Discovery of BRD4–HDAC Dual Inhibitors with Improved Fungal Selectivity and Potent Synergistic Antifungal Activity against Fluconazole-Resistant Candida albicans,Journal of Medicinal Chemistry

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Discovery of BRD4–HDAC Dual Inhibitors with Improved Fungal Selectivity and Potent Synergistic Antifungal Activity against Fluconazole-Resistant Candida albicans
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-04-10 , DOI: 10.1021/acs.jmedchem.3c00165
Zhuang Li ₁ , Yahui Huang ₂ , Jie Tu ₂ , Wanzhen Yang ₂ , Na Liu ₂ , Wei Wang _{1,

3} , Chunquan Sheng ₂

Affiliation

Over the past several decades, invasive fungal infections, especially candidiasis, have caused dramatic morbidity and mortality due to ineffective antifungal drugs and severe drug resistance. Herein, new BRD4–histone deacetylase (HDAC) inhibitors were designed to restore the susceptibility of Candida albicans (C. albicans) to fluconazole (FLC). Interestingly, several compounds showed excellent selectivity against fungal HDACs. In particular, compound B2 showed excellent synergistic effect with FLC against resistant C. albicans (FICI = 0.063) with high selectivity against fungal HDACs (SI = 1653) and low cytotoxicity. Compound B2 effectively synergized with FLC and prevented biofilm formation and morphological transition in resistant C. albicans, potentiating the antifungal activity of FLC in vivo and significantly reducing kidney fungal loads. Thus, this drug combination is promising in the treatment of resistant C. albicans infections.

中文翻译：

发现 BRD4-HDAC 双重抑制剂，具有改进的真菌选择性和对氟康唑耐药的白色念珠菌的有效协同抗真菌活性

在过去的几十年里，侵袭性真菌感染，尤其是念珠菌病，由于抗真菌药物无效和严重的耐药性，导致了显着的发病率和死亡率。在此，新的 BRD4-组蛋白脱乙酰酶 (HDAC) 抑制剂旨在恢复白色念珠菌( C. albicans ) 对氟康唑 (FLC) 的敏感性。有趣的是，几种化合物对真菌 HDAC 表现出出色的选择性。特别是，化合物B2与 FLC 对抗性白色念珠菌(FICI = 0.063) 表现出优异的协同作用，对真菌 HDACs (SI = 1653) 具有高选择性和低细胞毒性。化合物B2与 FLC 有效协同作用，阻止耐药白色念珠菌的生物膜形成和形态转变，增强 FLC在体内的抗真菌活性，显着降低肾脏真菌负荷。因此，这种药物组合有望用于治疗耐药性白色念珠菌感染。

更新日期：2023-04-10

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