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

Author:

Belinskaia Daria A.1,Voronina Polina A.1,Krivorotov Denis V.2,Jenkins Richard O.3,Goncharov Nikolay V.1

Affiliation:

1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez 44, St. Petersburg 194223, Russia

2. Research Institute of Hygiene, Occupational Pathology and Human Ecology, Federal Medical Biological Agency, p.o. Kuzmolovsky, St. Petersburg 188663, Russia

3. Leicester School of Allied Health Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK

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.

Funder

IEPhB

Publisher

MDPI AG

Subject

Pharmaceutical Science

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Organophospate-Induced Pathology: Mechanisms of Development, Principles of Therapy and Features of Experimental Studies;Российский физиологический журнал им  И  М  Сеченова;2023-10-01

2. Organophospate-Induced Pathology: Mechanisms of Development, Principles of Therapy and Features of Experimental Studies;Journal of Evolutionary Biochemistry and Physiology;2023-09

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