Sepsova V

General

Full name : Sepsova Vendula

First name : Vendula

Mail : Faculty of Military Health Sciences\; Department of Toxicology\; Trebesska 1575\; Hradec Kralove\; 50001

Zip Code :

City :

Country : Czech Republic

Email : vendula.sepsova@unob.cz

Phone : +42097325517

Fax :

Website :

Directory :

References (28)

Title : Synthesis and biological assessment of KojoTacrines as new agents for Alzheimer's disease therapy - Dgachi_2019_J.Enzyme.Inhib.Med.Chem_34_163
Author(s) : Dgachi Y , Martin H , Malek R , Jun D , Janockova J , Sepsova V , Soukup O , Iriepa I , Moraleda I , Maalej E , Carreiras MC , Refouvelet B , Chabchoub F , Marco-Contelles J , Ismaili L
Ref : J Enzyme Inhib Med Chem , 34 :163 , 2019
Abstract : In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 +/- 0.24 microM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Abeta1-40 at 3 microM and 10 microM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.
ESTHER : Dgachi_2019_J.Enzyme.Inhib.Med.Chem_34_163
PubMedSearch : Dgachi_2019_J.Enzyme.Inhib.Med.Chem_34_163
PubMedID: 30482062

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

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

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

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

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

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

Title : The Evaluation of the Reactivating and Neuroprotective Efficacy of Two Newly Prepared Bispyridinium Oximes (K305, K307) in Tabun-Poisoned Rats-A Comparison with Trimedoxime and the Oxime K203 - Kassa_2017_Molecules_22_
Author(s) : Kassa J , Misik J , Hatlapatkova J , Karasova JZ , Sepsova V , Caisberger F , Pejchal J
Ref : Molecules , 22 : , 2017
Abstract : The ability of two newly developed oximes (K305, K307) to protect tabun-poisoned rats from tabun-induced inhibition of brain acetylcholinesterase, acute neurotoxic signs and symptoms and brain damage was compared with that of the oxime K203 and trimedoxime. The reactivating and neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose were evaluated. The reactivating efficacy of a newly developed oxime K305 is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime while the ability of the oxime K307 to reactivate tabun-inhibited acetylcholinesterase (AChE) in the brain roughly corresponds to the reactivating efficacy of the oxime K203 and it is slightly lower compared to trimedoxime. In addition, only one newly developed oxime (K307) combined with atropine was able to markedly decrease tabun-induced neurotoxicity although it did not eliminate all tabun-induced acute neurotoxic signs and symptoms. These results correspond to the histopathological evaluation of tabun-induced brain damage. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes (especially trimedoxime) in the treatment of acute tabun poisonings.
ESTHER : Kassa_2017_Molecules_22_
PubMedSearch : Kassa_2017_Molecules_22_
PubMedID: 28696367

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

Title : The Antioxidant Additive Approach for Alzheimer's Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators - Benchekroun_2016_J.Med.Chem_59_9967
Author(s) : Benchekroun M , Romero A , Egea J , Leon R , Michalska P , Buendia I , Jimeno ML , Jun D , Janockova J , Sepsova V , Soukup O , Bautista-Aguilera OM , Refouvelet B , Ouari O , Marco-Contelles J , Ismaili L
Ref : Journal of Medicinal Chemistry , 59 :9967 , 2016
Abstract : Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway.
ESTHER : Benchekroun_2016_J.Med.Chem_59_9967
PubMedSearch : Benchekroun_2016_J.Med.Chem_59_9967
PubMedID: 27736061

