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

•36 new 2-arylethenylquinoline derivatives were synthesized as multifunctional anti-AD agents.•Most of compounds showed good inhibition of self-induced Aβ1–42 aggregation.•Compounds also exhibited strong antioxidation and metal chelating activity.•4b1 was the best compound as out of the synthesized compounds.

A series of new 2-arylethenylquinoline derivatives (4a1–4a12, 4b1–4b8, 4c1–4c4, 4d1–4d3 and 4e1–4e9) 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 Aβ1–42 aggregation effectively ranged from 23.6% to 83.9% at the concentration of 20 μM, and acted as potential antioxidants and biometal chelators. Their structure–activity relationships were obtained and discussed. In particular, compound 4b1, the most active compound, displayed strong inhibitory activity with an IC50 value of 9.7 μM for self-induced Aβ1–42 aggregation, good antioxidative activity with a value of 3.9-fold of Trolox, potent inhibitory activity for cholinesterase with IC50 values of 0.2 μM and 64.1 μM against butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE), respectively. Besides, 4b1 was also capable of disassembling the self-induced Aβ1–42 aggregation fibrils with a ratio of 59.8% at 20 μM concentration, and had a good metal chelating activity. Taken together, these results suggest that compound 4b1 might be a promising lead compound for AD treatment.

Graphical abstractThirty six new 2-arylethenylquinoline derivatives were synthesized as multifunctional anti-AD agents. These compounds had good activity of Aβ1–42 aggregation inhibition, cholinesterase inhibition, antioxidation, Aβ1–42 aggregation fibrils disassembly, and metal chelation. The most potential compound was 4b1. .Figure optionsDownload full-size imageDownload as PowerPoint slide