TY - JOUR
T1 - Discovery of BRD4-HDAC Dual Inhibitors with Improved Fungal Selectivity and Potent Synergistic Antifungal Activity against Fluconazole-Resistant Candida albicans
AU - Li, Zhuang
AU - Huang, Yahui
AU - Tu, Jie
AU - Yang, Wanzhen
AU - Liu, Na
AU - Wang, Wei
AU - Sheng, Chunquan
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (grant no. 21907106 to Y.H. and grant no. 81725020 to C.S.) and the Innovation Program of Shanghai Municipal Education Commission (grant no. 2019-01-07-00-07-E00073 to C.S.).
Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/4/27
Y1 - 2023/4/27
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.3c00165
DO - 10.1021/acs.jmedchem.3c00165
M3 - Article
C2 - 37037787
AN - SCOPUS:85152684538
SN - 0022-2623
VL - 66
SP - 5950
EP - 5964
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 8
ER -