Discovery of New Pyrazolone Carbothioamide Derivatives as Potent Antifungal Agents for the Treatment of Candidiasis and Cryptococcosis
Tingting Liang, Jie Tu, Qianqian He, Piaopiao Zou, Wanzhen Yang, Yahui Huang, Na Liu, Chunquan Sheng
Abstract
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 1, a series of new pyrazolone-carbothioamide derivatives were designed and assayed. In particular, compound A7 showed picomolar in vitro antifungal activity against Candida glabrata (MIC = 0.00012 μg/mL) and Cryptococcus neoformans (MIC = 0.00012 μg/mL), with excellent antivirulence effects. In the murine candidiasis and cryptococcosis models, compound A7 exhibited potent in vivo therapeutic efficacy. Interestingly, a mechanism investigation revealed that the antifungal activity of compound A7 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 A7 represents a promising lead with a new mechanism of action to combat candidiasis and cryptococcosis.