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

Abstract

Based on the structures of the reported compounds G884 [N-(3-(pentan-2-yloxy)phenyl)nicotinamide], E1210 [3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine], and 10 b [2-amino-N-((5-(3-fluorophenoxy)thiophen-2-yl)methyl)nicotinamide], 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 were found to exhibit potent in vitro antifungal activity against Candida albicans, with MIC80 values ranging from 0.0313 to 4.0 μg mL-1 . In particular, compounds 11 g [2-amino-N-((5-(((2-fluorophenyl)amino)methyl)thiophen-2-yl)methyl)nicotinamide] and 11 h [2-amino-N-((5-(((3-fluorophenyl)amino)methyl)thiophen-2-yl)methyl)nicotinamide] displayed excellent activity against C. albicans, with MIC80 values of 0.0313 μg mL-1 , and exhibited broad-spectrum antifungal activity against fluconazole-resistant C. albicans, C. parapsilosis, C. glabrata, and Cryptococcus neoformans, with a MIC80 range of 0.0313-2.0 μg mL-1 . Further studies by electron microscopy and laser confocal microscopy indicated that compound 11 g targets the cell wall and decreases GPI anchor content on the cell surface of C. albicans.