Discovery and evaluation of a marine-derived chlorinated flavone derivative CHNQD-02204 as a potent and selective antifungal agent against Candida albicans.

Fungal infections are a significant contributor to global morbidity and mortality, among which Candida albicans infections, a major cause of systemic candidiasis, have a mortality rate of approximately 40%. Developing effective and safe antifungal drugs with novel chemical scaffolds is urgently needed. In this study, more than 200 fungi from a deep-sea-derived fungal library were screened for anti-C. albicans activity, and a fungus Aspergillus candidus (CHNSCLM-1227) strain with strong activity was discovered. Using anti-C. albicans activity screening combined with LC-MS/MS-based molecular networking, six natural flavones (1-6) were identified, and among them, chlorflavonin (1) showed strong activity with an MIC value of 0.625 μg/mL. Guided by its activity and based on a diversified derivatization strategy, a total of 52 derivatives (7-58) were designed. Notably, a chlorinated flavone derivative, CHNQD-02204 (44) showed remarkable and selective in vitro antifungal activity against C. albicans, along with high safety (MIC = 0.025 μg/mL, SI > 1000). Mechanically, CHNQD-02204 (44) inhibited ergosterol production, thereby damaging the integrity of the fungal cell membrane and hindering the normal growth of C. albicans. It also prevented biofilm formation and morphological changes in cells. Moreover, CHNQD-02204 (44) exhibited excellent therapeutic efficacy in a murine model of systemic candidiasis (2.5 mg/kg, i.v., bid) and demonstrated high safety. These findings warrant further pharmaceutical exploration of the promising potential of CHNQD-02204 (44), a novel antifungal agent, for combating C. albicans infections.