Design, Synthesis, and Evaluation of Chalcone Derivatives as Multifunctional Agents against Alzheimer's Disease

Abstract

Fifteen chalcone derivatives 3a-3o were synthesized, and evaluated as multifunctional agents against Alzheimer's disease. In vitro studies revealed that these compounds inhibited self-induced Aβ_1-42 aggregation effectively ranged from 45.9-94.5 % at 20 μM, and acted as potential antioxidants. Their structure-activity relationships were summarized. In particular, (2E)-3-[4-(dimethylamino)phenyl]-1-(pyridin-2-yl)prop-2-en-1-one (3g) exhibited an excellent inhibitory activity of 94.5 % at 20 μM, and it could disassemble the self-induced Aβ_1-42 aggregation fibrils with ratio of 57.1 % at 20 μM concentration. In addition, compound 3g displayed good chelating ability for Cu²⁺ , and could effectively inhibit and disaggregate Cu²⁺ -induced Aβ aggregation. Moreover, compound 3g exerted low cytotoxicity, significantly reversed Aβ_1-42 -induced SH-SY5Y cell damage. More importantly, compound 3g remarkably ameliorated scopolamine-induced memory impairment in mice. In summary, all the results revealed compound 3g was a potential multifunctional agent for AD therapy.

Keywords: Alzheimer's disease; Aβ aggregation; chalcone; metal chelating; multifunctional.