1. Design, synthesis, and evaluation of salicyladimine derivatives as multitarget-directed ligands against Alzheimer's disease.
- Author
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Yang HL, Cai P, Liu QH, Yang XL, Fang SQ, Tang YW, Wang C, Wang XB, and Kong LY
- Subjects
- Amyloid beta-Peptides antagonists & inhibitors, Animals, Cell Survival drug effects, Dose-Response Relationship, Drug, Humans, Hydrogen Peroxide pharmacology, Imines chemical synthesis, Imines chemistry, Ligands, Lipopolysaccharides antagonists & inhibitors, Lipopolysaccharides pharmacology, Mice, Microglia drug effects, Microglia metabolism, Molecular Docking Simulation, Molecular Structure, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors chemical synthesis, Monoamine Oxidase Inhibitors chemistry, PC12 Cells, Peptide Fragments antagonists & inhibitors, Protein Aggregates drug effects, Rats, Salicylates chemical synthesis, Salicylates chemistry, Structure-Activity Relationship, Alzheimer Disease drug therapy, Drug Design, Imines pharmacology, Monoamine Oxidase Inhibitors pharmacology, Salicylates pharmacology
- Abstract
A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-β (Aβ) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aβ
1-42 aggregation (91.3±2.1%, 25μM), inhibition of hMAO-B (IC50 , 1.73±0.39μM), antioxidant effects (43.4±2.6μM of IC50 by DPPH method, 0.67±0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H2 O2 -induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs., (Copyright © 2017. Published by Elsevier Ltd.)- Published
- 2017
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