Discovery of Novel Tetrazoles Featuring a Pyrazole Moiety as Potent and Highly Selective Antifungal Agents.

In pursuit of developing novel azole antifungals with potent activity and high selectivity, a series of (2,3)-3-(substituted-1-pyrazol-3-yl)-2-(2,4-difluorophenyl)-1-(1-tetrazol-1-yl)butan-2-ol derivatives were designed and synthesized based on our previous work. All compounds exhibited excellent antifungal activities against spp. and H99 with minimum inhibitory concentration values ranging from <0.008 to 4 μg/mL, with some even showing moderate activity against 7544. The most active compounds (, , , , and displayed outstanding antifungal activity against six fluconazole-resistant clinical isolates and showed a potent inhibitory effect on biofilm formation of SC5314 and H99. In addition, compounds and showed no inhibition of human CYP1A2 and low inhibitory activity against CYP3A4, indicating minimal risk of drug-drug interactions. Taken together, these promising tetrazoles with high potency and good safety profiles warrant further investigation.