Synthesis and characterization of new inhibitors of cholinesterases based on N-phenylcarbamates: In vitro study of inhibitory effect, type of inhibition, lipophilicity and molecular docking

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dc.contributor.author Vorčáková, Katarína cze
dc.contributor.author Majekova, Magdalena cze
dc.contributor.author Horáková, Eva cze
dc.contributor.author Drabina, Pavel cze
dc.contributor.author Sedlák, Miloš cze
dc.contributor.author Štěpánková, Šárka cze
dc.date.accessioned 2019-05-22T08:27:02Z
dc.date.available 2019-05-22T08:27:02Z
dc.date.issued 2018 eng
dc.identifier.issn 0045-2068 eng
dc.identifier.uri https://hdl.handle.net/10195/72695
dc.description.abstract Based on current treatment of Alzheimer's disease, where the carbamate inhibitor Rivastigmine is used, two series of carbamate derivatives were prepared: (i) N-phenylcarbamates with additional carbamate group (1-12) and (ii) N-phenylcarbamates with monosaccharide moiety (13-24). All compounds were tested for the inhibitory effect on both of the cholinesterases, electric eel acetylcholinesterase (eeAChE) and butyrylcholinesterase from equine serum (eqBChE) and the inhibitory activity (expressed as IC50 values) was compared with that of the established drugs Galanthamine and Rivastigmine. The compounds with two carbamate groups 1-12 revealed higher inhibitory efficiency on both cholinesterases in compared with monosaccharide derived carbamates 13-24 and with Rivastigmine. The significant decrease of inhibitory efficiency on eqBChE (also for eeAChE but in less manner) was observed after deacetalization of monosaccharide. Moreover, the type of inhibitory mechanism of five chosen compounds was studied. It was found, that compounds with two carbamate groups act presumably via a mixed inhibitory mechanism and the compounds with monosaccharide moiety act as non-competitive inhibitors. The lipophilicity of tested compounds was determined using partition coefficient. Specific positions of the inhibitors in the binding sites of cholinesterases were determined using molecular modeling and the results indicate the importance of phenylcarbamate orientation in the catalytic gorges of both enzymes. eng
dc.format p. 280-289 eng
dc.language.iso eng eng
dc.publisher Elsevier Science Inc. eng
dc.relation.ispartof Bioorganic Chemistry, volume 78, issue: August eng
dc.rights pouze v rámci univerzity eng
dc.subject Carbamates eng
dc.subject Monosaccharide derivatives eng
dc.subject Cholinesterases eng
dc.subject IC50 eng
dc.subject Molecular modeling eng
dc.subject karbamáty cze
dc.subject monosacharidy cze
dc.subject cholinesterázy cze
dc.subject IC50 cze
dc.subject molekulární docking cze
dc.title Synthesis and characterization of new inhibitors of cholinesterases based on N-phenylcarbamates: In vitro study of inhibitory effect, type of inhibition, lipophilicity and molecular docking eng
dc.title.alternative Syntéza a charakterizace nových inhibitorů cholinesteráz na bázi N-fenylkarbamátů: in vitro studium inhibiční aktivity, typu inhibice, lipofility a molkulární modelování cze
dc.type article eng
dc.description.abstract-translated Byly připraveny dvě série karbamátových derivátů: N-fenylkarbamáty s další karbamátovou skupinou a N-fenylkarbamáty s monosacharidovou částí. U všech derivátů byly stanoveny hodnoty IC50 při inhibici ACHE z paúhoře elektrického a BCHE z koňského séra a tyto hodnoty byly porovnány s hodnotami IC50 standardů - rivastigminu a galanthaminu. Deriváty se dvěma karbamovými skupinami vykazovaly vyšší účinnost při inhbici cholinesteráz než deriváty s monosacharidou částí. Sloučeniny se dvěma karbamovými skupinami působí jako smíšené inhibitory, kdežto deriváty se sacharidovou částí jako nekompetitivní inhibitory. Pro určení lipofility testovaných sloučenin byl stanoven rozdělovací koeficient. Metodou molekulárního modelování byl objasněn způsob vazby studovaných derivátů do aktivního místa enzymů. cze
dc.peerreviewed yes eng
dc.publicationstatus published eng
dc.identifier.doi 10.1016/j.bioorg.2018.03.012 eng
dc.identifier.wos 000433242100030 eng
dc.identifier.scopus 2-s2.0-85044773150
dc.identifier.obd 39881505 eng


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