Vasicine-Based Synergistic Antifungal Agents against FLC-Resistant Candida albicans Targeting Ras/cAMP/PKA Pathway

A series of novel vasicine-based derivatives were designed and synthesized, and in vitro antifungal activities were evaluated. Most compounds showed synergistic antifungal effects with fluconazole (FLC) against FLC-resistant C. albicans . Compound 3n exhibited the best activity (MIC 50 = 1.29 μM, FICI = 0.01) with no obvious cytotoxicity to 16HBE cells. Mechanistic studies revealed that 3n combined with FLC inhibited biofilm formation and efflux pump activity, and synergistically targeted the Ras/cAMP/PKA pathway to block yeast-to-hyphae transition. This dual mechanism provides a new strategy for treating FLC-resistant C. albicans infections.