Dolezal R

References (36)

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

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

Title : 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 : Accuracy and precision of binding free energy prediction for a tacrine related lead inhibitor of acetylcholinesterase with an arsenal of supercomputerized molecular modelling methods: a comparative study - Dolezal_2021_J.Biomol.Struct.Dyn__1
Author(s) : Dolezal R
Ref : J Biomol Struct Dyn , :1 , 2021
Abstract : Nowadays, advanced computational chemistry methods offer various strategies for revealing prospective hit structures in drug development essentially through accurate binding free energy predictions. After the era of molecular docking and quantitative structure-activity relationships, much interest has been lately oriented to perturbed molecular dynamic approaches like replica exchange with solute tempering and free energy perturbation (REST/FEP) and the potential of the mean force with adaptive biasing and accelerated weight histograms (PMF/AWH). Both of these receptor-based techniques can exploit exascale CPU&GPU supercomputers to achieve high throughput performance. In this fundamental study, we have compared the predictive power of a panel of supercomputerized molecular modelling methods to distinguish the major binding modes and the corresponding binding free energies of a promising tacrine related potential antialzheimerics in human acetylcholinesterase. The binding free energies were estimated using flexible molecular docking, molecular mechanics/generalized Born surface area/Poisson-Boltzmann surface area (MM/GBSA/PBSA), transmutation REST/FEP with 12 x 5 ns/ windows, annihilation FEP with 20 x 5 ns/ steps, PMF with weight histogram analysis method (WHAM) and 40 x 5 ns samples, and PMF/AWH with 10 x 100 ns replicas. Confrontation of the classical approaches such as canonical molecular dynamics and molecular docking with alchemical calculations and steered molecular dynamics enabled us to show how large errors in deltaG predictions can be expected if these in silico methods are employed in the elucidation of a common case of enzyme inhibition.Communicated by Ramaswamy H. Sarma.
ESTHER : Dolezal_2021_J.Biomol.Struct.Dyn__1
PubMedSearch : Dolezal_2021_J.Biomol.Struct.Dyn__1
PubMedID: 34323654

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

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

Title : Surface screening, molecular modeling and in vitro studies on the interactions of aflatoxin M1 and human enzymes acetyl- and butyrylcholinesterase - de Almeida_2019_Chem.Biol.Interact_13ChEPon_308_113
Author(s) : de Almeida JSFD , Cavalcante SFA , Dolezal R , Kuca K , Musilek K , Jun D , Franca TCC
Ref : Chemico-Biological Interactions , 308 :113 , 2019
Abstract : Aflatoxin M1 (AFM1) is a mycotoxin produced by Aspergillus fungi and found in contaminated milk, breastfeed and dairy products, being highly toxic and carcinogenic to humans and other mammalian species. It is also produced in the human body as a metabolite of aflatoxin B1 (AFB1), one of the most toxic natural products known. Previous studies have shown that AFM1 is a potential inhibitor of the enzyme acetylcholinesterase (AChE), and therefore, a potential neurotoxic agent. In this work, surface screening (SS) and molecular dynamics (MD) simulation on human acetylcholinesterase AChE (HssAChE) were performed to corroborate literature data regarding preferential binding sites and type of inhibition. Also, an inedited theoretical study on the interactions of AFM1 with human butyrylcholinesterase (HssBChE) was performed. In vitro inhibition tests on both enzymes were done to support theoretical results. MD simulations suggested the catalytic anionic site of HssAChE as the preferential binding site for AFM1 and also that this metabolite is not a good inhibitor of HssBChE, corroborating previous studies. In vitro assays also corroborated molecular modeling studies by showing that AFM1 did not inhibit BChE and was able to inhibit AChE, although not as much as AFB1.
ESTHER : de Almeida_2019_Chem.Biol.Interact_13ChEPon_308_113
PubMedSearch : de Almeida_2019_Chem.Biol.Interact_13ChEPon_308_113
PubMedID: 31100275

