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

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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 IC 50 (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.