Design, synthesis and bioactivity evaluation of triazole antifungal drugs with phenylthiophene structure

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-09-06 DOI:10.1016/j.bioorg.2024.107785

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Abstract

Invasive fungal infections have high morbidity and mortality rates and have become one of the most serious threats to human health. In the present study, a series of triazole antifungal derivatives with phenylthiophene backbone were obtained by structural modification of the lead compound using Iodiconazole as the lead compound. Among them, compound 19g is a triazole antifungal compound with 4-chloro-2-fluoro phenylthiophene backbone, which showed optimal antifungal activity against Candida albicans, Cryptococcus neoformans, and Aspergillus, with a MIC₈₀ value of 0.0625 μg/mL. In addition, compounds 19e, 19f, 19g, 19h, 19i and 19k exhibited different levels of inhibitory activity against fluconazole-resistant strains with MIC₈₀ values ranging from 0.0625 μg/mL to 32 μg/mL. Since compound 19g had optimal in vitro antifungal activity, we selected 19g for human liver microsomal stability and CYP enzyme inhibition assays as well as further evaluated the inhibitory activity of compound 19g on normal and cancerous cells in humans. Finally, we verified the inhibitory effect of compound 19g on the filamentation of Candida albicans and determined the mechanism of action by sterol composition analysis.

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苯基噻吩结构三唑类抗真菌药物的设计、合成和生物活性评价

侵袭性真菌感染具有很高的发病率和死亡率，已成为人类健康最严重的威胁之一。本研究以碘环唑为先导化合物，通过对先导化合物进行结构改造，获得了一系列以苯基噻吩为骨架的三唑类抗真菌衍生物。其中，化合物 19g 是一种以 4-氯-2-氟苯基噻吩为骨架的三唑类抗真菌化合物，对白色念珠菌、新型隐球菌和曲霉菌具有最佳的抗真菌活性，其 MIC80 值为 0.0625 μg/mL。此外，化合物 19e、19f、19g、19h、19i 和 19k 对氟康唑耐药菌株具有不同程度的抑制活性，MIC80 值从 0.0625 μg/mL 到 32 μg/mL。由于化合物 19g 具有最佳的体外抗真菌活性，我们选择 19g 进行了人体肝微粒体稳定性和 CYP 酶抑制实验，并进一步评估了化合物 19g 对人体正常细胞和癌细胞的抑制活性。最后，我们验证了化合物 19g 对白色念珠菌菌丝的抑制作用，并通过甾醇成分分析确定了其作用机制。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.