Biological Activity of Silver(I)-1,10-Phenanthroline Complexes Against Fonsecaea pedrosoi: In Silico Predictions, In Vitro Macrophage Interactions and In Vivo Efficacy in Galleria mellonella

<b>Background/Objectives:</b><i>Fonsecaea pedrosoi</i> causes chromoblastomycosis, a neglected chronic subcutaneous mycosis that remains difficult to treat. In this study, we evaluated the toxicity and the antifungal effect of [Ag(1,10-phenanthroline)₂]ClO₄ (Ag-phen) and [Ag₂(3,6,9-trioxaundecanedioate)(1,10-phenanthroline)₄]·EtOH (Ag-tdda-phen) against <i>F. pedrosoi</i> using in silico, in vitro and in vivo approaches. <b>Methods:</b> Pharmacokinetic and toxicological parameters were predicted using ADMETlab 2.0. The toxicity of the complexes was assessed using sheep red blood cells, RAW 264.7 macrophage cells, and larvae of <i>Tenebrio molitor</i> and <i>Galleria mellonella</i>. The effects of these complexes on macrophage adhesion capacity and reactive oxygen species (ROS) production were also investigated using Giemsa staining and dichlorofluorescein diacetate, respectively. In addition, their impact on the survival of <i>G. mellonella</i> larvae infected with conidia was evaluated. <b>Results:</b> Overall, computational analyses predicted favorable tolerability profiles for both complexes. In vitro assays with red blood cells and macrophages demonstrated that they exhibited selectivity indexes >10 against <i>F. pedrosoi.</i> These findings were corroborated by in vivo experiments in which both complexes were injected into insect larvae; the complexes demonstrating good tolerability at concentrations of up to 500 mg/L. Macrophage infection assays revealed that Ag-tdda-phen and Ag-phen markedly reduced the number of intracellular conidia. These effects appear to be associated with oxidative stress, as macrophage production of ROS significantly increased following treatment with the complexes. Furthermore, Ag-tdda-phen improved the survival of <i>G. mellonella</i> larvae infected with <i>F. pedrosoi</i>, demonstrating a protective effect. <b>Conclusions:</b> Collectively, our findings support the notion that silver(I)-phen derivatives represent promising candidates for the development of therapeutic options against CBM infections caused by <i>F. pedrosoi</i>.