Synthesis and Biological Evaluation of Novel 2‐Aminonicotinamide Derivatives as Antifungal Agents

Based on the structures of the reported compounds G884, E1210, and 10b which inhibit the biosynthesis of glycosylphosphatidylinositol (GPI)-anchored proteins in fungi, a series of novel 2-aminonicotinamide derivatives were designed, synthesized and evaluated for in vitro antifungal activity. Most of these compounds exhibited potent in vitro antifungal activity against Candida albicans with MIC80 values ranging from 0.0313 to 4.0 µg/mL. Especially, compounds 11g and 11h displayed excellent activity against Candida albicans with MIC80 values of 0.0313 µg/mL, and exhibited broad-spectrum antifungal activity against fluconazole-resistant Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Candida glabrata with MIC80 a range of 0.0313 ~ 2.0 µg/mL. Further reaserch by electron microscopy and laser confocal microscopy indicated that compound 11g targeted the cell wall and decreased GPI anchor content on the cell surface of C. albicans.