Antifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability

Antimicrob Agents Chemother. 2020 Sep 21;64(10):e00899-20. doi: 10.1128/AAC.00899-20. Print 2020 Sep 21.

Abstract

The glycosylphosphatidylinositol anchor biosynthesis inhibitor gepinacin demonstrates broad-spectrum antifungal activity and negligible mammalian toxicity in culture but is metabolically labile. The stability and bioactivity of 39 analogs were tested in vitro to identify LCUT-8, a stabilized lead with increased potency and promising single-dose pharmacokinetics. Unfortunately, no antifungal activity was seen at the maximum dosing achievable in a neutropenic rabbit model. Nevertheless, structure-activity relationships identified here suggest strategies to further improve compound potency, solubility, and stability.

Keywords: Gwt1; candidiasis; glycosylphosphatidylinositol; microsome metabolism; structure-activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antifungal Agents* / pharmacology
  • Antifungal Agents* / therapeutic use
  • Glycosylphosphatidylinositols*
  • Rabbits
  • Structure-Activity Relationship

Substances

  • Antifungal Agents
  • Glycosylphosphatidylinositols