Benkova M

References (9)

Title : Synthesis and Decontamination Effect on Chemical and Biological Agents of Benzoxonium-Like Salts - Markova_2021_Toxics_9_
Author(s) : Markova A , Hympanova M , Matula M , Prchal L , Sleha R , Benkova M , Pulkrabkova L , Soukup O , Krocova Z , Jun D , Marek J
Ref : Toxics , 9 : , 2021
Abstract : Benzoxonium chloride belongs to the group of quaternary ammonium salts, which have been widely used for decades as disinfectants because of their high efficacy, low toxicity, and thermal stability. In this study, we have prepared the C(10)-C(18) set of benzoxonium-like salts to evaluate the effect of their chemical and biological decontamination capabilities. In particular, biocidal activity against a panel of bacterial strains including Staphylococcus aureus in biofilm form was screened. In addition, the most promising compounds were successfully tested against Francisella tularensis as a representative of potential biological warfare agents. From a point of view of chemical warfare protection, the efficiency of BOC-like compounds to degrade the organophosphate simulant fenitrothion was examined. Notwithstanding that no single compound with universal effectiveness was identified, a mixture of only two compounds from this group would be able to satisfactorily cover the proposed decontamination spectrum. In addition, the compounds were evaluated for their cytotoxicity as a basic safety parameter for potential use in practice. In summary, the dual effect on chemical and biological agents of benzoxonium-like salts offer attractive potential as active components of decontamination mixtures in the case of a terrorist threat or chemical or biological accidents.
ESTHER : Markova_2021_Toxics_9_
PubMedSearch : Markova_2021_Toxics_9_
PubMedID: 34564373

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

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

Title : 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 : 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 : 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 : Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer's Disease - Wieckowska_2018_ACS.Chem.Neurosci_9_1195
Author(s) : Wieckowska A , Wichur T , Godyn J , Bucki A , Marcinkowska M , Siwek A , Wieckowski K , Zareba P , Knez D , Gluch-Lutwin M , Kazek G , Latacz G , Mika K , Kolaczkowski M , Korabecny J , Soukup O , Benkova M , Kiec-Kononowicz K , Gobec S , Malawska B
Ref : ACS Chem Neurosci , 9 :1195 , 2018
Abstract : Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, and amyloid beta antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT6 receptors ( Ki = 18 nM) and noncompetitive inhibitor of cholinesterases (IC50 hAChE = 14 nM, IC50 eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid beta antiaggregation activity (IC50 = 1.27 muM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.
ESTHER : Wieckowska_2018_ACS.Chem.Neurosci_9_1195
PubMedSearch : Wieckowska_2018_ACS.Chem.Neurosci_9_1195
PubMedID: 29384656

Title : Pyridinium Oximes with Ortho-Positioned Chlorine Moiety Exhibit Improved Physicochemical Properties and Efficient Reactivation of Human Acetylcholinesterase Inhibited by Several Nerve Agents - Zorbaz_2018_J.Med.Chem_61_10753
Author(s) : Zorbaz T , Malinak D , Marakovic N , Macek Hrvat N , Zandona A , Novotny M , Skarka A , Andrys R , Benkova M , Soukup O , Katalinic M , Kuca K , Kovarik Z , Musilek K
Ref : Journal of Medicinal Chemistry , 61 :10753 , 2018
Abstract : Six chlorinated bispyridinium mono-oximes, analogous to potent charged reactivators K027, K048, and K203, were synthesized with the aim of improving lipophilicity and reducing the p Ka value of the oxime group, thus resulting in a higher oximate concentration at pH 7.4 compared to nonchlorinated analogues. The nucleophilicity was examined and the p Ka was found to be lower than that of analogous nonchlorinated oximes. All the new compounds efficiently reactivated human AChE inhibited by nerve agents cyclosarin, sarin, and VX. The most potent was the dichlorinated analogue of oxime K027 with significantly improved ability to reactivate the conjugated enzyme due to improved binding affinity and molecular recognition. Its overall reactivation of sarin-, VX-, and cyclosarin-inhibited AChE was, respectively, 3-, 7-, and 8-fold higher than by K027. Its universality, PAMPA permeability, favorable acid dissociation constant coupled with its negligible cytotoxic effect, and successful ex vivo scavenging of nerve agents in whole human blood warrant further analysis of this compound as an antidote for organophosphorus poisoning.
ESTHER : Zorbaz_2018_J.Med.Chem_61_10753
PubMedSearch : Zorbaz_2018_J.Med.Chem_61_10753
PubMedID: 30383374