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

Abstract

A series of novel hybrid 8-hydroxyquinoline-indole derivatives (<b>7a-7e</b>, <b>12a-12b</b> and <b>18a-18h</b>) were synthesized and screened for inhibitory activity against self-induced and metal-ion induced Aβ_1-42 aggregation as potential treatments for Alzheimer's disease (AD). In vitro studies identified the most inhibitory compounds against self-induced Aβ_1-42 aggregation as <b>18c</b>, <b>18d</b> and <b>18f</b> (EC₅₀ = 1.72, 1.48 and 1.08 µM, respectively) compared to the known anti-amyloid drug, clioquinol (<b>1</b>, EC₅₀ = 9.95 µM). The fluorescence of thioflavin T-stained amyloid formed by Aβ_1-42 aggregation in the presence of Cu²⁺ or Zn²⁺ ions was also dramatically decreased by treatment with <b>18c</b>, <b>18d</b> and <b>18f</b>. The most potent hybrid compound <b>18f</b> afforded 82.3% and 88.3% inhibition, respectively, against Cu²⁺- induced and Zn²⁺- induced Aβ_1-42 aggregation. Compounds <b>18c</b>, <b>18d</b> and <b>18f</b> were shown to be effective in reducing protein aggregation in HEK-tau and SY5Y-APP_Sw cells. Molecular docking studies with the most active compounds performed against Aβ_1-42 peptide indicated that the potent inhibitory activity of <b>18d</b> and <b>18f</b> were predicted to be due to hydrogen bonding interactions, π-π stacking interactions and π-cation interactions with Aβ_1-42, which may inhibit both self-aggregation as well as metal ion binding to Aβ_1-42 to favor the inhibition of Aβ_1-42 aggregation.