Synthesis, Stability Studies, and Antifungal Evaluation of Substituted α- and β-2,3-Dihydrofuranaphthoquinones against and .

Sporotrichosis is a neglected fungal infection caused by spp., which have a worldwide distribution. The standard antifungal itraconazole has been recommended as a first-line therapy. However, failure cases in human and feline treatment have been reported in recent years. This study aimed to synthesize several α- and β-2,3-dihydrofuranaphthoquinones and evaluate them against and -the main etiological agents of sporotrichosis in Brazil. The stability of these compounds was also investigated under different storage conditions for 3 months. The samples were removed at 0, 60, and 90 days and assessed by ¹H-NMR, and their in vitro antifungal susceptibility was tested. Furthermore, we evaluated the superficial changes caused by the most effective and stable compounds using scanning electron microscopy and determined their effects when combined with itraconazole. Nine dihydrofuranaphthoquinones showed good antifungal activity and stability, with MIC values of 2⁻32 µM. Compounds and were the most active dihydrofuranaphthoquinones in vitro for both species; in fungi, these compounds induced yeast⁻hyphae conversion and alteration in the hyphae and conidia structures. Compound also exhibited a synergistic activity with itraconazole against , with a ΣFIC index value of 0.3. Our results indicate that Compounds and are potential candidates for the development of new antifungal agents for the treatment of sporotrichosis.