Synthesis of kanamycin-azole hybrids and investigation of their antifungal activities

The World Health Organization (WHO) recognizes Candida albicans and Cryptococcus neoformans as the critical priority fungal pathogens for which therapeutic solutions are needed. Azole-based antifungal agents, including triazoles, diazoles, and thiazoles, are widely used in the treatments for fungal infections. In light of past successes in the transformation of antibacterial kanamycin into antifungal derivatives via chemical modifications, a new library of kanamycin-azole hybrids was synthesized and tested against a panel of azole-resistant and susceptible Candida and Cryptococcus strains. Structure activity relationship (SAR) studies revealed pivotal roles for antifungal activity of the azole ring (imidazole vs triazole) and halogen substituents on the benzene ring (F vs Cl). Most notably, hybrids 13, 14 and 15 were active against resistant C. albicans, C. tropicalis and C. neoformans strains and non-toxic towards mammalian cells. Mode of action investigations using fluorogenic dyes, (SYTOX^TM) showed the fungal active compounds could permeabilize fungal membranes even at ¼ MICs. These findings reveal novel azole-based antifungals that could offer new therapeutic options for candidiasis and cryptococcosis.