(-)-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: Shaobing Cheng, Wei Zheng, Ping Gong, Qiang Zhou, Qiong Xie, Lining Yu, Peiyi Zhang, Liangkang Chen, Juan Li, Jianxing Chen, Hailin Chen, Hongzhuan Chen
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 13 Pg. 3110-8 (Jul 01 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 26025073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• 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

Topics

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