Semi-synthetic derivatives of the triterpene enfumafungin were recently described as new inhibitors of fungal �-1,3-glucan synthase that showed good oral anti-fungal activity in animal models. Modifications of the CD rings and the pendant side shain of the molecule were conducted to evaluate the role of these regions in the anti-fungal activity. Conversion of the carboxylic acid to esters, amides and heterocycles led to compounds with good in vitro potency. Introduction of hydroxyl and keto groups onto the C-ring were achieved via metal-catalyzed oxidations. Notably, the introduction of a carbonyl at C-12 yielded compounds that showed good GS activity, anti-fungal activity (vs. C. albicans MY1055), selectivity (vs. S. aureus) and were less sensitive to serum effects; these analogs demonstrated in vivo efficacy in models of disseminated candidiasis. Radical-mediated decarboxylation resulted in remote functionalization of the pendant side chain allowing investigation of this region. The effects of these modifications will be described.

Semisynthetic β-1,3-glucan synthase (GS) inhibitors with potent antifungal activity

243rd National Meeting (2012)

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