Discovery of New Pyrazolone Carbothioamide Derivatives as Potent Antifungal Agents for the Treatment of Candidiasis and Cryptococcosis

The morbidity and mortality of invasive fungal infections are increasing rapidly. Developing effective and safe antifungal drugs with novel chemical scaffolds and mechanisms is urgently needed. On the basis of our previously identified Pdr1-KIX inhibitor <b>1</b>, a series of new pyrazolone-carbothioamide derivatives were designed and assayed. In particular, compound <b>A7</b> showed picomolar <i>in vitro</i> antifungal activity against <i>Candida glabrata</i> (MIC = 0.00012 μg/mL) and <i>Cryptococcus neoformans</i> (MIC = 0.00012 μg/mL), with excellent antivirulence effects. In the murine candidiasis and cryptococcosis models, compound <b>A7</b> exhibited potent <i>in vivo</i> therapeutic efficacy. Interestingly, a mechanism investigation revealed that the antifungal activity of compound <b>A7</b> is independent of KIX binding. It disrupted the iron homeostasis of fungal cells and then induced oxidative stress damages by accumulating the reactive oxygen species and lipid peroxides. Therefore, compound <b>A7</b> represents a promising lead with a new mechanism of action to combat candidiasis and cryptococcosis.