Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease

Date

2023-08-19

Advisors

Journal Title

Journal ISSN

ISSN

1999-4923

Volume Title

Publisher

MPDI

Type

Article

Peer reviewed

Yes

Abstract

The etiology and pathogenesis of Alzheimer’s disease are multifactorial, so one of the treatment strategies is the development of the drugs that affect several targets associated with the pathogenesis of the disease. Within this roadmap, we investigated the interaction of several substituted 1,3-dihydro-2-oxo-1H-benzimidazol-2-ones with their potential molecular targets: cholinesterases (ChE) and three types of the Gs-protein-coupled serotonin receptors (5-HTR) 5-HT6, 5-HT4 and 5-HT7 (5-HT4R, 5-HT6R and 5-HT7R, respectively). A microplate modification of the Ellman method was used for the biochemical analysis of the inhibitory ability of the drugs towards ChE. Molecular modeling methods, such as molecular docking and molecular dynamics (MD) simulation in water and the lipid bilayer, were used to study the interaction of the compounds with ChE and 5-HTR. In vitro experiments showed that the tested compounds had moderate anticholinesterase activity. With the help of molecular modeling methods, the mechanism of interaction of the tested compounds with ChE was investigated, the binding sites were described and the structural features of the drugs that determine the strength of their anticholinesterase activity were revealed. Primary in silico evaluation showed that benzimidazole–carboxamides effectively bind to 5-HT4R and 5-HT7R. The pool of the obtained data allows us to choose N-[2-(diethylamino)ethyl]-2-oxo-3-(tert-butyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride (compound 13) as the most promising for further experimental development.

Description

open access article

Keywords

Citation

Belinskaia, D.A., Voronina, P.A., Krivorotov, D.V., Jenkins, R.O. and Goncharov, N.V. (2023) Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease. Pharmaceutics, 15 (8), 2159

Rights

Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/

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