Total synthesis and structure–activity relationships of new echinocandin-like antifungal cyclolipohexapeptides

A series of new echinocandin-like cyclolipohexapeptides were designed and total synthesized via solution phase [3 + 3]-segment coupling strategy with an attempt to improve antifungal activity. The designed compounds showed potent antifungal activities with broad spectrum. In particular, 11 compounds (i.e. 28a–e, 28g, 28i–j, 29a, 29c and 29e) showed better in vitro antifungal activities against Candida albicans or Aspergillus fumigatus than caspofungin. Moreover, the synthesized compounds provided new SAR information for the echinocandins. The findings in this work suggested that the “left” tripeptide segment of cyclolipohexapeptide scaffold might be a hydrophilic structural motif, whereas the “right” lipopeptide segment was preferred as a hydrophobic core. The amino acid component of the cyclolipohexapeptide scaffold could significantly affect the SAR of the side chains.

Graphical abstract28 new antifungal cyclohexalipopeptides were designed and synthesized. 11 target compounds were more active against Candida albicans or Aspergillus fumigatus than caspofungin and worth further structural optimization.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 28 new antifungal cyclohexalipopeptides were designed and total synthesized. ► 7 compounds showed higher antifungal activity against C. albicans than caspofungin. ► 5 compounds were more active against A. fumigatus than caspofungin.