla oblongata, whose function is necessary for the vital functions of respiration and circulation.
ESTHER : Kuca_2005_J.Appl.Toxicol_25_271
PubMedSearch : Kuca_2005_J.Appl.Toxicol_25_271
PubMedID: 16021679