title: Design, synthesis and biological activity of novel donepezil derivatives bearing N-benzyl pyridinium moiety as potent and dual binding site acetylcholinesterase inhibitors.
abstract: A series of new donepezil derivatives were designed synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase and self-induced β-amyloid (Aβ) aggregation, and moderate antioxidant activity. Especially, compound 5b presented the greatest ability to inhibit cholinesterase (IC50, 1.9 nM for eeAChE and 0.8 nM for hAChE), good inhibition of Aβ aggregation (53.7% at 20 μM) and good antioxidant activity (0.54 trolox equivalents). Kinetic and molecular modeling studies indicated that compound 5b was a mixed-type inhibitor, binding simultaneously to the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, compound 5b could reduce PC12 cells death induced by oxidative stress and Aβ (1-42). Moreover, in vivo experiments showed that compound 5b was nontoxic and tolerated at doses up to 2000 mg/kg. These results suggested that compound 5b might be an excellent multifunctional agent for AD treatment.
authors.affiliation: Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Jin-Shuai
authors.initials: JS
authors.lastname: Lan
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China. Electronic address: xiesaisainanchang@hotmail.com.
authors.forename: Sai-Sai
authors.initials: SS
authors.lastname: Xie
authors.affiliation: School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Ze-Yang
authors.initials: ZY
authors.lastname: Miao
authors.affiliation: Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: dingyue-2001@hotmail.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002470:Cell Survival; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077265:Donepezil; D015195:Drug Design; D004593:Electrophorus; D006801:Humans; D007189:Indans / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000648:ultrastructure; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*; D011726:Pyridinium Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D007189:Indans; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010880:Piperidines; D066329:Protein Aggregates; D011726:Pyridinium Compounds; C075222:amyloid beta-protein (1-42); D000077265:Donepezil; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase inhibitors antioxidant; Alzheimer's disease; Benzylpyridinium; Donepezil; Neuroprotection; β-Amyloid aggregation