Novel Cholinesterases Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216275%3A25310%2F16%3A39901558" target="_blank" >RIV/00216275:25310/16:39901558 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.3390/molecules21020191" target="_blank" >http://dx.doi.org/10.3390/molecules21020191</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/molecules21020191" target="_blank" >10.3390/molecules21020191</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Novel Cholinesterases Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

Popis výsledku v původním jazyce

Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 ?M. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)- phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 ?M), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 ?M). Results from molecular docking studies suggest that carbamate compounds, especially N,Ndiphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

Název v anglickém jazyce

Novel Cholinesterases Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

Popis výsledku anglicky

Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 ?M. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)- phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 ?M), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 ?M). Results from molecular docking studies suggest that carbamate compounds, especially N,Ndiphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

CE - Biochemie

OECD FORD obor

—

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Molecules

ISSN

1420-3049

e-ISSN

—

Svazek periodika

21

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

10

Strana od-do

"191-1"-"191-10"

Kód UT WoS článku

000371895900005

EID výsledku v databázi Scopus

—