Discovery of Novel 8-Hydroxyquinoline Derivatives with Potent In Vitro and In Vivo Antifungal Activity

J Med Chem. 2023 Dec 14;66(23):16364-16376. doi: 10.1021/acs.jmedchem.3c01771. Epub 2023 Nov 17.

Abstract

Fungal pathogens can cause life-threatening infections, yet current antifungals are inadequate at treating many of these, highlighting the importance of novel drug discovery. Here, we report hit compound L14, a novel 8-hydroxyquinoline derivative with potent and broad-spectrum antifungal activity. In vitro experiments exhibited that L14 had better activity and lower cytotoxicity than that of clioquinol and showed synergy in combination with fluconazole (FLC). In a Candida albicans-infected murine model, L14 at 2 mg/kg showed better in vivo efficacy than clioquinol at reducing fungal burden and extending the survival of C. albicans-infected mice. In addition, L14 alone or in combination with FLC had significant inhibitory activity against hypha and biofilm formation. Overall, our data indicated that 8-hydroxyquinoline derivative L14 has favorable pharmacokinetics and acceptable safety profiles and could be further investigated as a promising antifungal hit compound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antifungal Agents / pharmacology
  • Antifungal Agents / therapeutic use
  • Candida albicans
  • Candidiasis* / drug therapy
  • Candidiasis* / microbiology
  • Clioquinol* / therapeutic use
  • Drug Resistance, Fungal
  • Drug Synergism
  • Fluconazole / pharmacology
  • Mice
  • Microbial Sensitivity Tests
  • Oxyquinoline / pharmacology
  • Oxyquinoline / therapeutic use

Substances

  • Antifungal Agents
  • Clioquinol
  • Fluconazole
  • Oxyquinoline