Identification of novel and potent triazoles targeting CYP51 for antifungal: Design, synthesis, and biological study

Invasive fungal infections (IFIs) are emerging as a serious infectious disease worldwide. Due to the lack of effective antifungal drugs and serious drug resistance, the number of people with low immunity is increasing, leading to high morbidity and mortality. Azole drugs targeting CYP51 are widely used in the treatment of invasive fungal infections. By analyzing representative azole antifungal drugs, the characteristics of pharmacophore were summarized. The binding mode of lead compound Iodiconazole was analyzed, and it was found that the narrow hydrophobic cavity was not fully occupied. Therefore, a series of triazole compounds were designed and synthesized by fragment growth strategy. Most of the compounds showed strong inhibitory activity against pathogenic fungi, among which compound A33 showed excellent inhibitory activity against pathogenic fungi and drug-resistant strains. In addition, the preferred compound A33 can prevent fungal phase transition, the formation of fungal biofilm, and show satisfactory fungicidal activity. In addition, the compound A33 was almost non-toxic to mammalian HUVEC cell. These results strongly suggested that compound A33 was worth further investigation as a potential azole inhibitor. [Display omitted] •Based on the Iodiconazole, a series of novel CYP51 inhibitors were designed and synthesized.•Compound A33 exhibited excellent antifungal activities against pathogenic fungi.•Compound A33 displayed potent antifungal activities on against FLC-resistant strain.•Compound A33 inhibited the formation of fungal biofilm.•Compound A33 demonstrated excellent fungicidal activity.