Click Chemistry Approach to Derivatisation of Fluconazole

The emergence of antimicrobial resistance necessitates the development of structurally novel agents with improved biological profiles. In this study, a series of new derivatives of fluconazole were designed, synthesized, and evaluated for antifungal activity. The synthetic approach involved esterification of hydroxyl group of fluconazole with an azide-group-containing benzoyl chloride, followed by copper-catalyzed azide–alkyne cycloaddition (CuAAC). The optimized catalytic system was based on a copper(I) catalyst generated from copper(II) palmitate and ascorbic acid. The transformations of the azide-containing derivatives were then performed. The obtained compounds were tested against reference strains of clinically relevant Candida spp., including C. albicans ATCC 10231, C. parapsilosis ATCC 22019, C. krusei ATCC 14243, C. auris CDC B11903, C. tropicalis ATCC 1369, C. glabrata ATCC 15126, and C. lusitaniae ATCC 3449. Some of the obtained derivatives showed very low toxicity in the MTT-based cell viability assay while maintaining high antifungal activity against selected strains.