Design, synthesis, and biological evaluation of 2-arylethenylquinoline derivatives as multifunctional agents for the treatment of Alzheimer's disease

A series of new 2-arylethenylquinoline derivatives (4a(1)-4a(12), 4b(1)-4b(8), 4c(1)-4c(4), 4d(1)-4d(3) and 4e(1)-4e(9)) were designed, synthesized, and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro studies showed that these synthetic compounds inhibited self-induced A beta(1-42) aggregation effectively ranged from 23.6% to 83.9% at the concentration of 20 mu M, and acted as potential antioxidants and biometal chelators. Their structure-activity relationships were obtained and discussed. In particular, compound 4b(1), the most active compound, displayed strong inhibitory activity with an IC50 value of 9.7 mu M for self-induced A beta(1-42) aggregation, good antioxidative activity with a value of 3.9-fold of Trolox, potent inhibitory activity for cholinesterase with IC50 values of 0.2 mu M and 64.1 mu M against butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE), respectively. Besides, 4b(1) was also capable of disassembling the self-induced A beta(1-42) aggregation fibrils with a ratio of 59.8% at 20 mu M concentration, and had a good metal chelating activity. Taken together, these results suggest that compound 4b(1) might be a promising lead compound for AD treatment. (C) 2014 Elsevier Masson SAS. All rights reserved.