Antifungal activity of a maleimide derivative: disruption of cell membranes and interference with iron ion homoeostasis

Fungal infections caused by <i>Candida albicans</i> have posed a persistent threat to human health. Existing clinical antifungal drugs are constrained by issues such as drug resistance and side effects. Compounds containing maleimide rings have been verified to possess antifungal properties, although the specific molecular mechanisms by which they exert this activity have yet to be fully understood. A total of 40 compounds containing maleimide rings were synthesised in the present study, and 12 derivatives that possessed antifungal properties were subsequently identified. The maleimide compound 5 (MPD) with the most potent activity demonstrated fungicidal action at a concentration that was twice as potent as the minimal inhibitory concentration and effectively prevented the formation of biofilms. Furthermore, the mechanistic studies revealed that MPD interfered with iron ion homoeostasis by reducing intracellular iron concentration inside cells, which led to the inhibition of ergosterol biosynthesis and increased cell membrane permeability, resulting in the leakage of intracellular trehalose. In addition, MPD was observed to perturb cell wall biosynthesis by reducing the activity of chitin synthase. Moreover, MPD was found to demonstrate therapeutical efficacy <i>in vivo</i> when assessed using a <i>Caenorhabditis elegans-C. albicans</i> infection model.