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

Sporotrichosis is a neglected fungal infection caused by Sporothrix 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 Sporothrix schenckii and Sporothrix brasiliensis-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 6 and 10 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 10 also exhibited a synergistic activity with itraconazole against S. schenckii, with a ΣFIC index value of 0.3. Our results indicate that Compounds 6 and 10 are potential candidates for the development of new antifungal agents for the treatment of sporotrichosis.