Discovery of highly potent novel antifungal azoles by structure-based rational design

Abstract

On the basis of the active site of lanosterol 14alpha-demethylase from Candida albicans (CACYP51), a series of new azoles were designed and synthesized. All the new azoles show excellent in vitro activity against most of the tested pathogenic fungi, which represent a class of promising leads for the development of novel antifungal agents. The MIC(80) value of compounds 8c, 8i and 8n against C. albicans is 0.001 microg/mL, indicating that these compounds are more potent than fluconazole, itraconazole and voriconazole. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the compounds. The designed compounds interact with CACYP51 through hydrophobic, van der Waals and hydrogen-bonding interactions.