Design and Synthesis of Novel Hybrid 8-Hydroxy Quinoline-Indole Derivatives as Inhibitors of Aβ Self-Aggregation and Metal Chelation-Induced Aβ Aggregation.

A series of novel hybrid 8-hydroxyquinoline-indole derivatives (, and ) were synthesized and screened for inhibitory activity against self-induced and metal-ion induced Aβ aggregation as potential treatments for Alzheimer's disease (AD). In vitro studies identified the most inhibitory compounds against self-induced Aβ aggregation as , and (EC = 1.72, 1.48 and 1.08 µM, respectively) compared to the known anti-amyloid drug, clioquinol (, EC = 9.95 µM). The fluorescence of thioflavin T-stained amyloid formed by Aβ aggregation in the presence of Cu or Zn ions was also dramatically decreased by treatment with , and . The most potent hybrid compound afforded 82.3% and 88.3% inhibition, respectively, against Cu- induced and Zn- induced Aβ aggregation. Compounds , and were shown to be effective in reducing protein aggregation in HEK-tau and SY5Y-APP cells. Molecular docking studies with the most active compounds performed against Aβ peptide indicated that the potent inhibitory activity of and were predicted to be due to hydrogen bonding interactions, π-π stacking interactions and π-cation interactions with Aβ which may inhibit both self-aggregation as well as metal ion binding to Aβ to favor the inhibition of Aβ aggregation.