N(14)-phenyl-substituted evodiamine derivatives for the treatment of superficial fungal infections by inhibiting xanthine dehydrogenase.

The high prevalence and drug resistance of superficial fungal infections (SFIs) pose a serious global public health challenge, urgently necessitating the development of novel antifungal drugs with unique structures and novel targets. Evodiamine derivatives are promising antifungal drug leads, yet they suffer from suboptimal activity and unclear action mechanisms. In this study, a series of N(14)-phenyl evodiamine derivatives were designed, synthesized and tested for their biological activities. Among them, compound 33 exhibited potent antifungal effects against Trichophyton rubrum (T. rubrum) and Trichophyton mentagrophytes (T. mentagrophytes) in vitro. Additionally, compound 33 showed excellent in vivo antifungal efficacy in T. rubrum-infected guinea pigs. Mechanistic studies using pull-down-LC-MS/MS, transcriptome sequencing, enzyme inhibition assays, and xanthine supplementation experiments uncovered that compound 33 potently targets xanthine dehydrogenase (XDH), thereby disrupting the purine metabolism pathway and consequently impairing fungal viability. Notably, compound 33 demonstrated a lower propensity to induce fungal resistance compared to the first-line clinical drug ketoconazole (KCZ) and retained efficacy against KCZ-resistant strains. These results highlight the potential of compound 33 as XDH-targeted agents for treating SFIs.