Synthesis of a New Peptide-Coumarin Conjugate: A Potential Agent against Cryptococcosis

Authors: Ferreira, Soraya Z.; Carneiro, Hellem C.; Lara, Hugo A.; Alves, Rosemeire B.; Resende, Jarbas M.; Oliveira, Heloisa M.; Silva, Luciana M.; Santos, Daniel A.; Freitas, Rossimiriam P.; ACS Medicinal Chemistry Letters; (2015); 10.1021/ml500393q

Antimicrobial peptides (AMPs) are currently being investigated as potential sources of novel therapeutics against an increasing number of microorganisms resistant to conventional antibiotics. The conjugation of an AMP to other bioactive compounds is an interesting approach for the development of new derivatives with increased antimicrobial efficiency and broader spectra of action. In this work, the synthesis of a new peptide-coumarin conjugate via copper(I)-catalyzed azide-alkyne cycloaddition is described. The conjugate was assayed for in vitro cytotoxicity and displayed antifungal activity against Cryptococcus gattii and Cryptococcus neoformans. Additionally, the conjugate exhibited increased antifungal efficacy when compared with the individual peptide, coumarin, or triazole moieties. Treatment of C. gattii with the peptide-coumarin conjugate enhanced the production of reactive oxygen species, suggesting that the oxidative burst plays an important role in the mechanism of action of the conjugate.