New �-1,3-glucan synthase inhibitors derived from enfumafungin that showed oral activity in pre-clinical models of disseminated fungal disease were described recently. Modifications of the A ring substituents were conducted to evaluate the role of this region in the anti-fungal activity. Ether linkage replacements were examined initially to alter the base character of the C-3 sidechain. Further explorations of the A-ring were carried out by exploiting a transition metal-catalyzed C-H insertion to allow selective cyclization between the 3- and 24-positions. The resulting cyclic sulfamates were further modified at the nitrogen atom. Also, presumed intramolecular participation of neighboring functional groups enabled directed substitution of the C-25 hydroxyl group with acyl hydrazides. These efforts identified analogs with in vitro potency as �-1,3-glucan synthase inhibitors and activity in fungal susceptibility assays vs. C. albicans MY1055. First in-class compounds were advanced into models of disseminated candidiasis.

Antifungal activity of semisynthetic β-1,3-glucan synthase (GS) inhibitors

243rd National Meeting (2012)

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