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

Abstract

In pursuit of developing novel azole antifungals with potent activity and high selectivity, a series of (2<i>R</i>,3<i>S</i>)-3-(substituted-1<i>H</i>-pyrazol-3-yl)-2-(2,4-difluorophenyl)-1-(1<i>H</i>-tetrazol-1-yl)butan-2-ol derivatives were designed and synthesized based on our previous work. All compounds exhibited excellent <i>in vitro</i> antifungal activities against <i>Candida</i> spp. and <i>Cryptococcus neoformans</i> H99 with minimum inhibitory concentration values ranging from <0.008 to 4 μg/mL, with some even showing moderate activity against <i>Aspergillus fumigatus</i> 7544. The most active compounds (<b>8</b>, <b>11</b>, <b>15</b>, <b>24</b>, and <b>25)</b> displayed outstanding antifungal activity against six fluconazole-resistant <i>C. auris</i> clinical isolates and showed a potent inhibitory effect on biofilm formation of <i>C. albicans</i> SC5314 and <i>C. neoformans</i> H99. In addition, compounds <b>11</b> and <b>15</b> 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 <i>in vitro</i> potency and good safety profiles warrant further investigation.