Abstract

Azole antifungals are an important class of antifungal drugs due to their low cost, ability to be administered orally, and broad-spectrum activity. However, their widespread and long-term use have given rise to adaptation mechanisms that render these compounds less effective against common fungal pathogens, including Candida albicans. New antifungals are desperately needed as drug-resistant strains become more prevalent. We recently showed that copper supplementation potentiates the activity of the azole antifungal fluconazole against the opportunistic fungal pathogen C. albicans. Here, we report eight new azole analogues derived from fluconazole in which one triazole group has been replaced with a metal-binding group, a strategy designed to enhance potentiation of azole antifungal activity by copper. The bioactivity of all eight compounds was tested and compared to that of fluconazole. Three of the analogues showed activity against C. albicans and two had lower levels of trailing growth. One compound, Flu-TSCZ, was found to impact the levels, speciation, and bioavailability of cellular metals.

Graphic abstract

中文翻译：

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具有金属结合基序的氟康唑类似物会影响金属依赖性过程，并在白色念珠菌中表现出抗真菌活性。

摘要

唑类抗真菌药因其成本低、口服给药和广谱活性而成为一类重要的抗真菌药物。然而，它们的广泛和长期使用已经产生了适应机制，使得这些化合物对抗常见真菌病原体（包括白色念珠菌）的效果较差。随着耐药菌株变得更加普遍，迫切需要新的抗真菌药物。我们最近表明，补充铜可以增强唑类抗真菌药物氟康唑对抗机会性真菌病原体白色念珠菌的活性。在这里，我们报告了八种新的由氟康唑衍生的唑类类似物，其中一个三唑基团被金属结合基团取代，这是一种旨在增强铜增强唑类抗真菌活性的策略。测试了所有八种化合物的生物活性，并与氟康唑的生物活性进行了比较。其中三种类似物显示出抗白色念珠菌的活性，两种类似物具有较低水平的拖尾生长。人们发现一种化合物 Flu-TSCZ 会影响细胞金属的水平、形态和生物利用度。

图文摘要