Onder_2022_J.Mol.Graph.Model_115_108210

Reference

Title : Identifying highly effective coumarin-based novel cholinesterase inhibitors by in silico and in vitro studies - Onder_2022_J.Mol.Graph.Model_115_108210
Author(s) : Onder FC , Sahin K , Senturk M , Durdagi S , Ay M
Ref : J Mol Graph Model , 115 :108210 , 2022
Abstract :

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(I) 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.

PubMedSearch : Onder_2022_J.Mol.Graph.Model_115_108210
PubMedID: 35623143

Related information

Citations formats

Onder FC, Sahin K, Senturk M, Durdagi S, Ay M (2022)
Identifying highly effective coumarin-based novel cholinesterase inhibitors by in silico and in vitro studies
J Mol Graph Model 115 :108210

Onder FC, Sahin K, Senturk M, Durdagi S, Ay M (2022)
J Mol Graph Model 115 :108210