Semisynthesis and Biological Evaluation of Xanthone Amphiphilics as Selective, Highly Potent Antifungal Agents to Combat Fungal Resistance

New efficient antifungal agents are
urgently needed to treat drug-resistant
fungal infections. Here, we designed and synthesized a series of cationic
xanthone amphiphilics as antifungal agents from natural α-mangostin
to combat fungal resistance. The attachment of cationic residues on
the xanthone scaffold of α-mangostin resulted in interesting
antifungal agents with a novel mode of action. Two lead compounds
(1 and 2) showed potent antifungal activity
against a wide range of fungal pathogens, including drug-resistant Candida albicans, Aspergillus, and Fusarium strains and low cytotoxicity
and hemolytic activity against mammalian cells. Both compounds can
kill fungus rapidly by directly disrupting fungal cell membranes and
avoid developing drug resistance. Additionally, compound 1 exhibited potent in vivo antifungal activity in the murine model
of fungal keratitis. To our knowledge, membrane-targeting xanthone-based
antifungals have not been reported previously. These results demonstrated
that compounds 1 and 2 may be promising
candidates for treating drug-resistant fungal infections.