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Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease
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-dih...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10459044/ https://www.ncbi.nlm.nih.gov/pubmed/37631373 http://dx.doi.org/10.3390/pharmaceutics15082159 |
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author | Belinskaia, Daria A. Voronina, Polina A. Krivorotov, Denis V. Jenkins, Richard O. Goncharov, Nikolay V. |
author_facet | Belinskaia, Daria A. Voronina, Polina A. Krivorotov, Denis V. Jenkins, Richard O. Goncharov, Nikolay V. |
author_sort | Belinskaia, Daria A. |
collection | PubMed |
description | 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 G(s)-protein-coupled serotonin receptors (5-HTR) 5-HT(6), 5-HT(4) and 5-HT(7) (5-HT(4)R, 5-HT(6)R and 5-HT(7)R, 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-HT(4)R and 5-HT(7)R. 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. |
format | Online Article Text |
id | pubmed-10459044 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-104590442023-08-27 Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease Belinskaia, Daria A. Voronina, Polina A. Krivorotov, Denis V. Jenkins, Richard O. Goncharov, Nikolay V. Pharmaceutics Article 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 G(s)-protein-coupled serotonin receptors (5-HTR) 5-HT(6), 5-HT(4) and 5-HT(7) (5-HT(4)R, 5-HT(6)R and 5-HT(7)R, 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-HT(4)R and 5-HT(7)R. 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. MDPI 2023-08-19 /pmc/articles/PMC10459044/ /pubmed/37631373 http://dx.doi.org/10.3390/pharmaceutics15082159 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Belinskaia, Daria A. Voronina, Polina A. Krivorotov, Denis V. Jenkins, Richard O. Goncharov, Nikolay V. Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease |
title | Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease |
title_full | Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease |
title_fullStr | Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease |
title_full_unstemmed | Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease |
title_short | Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease |
title_sort | anticholinesterase and serotoninergic evaluation of benzimidazole–carboxamides as potential multifunctional agents for the treatment of alzheimer’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10459044/ https://www.ncbi.nlm.nih.gov/pubmed/37631373 http://dx.doi.org/10.3390/pharmaceutics15082159 |
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