2. Academic Validation
  3. Discovery of BRD4-HDAC Dual Inhibitors with Improved Fungal Selectivity and Potent Synergistic Antifungal Activity against Fluconazole-Resistant Candida albicans

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

  • J Med Chem. 2023 Apr 27;66(8):5950-5964. 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
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, People's Republic of China.
  • 3 Department of Pharmacology and Toxicology, College of Pharmacy, and BIO5 Institute, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721-0207, United States.
PMID: 37037787 DOI: 10.1021/acs.jmedchem.3c00165
Abstract

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.

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