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

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

Title : 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 : A comparison of the reactivating and therapeutic efficacy of two newly developed oximes (K727 and K733) with oxime k203 and trimedoxime in tabun-poisoned rats and mice - Kassa_2015_Basic.Clin.Pharmacol.Toxicol_116_367
Author(s) : Kassa J , Sepsova V , Tumova M , Horova A , Musilek K
Ref : Basic Clin Pharmacol Toxicol , 116 :367 , 2015
Abstract : The reactivating and therapeutic efficacy of three original bispyridinium oximes (K727, K733 and K203) and one currently available oxime (trimedoxime) was evaluated in tabun-poisoned rats and mice. The oxime-induced reactivation of tabun-inhibited acetylcholinesterase was measured in diaphragm and brain of tabun-poisoned rats. The results showed that the reactivating efficacy of two recently developed oximes (K727 and K733) does not achieve the level of the reactivation of tabun-inhibited acetylcholinesterase induced by oxime K203 and trimedoxime. While all oximes studied were able to increase the activity of tabun-inhibited acetylcholinesterase in diaphragm, oxime K733 was not able to reactivate tabun-inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While both recently developed oximes were able to reduce acute toxicity of tabun less than 1.5-fold, another original oxime K203 and commonly used trimedoxime reduced the acute toxicity of tabun almost two times. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of oxime K203 and trimedoxime, and therefore, they are not suitable for their replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.
ESTHER : Kassa_2015_Basic.Clin.Pharmacol.Toxicol_116_367
PubMedSearch : Kassa_2015_Basic.Clin.Pharmacol.Toxicol_116_367
PubMedID: 25225130

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 : A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium oximes (K727, K733) with the oxime HI-6 and obidoxime in sarin-poisoned rats and mice - Kassa_2015_Toxicol.Mech.Methods_25_229
Author(s) : Kassa J , Sepsova V , Matouskova L , Horova A , Musilek K
Ref : Toxicol Mech Methods , 25 :229 , 2015
Abstract : The ability of two novel bispyridinium oximes K727 and K733 and currently available oximes (HI-6, obidoxime) to reactivate sarin-inhibited acetylcholinesterase and to reduce acute toxicity of sarin was evaluated. To investigate the reactivating efficacy of the oximes, the rats were administered intramuscularly with atropine and oximes in equitoxic doses corresponding to 5% of their LD50 values at 1 min after the intramuscular administration of sarin at a dose of 24 microg/kg (LD50). The activity of acetylcholinesterase was measured at 60 min after sarin poisoning. The LD50 value of sarin in non-treated and treated mice was assessed using probit-logarithmical analysis of death occurring within 24 h after intramuscular administration of sarin at five different doses. In vivo determined percentage of reactivation of sarin-inhibited rat blood, diaphragm and brain acetylcholinesterase showed that the potency of both novel oximes K727 and K733 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating efficacy of obidoxime. On the other hand, the oxime HI-6 was found to be the most efficient reactivator of sarin-inhibited acetylcholinesterase. While the oxime HI-6 was able to reduce the acute toxicity of sarin >3 times, both novel oximes and obidoxime decreased the acute toxicity of sarin <2 times. Based on the results, we can conclude that the reactivating and therapeutic efficacy of both novel oximes K727 and K733 is significantly lower compared to the oxime HI-6 and, therefore, they are not suitable for the replacement of the oxime HI-6 for the antidotal treatment of acute sarin poisoning.
ESTHER : Kassa_2015_Toxicol.Mech.Methods_25_229
PubMedSearch : Kassa_2015_Toxicol.Mech.Methods_25_229
PubMedID: 25894563

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

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

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

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

Title : The evaluation of the reactivating and therapeutic efficacy of two novel oximes (K361 and K378) in comparison with the oxime K203 and trimedoxime in tabun-poisoned rats and mice - Kassa_2014_Toxicol.Mech.Methods_24_173
Author(s) : Kassa J , Sepsova V , Tumova M , Musilek K , Horova A
Ref : Toxicol Mech Methods , 24 :173 , 2014
Abstract : Abstract The potency of two newly developed oximes (K361 and K378) to reactivate tabun-inhibited cholinesterase and to reduce acute toxicity of tabun was compared with the oxime K203 and trimedoxime using in vivo methods. The study determining percentage of reactivation of tabun-inhibited diaphragm cholinesterase in poisoned rats showed that the reactivating efficacy of the oxime K378 is slightly lower than the reactivating potency of the oxime K203 and trimedoxime while the ability of the oxime K361 to reactivate tabun-inhibited cholinesterase is markedly lower compared with the oxime K203 and trimedoxime. In the brain, the potency of both newly developed oximes to reactivate tabun-inhibited cholinesterase was negligible. The therapeutic efficacy of both newly developed oximes roughly corresponds to their weak reactivating efficacy. Their potency to reduce acute toxicity of tabun was significantly lower compared with the oxime K203 as well as trimedoxime. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.
ESTHER : Kassa_2014_Toxicol.Mech.Methods_24_173
PubMedSearch : Kassa_2014_Toxicol.Mech.Methods_24_173
PubMedID: 24295433

