Design, Synthesis, and Biological Activity Evaluation of Deuterated Diphenyl Azole Alcohol-Based CYP51 Inhibitors

In recent years, the incidence of invasive fungal infections (IFIs) has risen significantly, leading to increased clinical use of azole antifungals. However, their therapeutic utility remains limited by emerging drug resistance, inadequate oral bioavailability, and adverse effects. This study focused on optimizing <i>in vivo</i> pharmacokinetic properties through a molecular hybridization strategy, integrating structural features of <b>Oteseconazole</b> and <b>A33</b>. After multiple rounds of structural refinement, a series of deuterated biphenyl aryl azolol derivatives were developed. Compound <b>C52</b> demonstrated potent broad-spectrum antifungal activity <i>in vitro</i>, antibiofilm properties, and inhibition of fungal morphological transition. Notably, it exhibited favorable pharmacokinetic characteristics, with an oral bioavailability (F) of 63.4%. <i>In vivo</i> efficacy studies revealed that the compound significantly prolonged survival in murine models and maintained potent activity against drug-resistant strain <i>17</i>^<i>#</i>. These findings position compound <b>C52</b> as a promising CYP51-targeting candidate for treating IFIs, establishing a robust chemical foundation for developing next-generation antifungal therapeutics.