Design, synthesis, and activity evaluation of novel tetrazole-based CYP51 inhibitors

Invasive fungal infections remain a major clinical challenge due to their high incidence and mortality rates. Azole antifungal agents, such as fluconazole (FLC), have been widely used as first-line treatments owing to their broad-spectrum efficacy and relatively favorable safety profiles. However, a significant limitation of these drugs is their potent inhibition of human CYP3A4, which often leads to severe drug-drug interactions (DDIs). To address this issue, compound 17a, a triazole-derived lead, was selected for the design and synthesis of 26 novel tetrazole derivatives. Among these, compound T24 demonstrated potent and broad-spectrum antifungal activity, including efficacy against drug-resistant fungal strains. Additionally, T24 exhibited fungicidal activity against Candida parapsilosis, anti-biofilm activity, and the ability to inhibit fungal morphological transitions. Importantly, T24 showed no significant cytotoxicity toward human tumor cell lines or normal human cells. Most critically, in vitro CYP inhibition assays revealed that T24 did not significantly inhibit five major CYP isoforms, including CYP3A4, which is primarily responsible for azole-related drug interactions. These findings suggest that T24 represents a promising candidate for the development of next-generation antifungal agents with improved therapeutic indices and reduced risk of drug interactions.