The development of half-sandwich arene ruthenium(II) complexes with antifungal activity against resistant Candida albicans.

The escalating threat of drug-resistant fungal infections, particularly invasive candidiasis caused by Candida albicans, demands the development of novel antifungal agents. Herein, we report the synthesis and evaluation of a series of half-sandwich arene ruthenium(II) complexes bearing polypyridyl ligands. Among them, a lead complex Ru-6 [(η6-p-cymene)Ru(Br-Me-dppz)Cl]PF6, with Br-Me-dppz = 11-bromo-12- methyldipyrido [3,2-a:2',3'-c] phenazine, exhibited potent and broad-spectrum antifungal activity against C. albicans and other drug-resistant fungal pathogens. Ru-6 showed superior in vitro fungicidal activity compared with fluconazole, low hemolytic activity against mammalian red blood cells (HC50 > 81.22 μM), and a favorable selectivity index (IC50 ≈ 28.3 μM in HEK 293 T cells). Time-kill assays confirmed its rapid, concentration-dependent fungicidal action. Furthermore, Ru-6 demonstrated synergistic effects with fluconazole (FLC) and amphotericin B (AmB) and showed a low propensity to induce resistance in C. albicans over 20 serial passages. These results highlight half-sandwich arene ruthenium(II) polypyridyl complexes, particularly Ru-6, as promising lead candidates for combating resistant fungal infections.