Discovery of novel triazine thiosemicarbazide derivatives as potential synergists for combating invasive candidiasis.

Invasive candidiasis, particularly those caused by drug-resistant Candida albicans, poses a serious threat worldwide. To develop novel antifungal agents, a series of triazine thiosemicarbazide derivatives were designed and synthesized via structure optimization. Structure-activity relationship analysis revealed that the thiosemicarbazide moiety is essential for synergistic antifungal activity. Notably, compound A21 exhibited excellent synergistic effects with fluconazole (FCZ) against resistant C. albicans (lowest FICI range: 0.002-0.005), restoring the efficacy of other azoles and showing monotherapy activity against Candida glabrata (MIC = 1 μg/mL) and Cryptococcus neoformans (MIC = 4 μg/mL). Mechanistically, A21 reversed FCZ resistance by downregulating ERG genes, as well as drug resistance- and virulence-related genes, when combined with FCZ. With enhanced metabolic stability in human liver microsomes (HLM) and mouse liver microsomes (MLM) and a favorable safety profile, A21 in combination with FCZ displayed potent in vivo efficacy against Galleria mellonella and mice infected with resistant C. albicans. Therefore, A21 represents a promising lead for combating resistant candidiasis.