title: Novel coumarin-3-carboxamides bearing N-benzylpiperidine moiety as potent acetylcholinesterase inhibitors.
abstract: 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.
authors.affiliation: Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Asadipour
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Alipour
authors.forename: Mona
authors.initials: M
authors.lastname: Jafari
authors.forename: Mehdi
authors.initials: M
authors.lastname: Khoobi
authors.forename: Saeed
authors.initials: S
authors.lastname: Emami
authors.forename: Hamid
authors.initials: H
authors.lastname: Nadri
authors.forename: Amirhossein
authors.initials: A
authors.lastname: Sakhteman
authors.forename: Alireza
authors.initials: A
authors.lastname: Moradi
authors.forename: Vahid
authors.initials: V
authors.lastname: Sheibani
authors.forename: Farshad
authors.initials: F
authors.lastname: Homayouni Moghadam
authors.forename: Abbas
authors.initials: A
authors.lastname: Shafiee
authors.forename: Alireza
authors.initials: A
authors.lastname: Foroumadi
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002091:Butyrylcholinesterase / Q000097:blood / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004593:Electrophorus; D006736:Horses; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D002800:Cholinesterase Inhibitors; D003374:Coumarins; D010880:Piperidines; C071293:1-benzylpiperidine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Coumarin; Docking; Kinetic study; N-Benzylpiperidine