title: (-)-Meptazinol-melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-β aggregation with high antioxidant potency for Alzheimer's therapy.
abstract: The multifactorial pathogenesis of Alzheimer's disease (AD) implicates that multi-target-directed ligands (MTDLs) intervention may represent a promising therapy for AD. Amyloid-β (Aβ) aggregation and oxidative stress, two prominent neuropathological hallmarks in patients, play crucial roles in the neurotoxic cascade of this disease. In the present study, a series of novel (-)-meptazinol-melatonin hybrids were designed, synthesized and biologically characterized as potential MTDLs against AD. Among them, hybrids 7-7c displayed higher dual inhibitory potency toward cholinesterases (ChEs) and better oxygen radical absorbance capacity (ORAC) than the parental drugs. Furthermore, compound 7c could effectively inhibit Aβ self-aggregation, showed favorable safety and the blood-brain barrier (BBB) permeability. Therefore, 7c may serve as a valuable candidate that is worthy of further investigations in the treatment of AD.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Shaobing
authors.initials: S
authors.lastname: Cheng
authors.affiliation: NPFPC Key Laboratory of Contraceptives Drugs & Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032, PR China. Electronic address: zhengwei726@126.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.affiliation: Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medical, 164 Lanxi Road, Shanghai 200062, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xie
authors.affiliation: NPFPC Key Laboratory of Contraceptives Drugs & Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032, PR China.
authors.forename: Lining
authors.initials: L
authors.lastname: Yu
authors.affiliation: NPFPC Key Laboratory of Contraceptives Drugs & Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032, PR China.
authors.forename: Peiyi
authors.initials: P
authors.lastname: Zhang
authors.affiliation: NPFPC Key Laboratory of Contraceptives Drugs & Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032, PR China.
authors.forename: Liangkang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China. Electronic address: lijuanpharm@gmail.com.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: NPFPC Key Laboratory of Contraceptives Drugs & Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032, PR China.
authors.forename: Jianxing
authors.initials: J
authors.lastname: Chen
authors.affiliation: NPFPC Key Laboratory of Contraceptives Drugs & Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032, PR China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008550:Melatonin / Q000031:analogs & derivatives*; D008621:Meptazinol / Q000031:analogs & derivatives*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D066329:Protein Aggregates / Q000187:drug effects; D066263:Protein Aggregation, Pathological / Q000378:metabolism / Q000517:prevention & control; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D008621:Meptazinol; D000110:Acetylcholinesterase; D008550:Melatonin
keywords: Alzheimer’s disease; Antioxidant; Aβ aggregation; Multi-target-directed ligands