Synthesis and evaluation of 4-substituted coumarins as novel acetylcholinesterase inhibitors

Abstract

A series of 4-hydroxycoumarin derivatives were designed and synthesized as new acetylcholinesterase (AChE) inhibitors which could be considered for Alzheimer's disease therapeutics. Among the 19 coumarin-derived compounds tested toward Electrophorus electricus acetylcholinesterase (eelAChE) and horse serum butyrylcholinesterase (eqBChE), N-(1-benzylpiperidin-4-yl)acetamide derivative 4m displayed highest AChE inhibitory activity (IC50 = 1.2 μM) and good selectivity (37 times). The docking study of the most potent compound 4m, indicated that Phe330 is responsible for ligand recognition and trafficking by forming π-cation interaction with benzylpiperidine moiety. Furthermore, the formation of an additional π–π interaction between coumarin moiety and Trp279 of peripheral anionic site could stabilize the ligand in the active site resulting in more potent inhibition of the enzyme.