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

Molecules. 2020 Aug 8;25(16):3610. doi: 10.3390/molecules25163610.


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 Aβ1-42 aggregation as potential treatments for Alzheimer's disease (AD). In vitro studies identified the most inhibitory compounds against self-induced Aβ1-42 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 Aβ1-42 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 Aβ1-42 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 Aβ1-42 peptide indicated that the potent inhibitory activity of 18d and 18f were predicted to be due to hydrogen bonding interactions, π-π stacking interactions and π-cation interactions with Aβ1-42, which may inhibit both self-aggregation as well as metal ion binding to Aβ1-42 to favor the inhibition of Aβ1-42 aggregation.

Keywords: Alzheimer’s disease; Aβ-aggregation; clioquinol analogues; hybrid 8-hydroxyquinoline-indole analogs; metal chelating agents.

MeSH terms

  • Amyloid beta-Peptides / chemistry*
  • Chelating Agents / chemistry*
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • HEK293 Cells
  • Humans
  • Indoles / chemistry*
  • Models, Molecular
  • Oxyquinoline / chemical synthesis
  • Oxyquinoline / chemistry*
  • Oxyquinoline / pharmacology*
  • Peptide Fragments / chemistry*
  • Protein Aggregates / drug effects*
  • Protein Structure, Secondary


  • Amyloid beta-Peptides
  • Chelating Agents
  • Indoles
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • Oxyquinoline