Publikace detail

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

Autoři: Krátký Martin | Štěpánková Šárka | Vorčáková Katarína | Švarcová Markéta | Vinšová Jarmila

Rok: 2016

Druh publikace: článek v odborném periodiku

Název zdroje: Molecules

Strana od-do: "191-1"-"191-10"

Tituly:

Jazyk	Název	Abstrakt	Klíčová slova
cze	Nové cholinesterázové inhibitory na bázi karbamátů a thiokarbamátů	Pomocí Ellmanovy metody byla sledována schopnost 20 nových salicylanilidových karbamátů a thiokarbamátů inhibovat acetylcholinesterázu a butyrylcholinesterázu.	karbamáty, cholinesterázy
eng	Novel Cholinesterases Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates	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 μM. 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 μM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 μM). 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.	acetylcholinesterase; butyrylcholinesterase; carbamate; enzyme inhibition; salicylanilide; thiocarbamate

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