Title : The interaction of quaternary reversible acetylcholinesterase inhibitors with the nicotinic receptor - Sepsova_2014_Physiol.Res_63_771
Author(s) : Sepsova V , Krusek J , Karasova JZ , Zemek F , Musilek K , Kuca K , Soukup O
Ref : Physiol Res , 63 :771 , 2014
Abstract : Acetylcholinesterase inhibitors (AChEIs) are used in the treatment of myasthenia gravis (MG). We investigated the effects of AChEIs on peripheral nicotinic receptors (nAChR), which play a crucial role in the treatment of MG symptoms. The positive modulation of those receptors by AChE inhibitors could have an added value to the anti-AChE activity and might be useful in the therapy of MG. Furthermore, to estimate the potential drawbacks of the compounds, cytotoxicity has been assessed on various cell lines. The whole-cell mode of the patch-clamp method was employed. The experiments were performed on medulloblastoma/rhabdomyosarcoma cell line TE671 expressing human embryonic muscle-like receptor with subunits alpha2betagammadelta. The effect of the compounds on cell viability was measured by standard MTT assay (Sigma Aldrich) on ACHN (renal cell adenocarcinoma), HeLa (immortal cell line derived from a cervical carcinoma), HEPG2 (hepatocellular carcinoma) and BJ (skin fibroblasts) cell lines. No positive modulation by the tested AChE inhibitors was observed. Moreover, the compounds exhibited antagonistic activity on the peripheral nAChR. Standard drugs used in MG treatment were shown to be less potent inhibitors of muscle-type nAChR than the newly synthesized compounds. The new compounds showed very little effect on cell viability, and toxicities were comparable to standards. Newly synthesized AChEIs inhibited peripheral nAChR. Furthermore, the inhibition was higher than that of standards used for the treatment of MG. They could be used for the study of nAChR function, thanks to their high antagonizing potency and fast recovery of receptor activity after their removal. However, since no positive modulation was observed, the new compounds do not seem to be promising candidates for MG treatment, even though their cytotoxic effect was relatively low.
ESTHER : Sepsova_2014_Physiol.Res_63_771
PubMedSearch : Sepsova_2014_Physiol.Res_63_771
PubMedID: 25157661

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

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

Title : The evaluation of the reactivating and therapeutic efficacy of three novel bispyridinium oximes (K454, K456, K458) in comparison with the oxime K203 and trimedoxime in tabun-poisoned rats and mice - Kassa_2013_Toxicol.Mech.Methods_23_94
Author(s) : Kassa J , Sepsova V , Musilek K , Horova A
Ref : Toxicol Mech Methods , 23 :94 , 2013
Abstract : The potency of three newly developed bispyridinium compounds (K454, K456, K458) to reactivate tabun-inhibited acetylcholinesterase and reduce tabun-induced lethal toxic effects was compared with the oxime K203 and trimedoxime using in vivo methods. The study determining percentage of reactivation of tabun-inhibited diaphragm and brain acetylcholinesterase in poisoned rats showed that the reactivating efficacy of all newly developed oximes is comparable with K203 but lower than the reactivating potency of trimedoxime in diaphragm. In the brain, their potency to reactivate tabun-inhibited acetylcholinesterase is lower compared with trimedoxime and the oxime K203. All three newly developed oximes were also found to be relatively effective in reducing lethal toxic effects in tabun-poisoned mice. Their therapeutic efficacy is consistent with the therapeutic potency of the oxime K203. On the other hand, their potency to reduce acute toxicity of tabun is significantly lower compared with trimedoxime. In conclusion, the reactivating and therapeutic potency of all three newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.
ESTHER : Kassa_2013_Toxicol.Mech.Methods_23_94
PubMedSearch : Kassa_2013_Toxicol.Mech.Methods_23_94
PubMedID: 22901042

