Developing Novel Coumarin-Containing Azoles Antifungal Agents by the Scaffold Merging Strategy for Treating Azole-Resistant Candidiasis

氟康唑 化学 微生物学 生物膜 抗真菌药 抗药性 药理学 白霉素类 体内 抗真菌 生物 细菌 生物技术 卡斯波芬金 遗传学
作者
Zhong-zuo Yan,Yanxiu Huang,Dongze Zhao,Zengye Li,Xin Wang,Mengbi Guo,Yu Wei,Yitong Wang,Yanhua Mou,Zhuang Hou,Chun Guo
出处
期刊:Journal of Medicinal Chemistry [American Chemical Society]
卷期号:66 (18): 13247-13265 被引量:12
标识
DOI:10.1021/acs.jmedchem.3c01254
摘要

The extensive use of antifungal drugs has resulted in severe drug resistance, making clinical treatment of fungal infections more difficult. Biofilm inhibitors can overcome drug resistance by inhibiting fungal biofilm formation. In this study, some coumarins with antibiofilm activity were merged into CYP51 inhibitors to produce novel molecules possessing potent antiresistance activity. As expected, most compounds exhibited excellent in vitro antifungal activity against pathogenic fungi, especially fluconazole-resistant candidiasis. Then, their mechanism was confirmed by sterol composition analysis and morphological observation. Biofilm inhibition and down-regulation of resistance-related genes were employed to confirm the compounds' antiresistance mechanisms. Significantly, compound A32 demonstrated fungicidal activity against fluconazole-resistant strain 904. Most importantly, compound A32 showed potent in vivo antifungal activity against pathogenic fungi and fluconazole-resistant strains. Preliminary pharmacokinetic and toxicity tests demonstrated that the compounds possessed favorable druggability. Taken together, compound A32 represents a promising lead to develop novel antifungal agents for treating azole-resistant candidiasis.
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