Discovery of highly potent triazole antifungal derivatives by heterocycle-benzene bioisosteric replacement

On the basis of our previously discovered triazole antifungal lead compounds, heterocycle-benzene bioisosteric replacement was used to improve their pharmacokinetic profile. The designed new triazole derivatives have good antifungal activity toward a wide range of pathogenic fungi. Their binding mode with the target enzyme was clarified by molecular docking. The MIC value of the highly potent compound 8f against Candida albicans, Candida tropicalis, and Gyptococcus neoformans is 0.016 mu g/mL, 0.004 mu g/mL, and 0.016 mu g/mL, respectively. Moreover, preliminary pharmacokinetic studies revealed that it showed improved oral absorption as compared to the lead compound iodiconazole and deserved for further evaluations. (C) 2013 Elsevier Masson SAS. All rights reserved.