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

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

Title : Molecular modeling studies on the interactions of aflatoxin B1 and its metabolites with the peripheral anionic site (PAS) of human acetylcholinesterase - de Almeida_2018_J.Biomol.Struct.Dyn__1
Author(s) : de Almeida JSFD , Cavalcante SFA , Dolezal R , Kuca K , Musilek K , Jun D , Franca TCC
Ref : J Biomol Struct Dyn , :1 , 2018
Abstract : Aflatoxins are secondary metabolites of the fungi Aspergillus flavus and A. parasiticus. Among them, aflatoxin B1 (AFB1) is the most frequent type in nature and also, the most carcinogenic for mammals. It can contaminate many kinds of food like seeds, oil, olives, milk, dairy products, corn and meat, causing acute and chronic damages to the organism, especially in the liver, being, for this reason, considered highly hepatotoxic. AFB1 is also a mixed inhibitor of the enzyme acetylcholinesterase (AChE). This fact, together with its high toxicity and carcinogenicity, turns AFB1 into a potential chemical and biological warfare agent, as well as its metabolites. In order to investigate this, we performed inedited molecular modeling studies on the interactions of AFB1 and its metabolites inside the peripheral anionic site (PAS) of human AChE (HssAChE), to verify their stability, suggest the preferential ways of inhibition, and compare their behavior to each other. Our results suggest that all metabolites can be better inhibitors of HssAChE than AFB1 and that AFBO and AFM1, the most toxic and carcinogenic metabolites of AFB1, are also the most effective HssAChE inhibitors among the AFB1 metabolites.
ESTHER : de Almeida_2018_J.Biomol.Struct.Dyn__1
PubMedSearch : de Almeida_2018_J.Biomol.Struct.Dyn__1
PubMedID: 29749305

Title : Molecular Modeling Studies on the Interactions of Aflatoxin B1 and Its Metabolites with Human Acetylcholinesterase. Part II: Interactions with the Catalytic Anionic Site (CAS) - de Almeida_2018_Toxins.(Basel)_10_
Author(s) : de Almeida JSFD , Dolezal R , Krejcar O , Kuca K , Musilek K , Jun D , Franca TCC
Ref : Toxins (Basel) , 10 : , 2018
Abstract : The most common type of aflatoxin (AFT) found in nature is aflatoxin B1 (AFB1). This micotoxin is extremely hepatotoxic and carcinogenic to mammals, with acute and chronic effects. It is believed that this could be related to the capacity of AFB1 and its metabolites in inhibiting the enzyme acetylcholinesterase (AChE). In a previous work, we performed an inedited theoretical investigation on the binding modes of these molecules on the peripheral anionic site (PAS) of human AChE (HssAChE), revealing that the metabolites can also bind in the PAS in the same way as AFB1. Here, we investigated the binding modes of these compounds on the catalytic anionic site (CAS) of HssAChE to compare the affinity of the metabolites for both binding sites as well as verify which is the preferential one. Our results corroborated with experimental studies pointing to AFB1 and its metabolites as mixed-type inhibitors, and pointed to the residues relevant for the stabilization of these compounds on the CAS of HssAChE.
ESTHER : de Almeida_2018_Toxins.(Basel)_10_
PubMedSearch : de Almeida_2018_Toxins.(Basel)_10_
PubMedID: 30257474

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Title : Preparation, in vitro screening and molecular modelling of monoquaternary compounds related to the selective acetylcholinesterase inhibitor BW284c51 - Benek_2014_Med.Chem_11_21
Author(s) : Benek O , Musilek K , Horova A , Dohnal V , Dolezal R , Kuca K
Ref : Med Chem , 11 :21 , 2014
Abstract : This paper describes preparation and in vitro evaluation of 19 compounds related to the selective experimental cholinesterase inhibitor BW284c51. The novel compounds were prepared as fragments of parent molecule BW284c51 and evaluated on the model of human recombinant acetylcholinesterase and human plasmatic butyrylcholinesterase. The IC(5)(0) values of the prepared compounds were compared to the parent molecule BW284c51. None of the compounds was superior to the parent drug, but two BW284c51 fragments showed promising hAChE inhibition in microM scale and improved selectivity. These two fragments were further subjected to the molecular modelling study and their enzyme interactions were rationalized. The structure-activity relationship of the prepared series was stated.
ESTHER : Benek_2014_Med.Chem_11_21
PubMedSearch : Benek_2014_Med.Chem_11_21
PubMedID: 24773345

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