Title : Oximes as inhibitors of acetylholinesterase - a structure-activity relationship (SAR) study - Sepsova_2011_Mil.Med.Sci.Lett_80_178
Author(s) : Sepsova V , Karasova JZ , Zemek F , Bennion BJ , Kuca K
Ref : Military Medical Science Letters , 80 :178 , 2011
Abstract : Acetylcholinesterase (AChE) reactivators (oximes) are generally used as antidotes in case of nerve agent poisoning. Because of their affinity to AChE, they may also act as weak inhibitors of AChE. Their inhibition potency against AChE was determined by an in vitro method based on the interaction between AChE and oxime reactivator in the concentration range 10-1 to 10-8 M. We used eel AChE for these assays. We found that AChE inhibition strongly depends on the oxime structure. The aim of the present study is to describe the structure-activity relationship (SAR) between oxime structure and inhibition of AChE. AChE reactivators tested include both monoquaternary and bisquaternary structures with the oxime group in different positions on the pyridine ring and with changes in the connecting linker in the case of the bisquaternary compounds.We found AChE inhibition to be highest in bisquaternary oximes that have a longer linker length and have the oxime group in the ortho position. Increased AChE inhibition in monoquaternary oximes was highest when the meta position was occupied by the oxime nucleophile. In addition, different substituents in the connecting chain (in case of bisquaternary oximes) modulated their inhibition potency.
ESTHER : Sepsova_2011_Mil.Med.Sci.Lett_80_178
PubMedSearch : Sepsova_2011_Mil.Med.Sci.Lett_80_178
PubMedID:

Title : The benefit of combinations of oximes for the reactivating and therapeutic efficacy of antidotal treatment of sarin poisoning in rats and mice - Kassa_2011_Basic.Clin.Pharmacol.Toxicol_109_30
Author(s) : Kassa J , Karasova JZ , Sepsova V , Caisberger F
Ref : Basic Clin Pharmacol Toxicol , 109 :30 , 2011
Abstract : The influence of the combinations of oximes on the reactivating and therapeutic efficacy of antidotal treament of acute sarin poisoning was evaluated in this study. The ability of two combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate sarin-inhibited acetylcholinesterase and reduce acute toxicity of sarin was compared with the reactivating and therapeutic efficacy of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo methods. Studies determining percentage of reactivation of sarin-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of the combination of oximes involving HI-6 and K203 is slightly higher than the reactivating efficacy of the most effective individual oxime in diaphragm and brain but the difference between them is not significant. The ability of combination of oximes involving HI-6 and trimedoxime to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating effects of the most effective individual oxime in blood as well as tissues. Moreover, both combinations of oximes were found to be as efficacious in the reduction of acute lethal toxic effects in sarin-poisoned mice as the most effective individual oxime. A comparison of reactivating and therapeutic efficacy of individual oximes showed that the oxime HI-6 is markedly more effective than the oxime K203 and trimedoxime. Based on the obtained data, we conclude that the antidotal treatment involving chosen combinations of oximes does not significantly influence the ability of the most effective individual oxime (HI-6) to reactivate sarin-inhibited rat acetylcholinesterase and to reduce acute toxicity of sarin in mice.
ESTHER : Kassa_2011_Basic.Clin.Pharmacol.Toxicol_109_30
PubMedSearch : Kassa_2011_Basic.Clin.Pharmacol.Toxicol_109_30
PubMedID: 21235715

Title : A comparison of the reactivating and therapeutic efficacy of chosen combinations of oximes with individual oximes against VX in rats and mice - Kassa_2011_Int.J.Toxicol_30_562
Author(s) : Kassa J , Karasova JZ , Sepsova V , Caisberger F , Bajgar J
Ref : Int J Toxicol , 30 :562 , 2011
Abstract : The ability of 2 combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate VX-inhibited acetylcholinesterase and reduce acute toxicity of VX was compared with the reactivating and therapeutic efficacy of antidotal treatment involving a single oxime (HI-6, trimedoxime, K203) in rats and mice. Our results showed that the reactivating efficacy of both combinations of oximes studied in rats is significantly higher than the reactivating efficacy of all individual oximes in diaphragm and roughly corresponds to the most effective individual oxime in blood and brain. Both combinations of oximes were found to be more effective in the reduction of acute lethal toxicity of VX in mice than the antidotal treatment involving the most efficacious individual oxime although the difference is not significant. Based on the obtained data, we can conclude that the antidotal treatment involving the chosen combinations of oximes brings benefit for the reactivation of VX-inhibited acetylcholinesterase in rats and for the antidotal treatment of VX-induced acute poisoning in mice.
ESTHER : Kassa_2011_Int.J.Toxicol_30_562
PubMedSearch : Kassa_2011_Int.J.Toxicol_30_562
PubMedID: 22013137