Razavi_2013_Eur.J.Med.Chem_64C_252

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 muM) 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 pi-cation interaction with benzylpiperidine moiety. Furthermore, the formation of an additional pi-pi 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.