The multifactorial pathogenesis of Alzheimer's disease (AD) implicates that multi-target-directed ligands (MTDLs) intervention may represent a promising therapy for AD. Amyloid-beta (A beta) 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 A beta 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. (C) 2015 Elsevier Ltd. All rights reserved.
[1]Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China.
[2]Shanghai Inst Planned Parenthood Res, NPFPC Key Lab Contracept Drugs & Devices, Shanghai 200032, Peoples R China.
[3]Shanghai Jiao Tong Univ, Sch Med, Inst Med Sci, Dept Pharmacol, Shanghai 200025, Peoples R China.
[4]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Shanghai 200062, Peoples R China.
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