Novel Pyrone-Based Biofilm Inhibitors against Azole-Resistant <i><i>Candida albicans</i></i>

<i>Candida albicans</i> is an opportunistic fungus that is pathogenic in immunocompromised patients with life-threatening diseases such as HIV and cancer. <i>C. albicans</i> is the most common fungal species isolated from biofilms formed on implanted medical devices or on human tissue. Biofilm development of <i>C. albicans</i> is mainly driven by a transition from yeast to hyphal form involving core proteins such as HWP and ALS. We designed and synthesized novel α-pyrone-based analogues to investigate their potential in inhibiting biofilm formation and hyphal development of <i>C. albicans</i> . Among the synthesized compounds, three compounds (<b>6f</b>, <b>6j</b>, and <b>6n</b>) significantly inhibited <i>C. albicans</i> biofilm formation and reduced cell aggregation and hyphal formation in a dose-dependent manner. These compounds had minimal effects on planktonic cell growth while significantly reducing biofilm formation at 20-50 μg/mL, suggesting novel candidate compounds for managing drug-resistant strains of <i>C. albicans</i> . The three compounds may represent promising therapeutic options with potential synergistic effects when combined with existing antifungal agents.