active organometallic-containing antimycotic agents.

Fungal infections represent a global problem, notably for immunocompromised patients in hospital, COVID-19 patient wards and care home settings, and the ever-increasing emergence of multidrug resistant fungal strains is a sword of Damocles hanging over many healthcare systems. Azoles represent the mainstay of antifungal drugs, and their mode of action involves the binding mode of these molecules to the fungal lanosterol 14α-demethylase target enzyme. In this study, we have prepared and characterized four novel organometallic derivatives of the frontline antifungal drug fluconazole (). Very importantly, enzyme inhibition and chemogenomic profiling demonstrated that lanosterol 14α-demethylase, as for fluconazole, was the main target of the most active compound of the series, (-(ferrocenylmethyl)-2-(2,4-difluorophenyl)-2-hydroxy--methyl-3-(1-1,2,4-triazol-1-yl)propan-1-aminium chloride, ). Transmission electron microscopy (TEM) studies suggested that induced a loss in cell wall integrity as well as intracellular features ascribable to late apoptosis or necrosis. The impressive activity of was further confirmed on clinical isolates, where antimycotic potency up to 400 times higher than fluconazole was observed. Also, showed activity towards azole-resistant strains. This finding is very interesting since the primary target of is the same as that of fluconazole, emphasizing the role played by the organometallic moiety. experiments in a mice model of infections revealed that reduced the fungal growth and dissemination but also ameliorated immunopathology, a finding suggesting that is active with added activity on the host innate immune response.