title: Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.
abstract: A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Aβ interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties (in silico). Among them, 5c demonstrated excellent AChE inhibition (IC50: 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE-induced and Cu(2+)-induced Aβ1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 μM). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against Aβ1-42-induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, NanJing 210009, People's Republic of China.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, NanJing 210009, People's Republic of China.
authors.forename: Pei
authors.initials: P
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, NanJing 210009, People's Republic of China.
authors.forename: Qiao-Hong
authors.initials: QH
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, NanJing 210009, People's Republic of China.
authors.forename: Ding-Qiao
authors.initials: DQ
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, NanJing 210009, People's Republic of China.
authors.forename: Xue-Lian
authors.initials: XL
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, NanJing 210009, People's Republic of China.
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, NanJing 210009, People's Republic of China. Electronic address: cpu_lykong@126.com.
authors.forename: Ling-Yi
authors.initials: LY
authors.lastname: Kong
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, NanJing 210009, People's Republic of China. Electronic address: xbwang@cpu.edu.cn.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Wang
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003300:Copper / Q000737:chemistry; D000077265:Donepezil; D015195:Drug Design; D006801:Humans; D007189:Indans / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D007700:Kinetics; D008099:Liver / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D066329:Protein Aggregates / Q000187:drug effects; D011487:Protein Conformation
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D007189:Indans; D010446:Peptide Fragments; D010880:Piperidines; D066329:Protein Aggregates; C078592:amyloid beta-protein (1-40); D003300:Copper; D000077265:Donepezil; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase inhibitors; Alzheimer's disease; Donepezil derivatives; Multifunctional agents; β-amyloid aggregation