Kucera T

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Full name : Kucera Tomas

First name : Tomas

Mail : Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01, Hradec Kralove

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Country : Czech Republic

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References (34)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Title : Interaction of Cucurbit[7]uril with Oxime K027, Atropine, and Paraoxon: Risky or Advantageous Delivery System? - Karasova_2020_Int.J.Mol.Sci_21_
Author(s) : Karasova JZ , Mzik M , Kucera T , Vecera Z , Kassa J , Sestak V
Ref : Int J Mol Sci , 21 : , 2020
Abstract : Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood-brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC-pharmacokinetics, toxicokinetics; acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks.
ESTHER : Karasova_2020_Int.J.Mol.Sci_21_
PubMedSearch : Karasova_2020_Int.J.Mol.Sci_21_
PubMedID: 33114215

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

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

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

Title : Some Possibilities to Study New Prophylactics against Nerve Agents - Bajgar_2019_Mini.Rev.Med.Chem_19_970
Author(s) : Bajgar J , Kassa J , Kucera T , Musilek K , Jun D , Kuca K
Ref : Mini Rev Med Chem , 19 :970 , 2019
Abstract : Nerve agents belong to the most dangerous chemical warfare agents and can be/were misused by terrorists. Effective prophylaxis and treatment is necessary to diminish their effect. General principles of prophylaxis are summarized (protection against acetylcholinesterase inhibition, detoxification, treatment "in advance" and use of different drugs). They are based on the knowledge of mechanism of action of nerve agents. Among different examinations, it is necessary to test prophylactic effectivity in vivo and compare the results with protection in vitro. Chemical and biological approaches to the development of new prophylactics would be applied simultaneously during this research. Though the number of possible prophylactics is relatively high, the only four drugs were introduced into military medical practice. At present, pyridostigmine seems to be common prophylactic antidote; prophylactics panpal (tablets with pyridostigmine, trihexyphenidyl and benactyzine), transant (transdermal patch containing HI-6) are other means introduced into different armies as prophylactics. Scavenger commercionally available is Protexia(R). Future development will be focused on scavengers, and on other drugs either reversible cholinesterase inhibitors (e.g., huperzine A, gallantamine, physostigmine, acridine derivatives) or other compounds.
ESTHER : Bajgar_2019_Mini.Rev.Med.Chem_19_970
PubMedSearch : Bajgar_2019_Mini.Rev.Med.Chem_19_970
PubMedID: 30827238

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

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

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

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