Combating fluconazole-resistant fungi with novel β-azole-phenylacetone derivatives

A series of β-azole-phenylacetone derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible fungal infections and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against five susceptible strains and five fluconazole-resistant strains. Antifungal activity tests showed that most of the compounds exhibited excellent antifungal activities against five pathogenic strains with MIC values in the range of 0.03–1  μ g/mL. Compounds with R 1  = 3-F substituted and 15o and 15ae exhibited moderate antifungal activities against fluconazole-resistant strains 17# and CaR with MIC values in the range of 1–8  μ g/mL. Compounds with R 1  = H or 2-F (such as 15a , 15o , 15p ) displayed moderate to good antifungal activity against fluconazole-resistant strains 632 , 901 and 904 with MIC values in the range of 0.125–4  μ g/mL. Notably, 15o and 15ae exhibited antifungal activity against five susceptible strains and five fluconazole-resistant strains. Preliminary mechanistic studies showed that the potent antifungal activity of compound 15ae stemmed from inhibition of C. albicans CYP51 . Compounds 15o , 15z and 15ae were nearly nontoxic to mammalian A549 cells.