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

• DOI: 10.1016/j.ejmech.2013.03.021
• Publication Date: 2013-03-18T15:26:59Z
• Authors: Seyyede Faeze Razavi; Mehdi Khoobi; Hamid Nadri; Amirhossein Sakht...; Alireza Moradi; Saeed Emami; Alireza Foroumadi; Abbas Shafiee
• Keywords: Moiety; Butyrylcholinesterase; Acetamide; Electrophorus; Docking (animal)

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.