Invasive fungal infections have become a serious public health problem. To tackle the challenges of limited efficacy in antifungal therapy and severe drug resistance, antifungal drugs with new mechanisms of action are urgently needed. Our previous study identified JIB-04 to be an inhibitor of fungal histone demethylase (HDM). To promote target validation and inhibitor design, herein a series of new JIB-04 derivatives were designed and synthesized. After the establishment of structure-activity relationship, compound A4 was identified to possess potent antifungal activity against Cryptococcus neoformans and Candida auris. Compared to lead compound JIB-04, compound A4 was a more potent HDM inhibitor and exhibited better water solubility, virulence factors inhibitory activity and in vivo antifungal potency. Collectively, this study further confirmed that fungal HDMs were potential antifungal targets and compound A4 was a promising antifungal lead compound.

中文翻译：

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发现新型真菌jumonji H3K27去甲基化酶抑制剂治疗新型隐球菌和耳念珠菌感染


侵袭性真菌感染已成为一个严重的公共卫生问题。为了应对抗真菌治疗疗效有限和严重耐药性的挑战，迫切需要具有新作用机制的抗真菌药物。我们之前的研究发现 JIB-04 是真菌组蛋白去甲基化酶 （HDM） 的抑制剂。为了促进靶点验证和抑制剂设计，本文设计并合成了一系列新的 JIB-04 衍生物。在建立构效关系后，化合物 A4 被鉴定对新型隐球菌和耳念珠菌具有强大的抗真菌活性。与先导化合物 JIB-04 相比，化合物 A4 是一种更有效的 HDM 抑制剂，表现出更好的水溶性、毒力因子抑制活性和体内抗真菌效力。总的来说，这项研究进一步证实了真菌 HDMs 是潜在的抗真菌靶点，化合物 A4 是一种很有前途的抗真菌先导化合物。