Evaluation of the antifungal potential of N, N chelating iridium(III) complexes

Candida species are opportunistic yeasts and the leading cause of invasive fungal infections in hospitals. These infections are associated with high morbidity and mortality and impose a significant burden on patients and healthcare systems. Their severity is exacerbated by the limited number of effective therapeutics and the growing prevalence of antifungal resistance, underscoring the urgent need for agents with novel mechanisms of action. In this work, we synthesized two half-sandwich iridium(III) complexes with the general formula [Ir(η⁵-Cp*)Cl(N, N)]X, where the N, N-chelating ligand is 1,10-phenanthroline-5,6-dione. The complexes differ only in the counterion (X): triflate for Ir1 and chloride for Ir2. Both complexes exhibited activity against all tested medically relevant fungi; however, their antifungal potency was strongly influenced by the nature of the counterion, with the triflate-containing complex Ir1 displaying superior efficacy and MIC values ranging from 0.3 to 0.5 µM against Candida spp. In vitro, Ir1 outperformed the clinically used antifungals caspofungin and fluconazole and retained activity against fluconazole-resistant strains. Ir1 also inhibited biofilm formation and appears to act, at least in part, by inducing reactive oxygen species (ROS). Remarkably, Ir1 exhibited low in vivo toxicity and effectively treated invasive Candida albicans infections in a zebrafish embryo model of disseminated candidiasis.