Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 24, Pages 10135-10150Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01348
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Funding
- National Medical Research Council
- Singhealth Foundation [NMRC/CBRG/0080/2015, NMRC/TCR/R1018]
- National Natural Science Foundation of China [51273072]
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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 alpha-mangostin to combat fungal resistance. The attachment of cationic residues on the xanthone scaffold of alpha-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.
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