title: Synthesis and evaluation of multi-target-directed ligands for the treatment of Alzheimer's disease based on the fusion of donepezil and melatonin.
abstract: A novel series of compounds obtained by fusing the acetylcholinesterase (AChE) inhibitor donepezil and the antioxidant melatonin were designed as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (eqBuChE and hBuChE), and β-amyloid (Aβ) aggregation, and to act as potential antioxidants and biometal chelators. Especially, 4u displayed a good inhibition of AChE (IC50 value of 193nM for eeAChE and 273nM for hAChE), strong inhibition of BuChE (IC50 value of 73nM for eqBuChE and 56nM for hBuChE), moderate inhibition of Aβ aggregation (56.3% at 20μM) and good antioxidant activity (3.28trolox equivalent by ORAC assay). Molecular modeling studies in combination with kinetic analysis revealed that 4u was a mixed-type inhibitor, binding simultaneously to catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4u could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results strongly indicated the hybridization approach is an efficient strategy to identify novel scaffolds with desired bioactivities, and further optimization of 4u may be helpful to develop more potent lead compound for AD treatment.
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: Jin
authors.initials: J
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: 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: Xue-Mei
authors.initials: XM
authors.lastname: Li
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: Fan
authors.initials: F
authors.lastname: Li
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 / Q000037:antagonists & inhibitors; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D000077265:Donepezil; D004593:Electrophorus; D006736:Horses; D006801:Humans; D007189:Indans / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D007501:Iron / Q000737:chemistry; D007700:Kinetics; D008550:Melatonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D055503:Protein Multimerization; D051381:Rats; D015032:Zinc / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D007189:Indans; D007211:Indoles; C000621442:N-(2-(1-benzylpiperidin-4-yl)ethyl)-3-(1H-indol-3-yl)propanamide; D010446:Peptide Fragments; D010880:Piperidines; C075222:amyloid beta-protein (1-42); D000077265:Donepezil; D007501:Iron; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D015032:Zinc; D008550:Melatonin
keywords: Alzheimer’s disease; Antioxidant activity; Biometal chelators; Cholinesterase; Donepezil; Melatonin