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

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Tarih

2022

Dergi Başlığı

Dergi ISSN

Cilt Başlığı

Yayıncı

Elsevier Science Inc

Erişim Hakkı

info:eu-repo/semantics/closedAccess

Özet

Inhibition 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.

Açıklama

Anahtar Kelimeler

Alzheimer's disease, Acetylcholinesterase, Inhibitors, Molecular docking, MD simulations, Substituent effect

Kaynak

Journal of Molecular Graphics & Modelling

WoS Q Değeri

Q2

Scopus Q Değeri

Q2

Cilt

115

Sayı

Künye