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

ABSTRACT: A series of novel hybrid 8-hydroxyquinoline-indole derivatives (7a-7e, 12a-12b and 18a-18h) were synthesized and screened for inhibitory activity against self-induced and metal-ion induced A?1-42 aggregation as potential treatments for Alzheimer's disease (AD). In vitro studies identified the most inhibitory compounds against self-induced A?1-42 aggregation as 18c, 18d and 18f (EC50 = 1.72, 1.48 and 1.08 µM, respectively) compared to the known anti-amyloid drug, clioquinol (1, EC50 = 9.95 µM). The fluorescence of thioflavin T-stained amyloid formed by A?1-42 aggregation in the presence of Cu2+ or Zn2+ ions was also dramatically decreased by treatment with 18c, 18d and 18f. The most potent hybrid compound 18f afforded 82.3% and 88.3% inhibition, respectively, against Cu2+- induced and Zn2+- induced A?1-42 aggregation. Compounds 18c, 18d and 18f were shown to be effective in reducing protein aggregation in HEK-tau and SY5Y-APPSw cells. Molecular docking studies with the most active compounds performed against A?1-42 peptide indicated that the potent inhibitory activity of 18d and 18f were predicted to be due to hydrogen bonding interactions, ?-? stacking interactions and ?-cation interactions with A?1-42, which may inhibit both self-aggregation as well as metal ion binding to A?1-42 to favor the inhibition of A?1-42 aggregation.

SUBMITTER: Bowroju SK 

PROVIDER: S-EPMC7463714 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature