In Silico Study, Synthesis, and In Vitro Evaluation of Acetylcholinesterase and Butyrylcholinesterase Inhibitory Activity of Novel N-Thiazole Substituted Acetamide Coumarin Derivatives.

Abstract

In this study, a structurally directed pharmacophore hybridization technique is used to combine the two essential structural scaffolds coumarin and thiazoles in search of a new class of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor for Alzheimer's disease (AD). A library of 120 compounds was designed in two series 5a(1-15), 5b(16-30), 5c(31-45), 5d(46-60), and 6a(61-75), 6b(76-90), 6c(91-105), 6d(106-120) using various substituted phenol, β-ketoesters, and thiazole derivatives. Eleven compounds were identified as potential hybrids using molecular property filter analysis and molecular docking studies, and they comprise N-substituted thiazole coumarin derivatives. The docking results indicated that compounds 5b16 and 5c35 exhibited strong binding interactions with GLY116, GLY117, TYR332, and HIS438 (ranging from -27.42 to -24.18 kcal/mol) and GLY119, ASP72, and PHE288 (ranging from -32.21 to -25.92 kcal/mol) when tested against AChE (1EVE) and BuChE (1P0I) inhibitors. These compounds were synthesized via conventional methods and characterized by different spectroscopic methods. In vitro anti-cholinesterase activity results indicated that two compounds, for example, 5b16 and 5c35 showed potent to moderate activity against AChE and BuChE with IC₅₀ (2.00 ± 0.09-29.63 ± 0.48) µM and (34.93 ± 0.62-17.92 ± 0.42) µM, respectively. Our study demonstrated the development of a novel class of hybrid coumarin thiazole derivatives as AChE and BuChE inhibitors, and these compounds could be utilized against ADs.