Antifungal effects of dibenzofuran derivatives against multi-azole resistant Candida albicans.

The emergence of multi-azole resistant Candida albicans strains poses a major therapeutic challenge, largely due to their biofilm formation and hyphal development. In this study, the antifungal and antivirulence properties of 18 dibenzofuran derivatives were evaluated against a multi-azole resistant C. albicans strain. Dibenzofuran-4‑boronic acid (DBFBA) and dibenzofuran-2-carboxaldehyde (DBFC) emerged as the most active compounds, with DBFBA exhibiting the MIC of 30 μg/mL. Both compounds inhibited 94-98% biofilm at 10 μg/mL, suppressed hyphal morphogenesis and impaired cell aggregation at sub-MICs (5 μg/mL). DBFBA and related boronic acid derivatives further demonstrated potent antifungal activities across clinically relevant Candida strains, such as C. glabrata, C. parapsilosis, and C. auris. Both compounds induced intracellular reactive oxygen species (ROS) and increased cellular ergosterol levels, supporting a mechanism distinct from direct ergosterol inhibition. Serial passage experiment revealed low propensity for resistance development compared with fluconazole. Drug interaction studies revealed synergy with terbinafine for both compounds. DBFBA additionally downregulated the virulence-associated iron acquisition gene RBT5. Importantly, both compounds showed minimal toxicity in HepG2 cells, Caenorhabditis elegans and Raphanus sativus models. In silico ADME analysis further supported both compounds favorable drug-like profile. These findings position dibenzofuran derivatives, particularly DBFBA, as promising antifungal candidates against azole-resistant Candida species.