Philippe Guerry

Inhibitors of 2,3-Oxidosqualene-Lanosterol Cyclase as Antifungal Agents

Most known antifungals act on enzymes involved in the biosynthesis of ergosterol, the main sterol in fungi. 2,3-Oxidosqualene-lanosterol cyclase is one of these enzymes; several inhibitors of the enzyme are known, which however have poor antifungal activity. A simple approach based on mechanistic considerations led to the synthesis of potent bifunctional inhibitors of 2,3-oxidosqualene-lanosterol cyclase. These amino-ketones represent the first cyclase inhibitors which also show an effective in vitro activity against a wide range of medically important fungi. A cell-free assay is presented, which allows accurate determination of IC50-values.