Exploration of piperazine-azole hybrids as antifungal agents against drug-resistant Candida albicans.

Candida albicans infections pose a growing threat to public health due to the rising prevalence of drug-resistant strains driven by the widespread use of antifungals. There is an urgent need to develop new agents capable of overcoming resistance. In this study, we designed and synthesized a series of novel piperazine-azole derivatives and evaluated their efficacy against fluconazole-resistant C. albicans. Among these, compound 5p demonstrated potent broad-spectrum antifungal activity and a unique dual-mechanism of action: it simultaneously disrupts the Ras/cAMP/PKA pathway by downregulating TPK2 to suppress hyphal formation and inhibits ergosterol biosynthesis via suppression of ERG3, ERG5, and ERG6. This dual targeting leads to ergosterol depletion, severe membrane disruption, and impaired cell wall integrity, culminating in rapid fungicidal activity superior to that of FLC. In a murine model of systemic candidiasis, 5p significantly enhanced survival, reduced fungal load in the kidneys, and strengthened host immune responses. These results highlight 5p as a promising multi-target lead compound for treating resistant fungal infections.