BRD4-HDAC 双重抑制剂的发现具有改善的真菌选择性和对氟康唑耐药的. 的强大协同抗真菌活性
Discovery of BRD4-HDAC Dual Inhibitors with Improved Fungal Selectivity and Potent Synergistic Antifungal Activity against Fluconazole-Resistant .
机构信息
State Key Laboratory of Bioengineering Reactor, and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, 130 Meilong Road, Shanghai 200237, China.
Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, People's Republic of China.
出版信息
J Med Chem. 2023 Apr 27;66(8):5950-5964. doi: 10.1021/acs.jmedchem.3c00165. Epub 2023 Apr 10.
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 () to fluconazole (FLC). Interestingly, several compounds showed excellent selectivity against fungal HDACs. In particular, compound showed excellent synergistic effect with FLC against resistant (FICI = 0.063) with high selectivity against fungal HDACs (SI = 1653) and low cytotoxicity. Compound effectively synergized with FLC and prevented biofilm formation and morphological transition in resistant , potentiating the antifungal activity of FLC and significantly reducing kidney fungal loads. Thus, this drug combination is promising in the treatment of resistant infections.
在过去几十年中，由于无效的抗真菌药物和严重的耐药性，侵袭性真菌感染（尤其是念珠菌病）导致发病率和死亡率显著上升。为此，人们设计了新型 BRD4-组蛋白去乙酰化酶（HDAC）抑制剂，以恢复对氟康唑（FLC）的敏感性。有趣的是，一些化合物对真菌 HDAC 表现出优异的选择性。特别是，化合物 对耐药的 （FICI = 0.063）与 FLC 表现出优异的协同作用，对真菌 HDAC 具有高选择性（SI = 1653）和低细胞毒性。化合物 可有效与 FLC 协同作用，防止耐药 形成生物膜和形态转变，增强 FLC 的抗真菌活性，并显著降低肾脏真菌负荷。因此，这种药物组合有望用于治疗耐药 感染。
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