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

• Published in: Journal of molecular graphics & modelling 2022-09, Vol.115, p.108210-108210, Article 108210
• Main Authors: Onder, Ferah Comert, Sahin, Kader, Senturk, Murat, Durdagi, Serdar, Ay, Mehmet
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Alzheimer's disease; Inhibitors; MD simulations; Molecular docking; Substituent effect
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2022.108210

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 KI 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. [Display omitted] •This study aims to focus on discovering new coumarin-based cholinesterase inhibitors.•Six coumarin carboxamide derivatives (A1, A2, B1-B4) were studied by integrated in silico 
and in vitro studies.•A1, A2 and B4 have higher average MM/GBSA scores than the neostigmine against BChE.•The promising inhibition result of AChE and BChE at nanomolar concentrations was obtained in in vitro analysis.•Thus, these compounds may be good candidates for further in vivo studies.