Synthesis and Hybrid SAR Property Modeling of Novel Cholinesterase Inhibitors

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216275%3A25310%2F21%3A39917857" target="_blank" >RIV/00216275:25310/21:39917857 - isvavai.cz</a>

Result on the web

<a href="https://www.mdpi.com/1422-0067/22/7/3444" target="_blank" >https://www.mdpi.com/1422-0067/22/7/3444</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/ijms22073444" target="_blank" >10.3390/ijms22073444</a>

Result language

angličtina

Original language name

Synthesis and Hybrid SAR Property Modeling of Novel Cholinesterase Inhibitors

Original language description

A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl(3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC50 = 36.05 mu M in the series, while benzyl{3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 mu M) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure-activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. pi-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10401 - Organic chemistry

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2021

Confidentiality

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

Name of the periodical

International Journal of Molecular Sciences

ISSN

1661-6596

e-ISSN

—

Volume of the periodical

22

Issue of the periodical within the volume

April

Country of publishing house

CH - SWITZERLAND

Number of pages

27

Pages from-to

3444

UT code for WoS article

000638674200001

EID of the result in the Scopus database

2-s2.0-85103003910