title: Synthesis and pharmacological evaluation of donepezil-based agents as new cholinesterase/monoamine oxidase inhibitors for the potential application against Alzheimer's disease.
abstract: In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of donepezil-like compounds were designed, synthesized and evaluated. In vitro studies showed that most of the designed compounds displayed potent inhibitory activities toward AChE, BuChE, MAO-B and MAO-A. Among them, w18 was a promising agent with balanced activities, which exhibited a moderate cholinesterase inhibition (IC50, 0.220 μM for eeAChE; 1.23 μM for eqBuChE; 0.454 μM for hAChE) and an acceptable inhibitory activity against monoamine oxidases (IC50, 3.14 μM for MAO-B; 13.4 μM for MAO-A). Moreover, w18 could also be a metal-chelator, and able to cross the blood-brain barrier with low cell toxicity on PC12 cells. Taken together, these results suggested that w18 might be a promising multitargeted compound for AD treatment.
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University , People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Li
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University , People's Republic of China.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Wang
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University , People's Republic of China.
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Wu
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University , People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University , People's Republic of China.
authors.forename: Sai-Sai
authors.initials: SS
authors.lastname: Xie
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University , People's Republic of China.
authors.forename: Jin-Shuai
authors.initials: JS
authors.lastname: Lan
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University , People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University , People's Republic of China.
authors.forename: Ling-Yi
authors.initials: LY
authors.lastname: Kong
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University , People's Republic of China.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Wang
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002470:Cell Survival; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004593:Electrophorus; D006736:Horses; D006801:Humans; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D010880:Piperidines; D000077265:Donepezil; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; cholinesterase; donepezil; molecular modeling; monoamine oxidase