The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action.

当前市场上与唑类药物有关的对真菌的性质和毒性的关注导致对新的唑类抗真菌剂的需求增加，而这些新的唑类抗真菌剂不存在这些问题特征。唑类的广泛使用已导致能够抵抗这些药物作用的真菌菌株。本文中，我们报道了具有烷基，芳基，环烷基和二烷基氨基取代基的新型氟康唑（FLC）类似物的合成和抗真菌活性。我们通过MIC测定和时间杀灭试验评估了它们的抗真菌活性，并通过对鼠红细胞的溶血活性以及对哺乳动物细胞的细胞毒性评估了它们的安全性。我们研究中最好的化合物对大多数测试的真菌菌株均表现出广谱活性，具有针对许多临床分离株的优异MIC值。发现最有前途的化合物的溶血性低于溶血性最低的FDA批准的唑类抗真菌药伏立康唑（VOR）。最后，我们证明了合成的烷基-氨基FLC类似物显示出链依赖性真菌膜破坏以及麦角固醇生物合成的抑制作为可能的作用机理。