The extensive use of fluconazole (FLC) and other azole drugs has caused the emergence and rise of azole-resistant fungi. The fungistatic nature of FLC in combination with toxicity concerns have resulted in an increased demand for new azole antifungal agents. Herein, we report the synthesis and antifungal activity of novel alkylated piperazines and alkylated piperazine-azole hybrids, their time-kill studies, their hemolytic activity against murine erythrocytes, as well as their cytotoxicity against mammalian cells. Many of these molecules exhibited broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against non-albicans Candida and Aspergillus strains. The most promising compounds were found to be less hemolytic than the FDA-approved antifungal agent voriconazole (VOR). Finally, we demonstrate that the synthetic alkylated piperazine-azole hybrids do not function by fungal membrane disruption, but instead by disruption of the ergosterol biosynthetic pathway via inhibition of the 14α-demethylase enzyme present in fungal cells.

中文翻译：

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烷基化哌嗪和哌嗪-Azole杂化物作为抗真菌剂

氟康唑（FLC）和其他唑类药物的广泛使用已引起抗唑类真菌的出现和增加。FLC的抑真菌性质与毒性问题相结合，导致对新的唑类抗真菌剂的需求增加。在本文中，我们报告了新型烷基化哌嗪和烷基化哌嗪-唑杂化物的合成和抗真菌活性，它们的时间杀灭研究，它们对鼠红细胞的溶血活性以及它们对哺乳动物细胞的细胞毒性。这些分子中的许多对所有测试的真菌菌株均表现出广谱活性，对非白色念珠菌和曲霉具有极佳的最小抑菌浓度（MIC）值。株。发现最有前途的化合物的溶血性低于FDA批准的抗真菌药伏立康唑（VOR）。最后，我们证明了合成的烷基化哌嗪-唑杂化物不是通过真菌膜破坏来起作用，而是通过抑制真菌细胞中存在的14α-脱甲基酶来破坏麦角固醇的生物合成途径。