Publication detail

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

Year: 2018

Type of publication: článek v odborném periodiku

Name of source: Bioorganic Chemistry

Publisher name: Elsevier Science Inc.

Place: New York

Page from-to: 280-289

Titles:

Language	Name	Abstract	Keywords
cze	Syntéza a charakterizace nových inhibitorů cholinesteráz na bázi N-fenylkarbamátů: in vitro studium inhibiční aktivity, typu inhibice, lipofility a molkulární modelování	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.	karbamáty; monosacharidy; cholinesterázy; IC50; molekulární docking
eng	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	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.	Carbamates; Monosaccharide derivatives; Cholinesterases; IC50; Molecular modeling

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