Identifying highly effective coumarin-based novel cholinesterase inhibitors by in silico and in vitro studies

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dc.authoridComert Onder, Ferah/0000-0002-4037-1979
dc.authoridAY, Mehmet/0000-0002-1095-1614
dc.contributor.authorOnder, Ferah Comert
dc.contributor.authorSahin, Kader
dc.contributor.authorSenturk, Murat
dc.contributor.authorDurdagi, Serdar
dc.contributor.authorAy, Mehmet
dc.date.accessioned2025-01-27T20:11:46Z
dc.date.available2025-01-27T20:11:46Z
dc.date.issued2022
dc.departmentÇanakkale Onsekiz Mart Üniversitesi
dc.description.abstractInhibition of high cholinesterase levels including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), is one of the most important strategies for the treatment of Alzheimer's disease (AD). Clinically limited drugs are used in the treatment of AD, so there is a need to find new effective inhibitors today. Therefore, in this study, synthesized six coumarin carboxamides (A1, A2, B1-B4) were evaluated against AChE and BChE by combined in silico and in vitro studies. The in vitro assessment of studied compounds revealed that A1, A2, B3, and B4 showed highest inhibition potential against AChE and BChE. As demonstrated with our structure activity relationship (SAR) study, the promising inhibition result of AChE at nanomolar concentrations was obtained with heterocyclic amines including pyrrolidine and N-methyl piperazine moieties for tertiary amide substituted coumarin compounds B3 and B4, displaying K-1 values of 9.78 nM and 8.07 nM, respectively. Thus, compounds B3 and B4 had around 5.7- and 6.9-fold more potency compared to the reference molecule, neostigmine. Moreover, coumarin-3-carboxamide derivative A1 bearing benzylmorpholine moiety on coumarin scaffold at position 3 displayed stronger inhibition potential against BChE. Furthermore, in order to better understand their molecular mechanisms in these targets, we conducted molecular docking and MD simulations. Our promising preclinical results show that the lead compounds A1, A2, B3 and B4 have high potential as effective inhibitors for the treatment of AD.
dc.identifier.doi10.1016/j.jmgm.2022.108210
dc.identifier.issn1093-3263
dc.identifier.issn1873-4243
dc.identifier.pmid35623143
dc.identifier.scopus2-s2.0-85130514796
dc.identifier.scopusqualityQ2
dc.identifier.urihttps://doi.org/10.1016/j.jmgm.2022.108210
dc.identifier.urihttps://hdl.handle.net/20.500.12428/20712
dc.identifier.volume115
dc.identifier.wosWOS:000811817200003
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherElsevier Science Inc
dc.relation.ispartofJournal of Molecular Graphics & Modelling
dc.relation.publicationcategoryinfo:eu-repo/semantics/openAccess
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_WoS_20250125
dc.subjectAlzheimer's disease
dc.subjectAcetylcholinesterase
dc.subjectInhibitors
dc.subjectMolecular docking
dc.subjectMD simulations
dc.subjectSubstituent effect
dc.titleIdentifying highly effective coumarin-based novel cholinesterase inhibitors by in silico and in vitro studies
dc.typeArticle

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