The inhibition of �-1,3-glucan synthase (GS) reduces the �-1,3-glucan content of the fungal cell wall, which alters the cell wall composition and leads to cell lysis. The clinical success of the echinocandin class of antifungal agents has demonstrated the effectiveness of GS inhibition as a target. The candins are well tolerated, broad spectrum agents but are limited to intravenous administration because of poor oral bioavailability. Enfumafungin (1) , a triterpene natural product, is a broad spectrum GS inhibitor that was isolated from Hormonema carpetanum by the Natural Products Department at Merck. Synthetic modifications were performed on the 2- and 3- positions of a previously reported 25-deoxyenfumafungin analog (2) . The replacement of the 2-acetoxy group with heterocyclic substituents in conjunction with the removal of the 3-�-glucoside moiety in favor of various amino ethers produced a potent, broad spectrum class of antifungal agents that were efficacious upon oral dosing in a mouse model of disseminated candidiasis. 

Novel enfumafungin derivatives: Orally active β-1,3-glucan synthase inhibitors

244th National Meeting (2012)

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