Novel coumarin-3-carboxamides bearing N-benzylpiperidine moiety as potent acetylcholinesterase inhibitors

• DOI: 10.1016/j.ejmech.2013.10.024
• Publication Date: 2013-10-23T16:45:05Z
• Authors: Ali Asadipour; Masoumeh Alipour; Mona Jafari; Mehdi Khoobi; Saeed Emami; Hamid Nadri; Amirhossein Sakht...; Alireza Moradi; Vahid Sheibani; Farshad Homayouni...; Abbas Shafiee; Alireza Foroumadi
• Keywords: Models, Molecular; Dose-Response Relationship, Drug; Molecular Structure; Amides; 01 natural sciences; 0104 chemical sciences; 3. Good health; Structure-Activity Relationship; Piperidines; Coumarins; Butyrylcholinesterase; Electrophorus; Acetylcholinesterase; Animals; Cholinesterase Inhibitors; Horses

Some novel coumarin-3-carboxamide derivatives linked to N-benzylpiperidine scaffold were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The screening results showed that most of compounds exhibited potent anti-AChE activity in the range of nM concentrations. Among them, compound 10c bearing an N-ethylcarboxamide linker and a 6-nitro substituent showed the most potent activity (IC₅₀ = 0.3 nM) and the highest selectivity (SI = 26,300). Compound 10c was 46-fold more potent than standard drug donepezil against AChE. The kinetic study revealed that compound 10c exhibited mixed-type inhibition against AChE. Protein-ligand docking study demonstrated that the target compounds have dual binding site interaction mode and these results are in agreement with kinetic study.