(-)-Meptazinol-melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-β aggregation with high antioxidant potency for Alzheimer's therapy

Shaobing Cheng; Wei Zheng; Ping Gong; Qiang Zhou; Qiong Xie; Lining Yu; Peiyi Zhang; Liangkang Chen; Juan Li; Jianxing Chen; Hailin Chen; Hongzhuan Chen

doi:10.1016/j.bmc.2015.04.084

(-)-Meptazinol-melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-β aggregation with high antioxidant potency for Alzheimer's therapy

Bioorg Med Chem. 2015 Jul 1;23(13):3110-8. doi: 10.1016/j.bmc.2015.04.084. Epub 2015 May 12.

Authors

Shaobing Cheng¹, Wei Zheng², Ping Gong³, Qiang Zhou⁴, Qiong Xie¹, Lining Yu⁵, Peiyi Zhang⁵, Liangkang Chen⁵, Juan Li⁶, Jianxing Chen⁵, Hailin Chen⁵, Hongzhuan Chen³

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
² NPFPC Key Laboratory of Contraceptives Drugs & Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032, PR China. Electronic address: [email protected].
³ Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
⁴ Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medical, 164 Lanxi Road, Shanghai 200062, PR China.
⁵ NPFPC Key Laboratory of Contraceptives Drugs & Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai 200032, PR China.
⁶ Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China. Electronic address: [email protected].

PMID: 26025073
DOI: 10.1016/j.bmc.2015.04.084

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.

Keywords: Alzheimer’s disease; Antioxidant; Aβ aggregation; Multi-target-directed ligands.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / chemistry
Amyloid beta-Peptides / antagonists & inhibitors*
Antioxidants / chemical synthesis
Antioxidants / pharmacology*
Cell Line, Tumor
Cell Membrane Permeability
Cell Survival / drug effects
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / pharmacology*
Drug Design
Humans
Melatonin / analogs & derivatives*
Meptazinol / analogs & derivatives*
Neurons / drug effects
Neurons / metabolism
Neurons / pathology
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / pharmacology*
Oxidative Stress
Peptide Fragments / antagonists & inhibitors*
Protein Aggregates / drug effects
Protein Aggregation, Pathological / metabolism
Protein Aggregation, Pathological / prevention & control
Reactive Oxygen Species / antagonists & inhibitors
Reactive Oxygen Species / chemistry

Substances

Amyloid beta-Peptides
Antioxidants
Cholinesterase Inhibitors
Neuroprotective Agents
Peptide Fragments
Protein Aggregates
Reactive Oxygen Species
amyloid beta-protein (1-40)
amyloid beta-protein (1-42)
Meptazinol
Acetylcholinesterase
Melatonin