When azoles meet silver: A chemistry power duo against fungi

Abstract

Azole derivatives represent one of the most important classes of antifungal agents, acting as inhibitors of fungal cytochrome P450-dependent lanosterol 14α-demethylase, a key enzyme involved in ergosterol biosynthesis. The coordination of azoles with silver(I) ions has attracted growing attention as the resulting metal complexes can exhibit improved biological activity and therapeutic profiles compared to the parent ligands. This article reports on the synthesis, structural characterization, and biological evaluation of silver(I) complexes with selected azoles used in the treatment of fungal infections (clotrimazole, econazole, and voriconazole). The synthesized complexes were characterized using NMR, IR, and UV-Vis spectroscopy, mass spectrometry, and cyclic voltammetry, while their crystal structures were determined by single-crystal X-ray diffraction analysis. In most cases, the synthesized complexes showed enhanced anti-Candida activity compared to the parent antifungal azoles. Moreover, the corresponding silver(I) complexes demonstrated better activity in preventing hyphae and biofilm formation by C. albicans at subinhibitory concentrations, which is a highly desirable property for a new antimicrobial agent. In addition, these complexes were significantly more effective at inhibiting ergosterol synthesis in the cell membrane of C. albicans at 0.5 × MIC. Taken together, these findings suggest that compounds formed via the complexation of silver(I) ions with antifungal azoles merit further investigation as potential new antifungal agents, offering improved efficacy and safety over clinically used azoles in the treatment of life-threatening Candida infections.