(−)-Meptazinol–melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-β aggregation with high antioxidant potency for Alzheimer's therapy. Issue 13 (1st July 2015)

• Record Type: Journal Article
• Authors: Cheng, Shaobing; Zheng, Wei; Gong, Ping; Zhou, Qiang; Xie, Qiong; Yu, Lining; Zhang, Peiyi; Chen, Liangkang; Li, Juan; Chen, Jianxing; Chen, Hailin; Chen, Hongzhuan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 13(2015)
• Page Start: 3110
• Page End: 3118
• Publication Date: 2015-07-01
• Subjects: AD Alzheimer's disease -- Aβ amyloid-β -- ACh acetylcholine -- AChE acetylcholinesterase -- AChEIs acetylcholinesterase inhibitors -- BChE butyrylcholinesterase -- BBB blood–brain barrier -- CAS catalytic anionic site -- ChEs cholinesterases -- CCK-8 cell counting kit-8 -- DMAP 4-dimethylaminopyridine -- EDCI 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride -- 5-HT 5-hydroxytryptamine -- Log P n-octanol/water partition coefficient -- MTDLs multi-target-directed ligands -- MEP meptazinol -- ORAC oxygen radical absorbance capacity -- OS oxidative stress -- PAS peripheral anionic site -- SAR structure–activity relationship -- TEM transmission electron microscope; Alzheimer's disease -- Multi-target-directed ligands -- Aβ aggregation -- Antioxidant; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.04.084
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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, hybrids7 –7c displayed higher dual inhibitory potency toward cholinesterases (ChEs) and better oxygen radical absorbance capacity (ORAC) than the parental drugs. Furthermore, compound7c 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.