Design, synthesis, and evaluation of salicyladimine derivatives as multitarget-directed ligands against Alzheimer’s disease

Publication date: Available online 27 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Hua-Li Yang, Pei Cai, Qiao-Hong Liu, Xue-Lian Yang, Si-Qiang Fang, Yan-Wei Tang, Cheng Wang, Xiao-Bing Wang, Ling-Yi Kong
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 Aβ1-42 aggregation (91.3±2.1%, 25 μM), inhibition of hMAO-B (IC50, 1.73±0.39 μM), antioxidant effects (43.4±2.6 μM 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, H2O2-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.

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