Gorecki L


Full name : Gorecki Lukas

First name : Lukas

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

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Country : Czech Republic

Email : gorecluk@fnhk.cz

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References (22)

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

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

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

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

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

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

Title : Rational design, synthesis and evaluation of uncharged, smart bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase - Gorecki_2020_J.Biol.Chem_295_4079
Author(s) : Gorecki L , Gerlits O , Kong X , Cheng X , Blumenthal DK , Taylor P , Ballatore C , Kovalevsky A , Radic Z
Ref : Journal of Biological Chemistry , 295 :4079 , 2020
Abstract : Corrected : Organophosphate (OP) intoxications from nerve agent and OP pesticide exposures are managed with pyridinium aldoxime-based therapies whose success rates are currently limited. The pyridinium cation hampers uptake into the central nervous system (CNS). Furthermore, it frequently binds to aromatic residues of OP-inhibited acetylcholinesterase (AChE) in orientations that are non-productive for AChE reactivation, and the structural diversity of OPs impedes efficient reactivation. Improvements of OP antidotes need to include much better access of AChE reactivators to the CNS and optimized orientation of the antidotes' nucleophile within the AChE active-center gorge. On the basis of X-ray structures of a CNS-penetrating reactivator, monoxime RS194B, reversibly bound to native and venomous agent X (VX)-inhibited human AChE (hAChE), here we created seven uncharged acetamido bis-oximes as candidate antidotes. Both oxime groups in these bis-oximes were attached to the same central, saturated heterocyclic core. Diverse protonation of the heterocyclic amines and oxime groups of the bis-oximes resulted in equilibration among up to 16 distinct ionization forms, including uncharged forms capable of diffusing into the CNS and multiple zwitterionic forms optimal for reactivation reactions. Conformationally diverse zwitterions that could act as structural antidote variants significantly improved in vitro reactivation of diverse OP-hAChE conjugates. Oxime group re-orientation of one of the bis-oximes, forcing it to point into the active center for reactivation, was confirmed by X-ray structural analysis. Our findings provide detailed structure-activity properties of several CNS-directed, uncharged aliphatic bis-oximes holding promise for use as protonation-dependent, conformationally adaptive, "smart" accelerated antidotes against OP toxicity.
ESTHER : Gorecki_2020_J.Biol.Chem_295_4079
PubMedSearch : Gorecki_2020_J.Biol.Chem_295_4079
PubMedID: 32019865
Gene_locus related to this paper: human-ACHE

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

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

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 : 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