Synthesis and evaluation of novel macrocyclic antifungal peptides

Echinocandins are a novel class of macrocyclic antifungal peptides that act by inhibiting the beta-(1,3)-D-glucan synthase complex, which is not present in mammalian cells. Due to the large number of hydroxyl groups present in these complex macrocyclic lipopeptides, most structure-activity relationship studies have relied upon semisynthetic derivatives. In order to probe the influence of the cyclic peptide backbone on the antifungal activity we developed a successful strategy for the synthesis of novel echinocandins analogues by on-resin ring closing metathesis or disulfide formation. The specific minimum inhibitory activity of each mimic was determined against Candida albicans. Our results indicate that ring size is an important factor for antifungal activity. (C) 2011 Elsevier Ltd. All rights reserved.