Scalable Access to N‑Acylindole Linkages: Enabling the Synthesis of Antitrypanosomal Noncanonical Cyclic Peptides for Chagas Disease.

Chagas disease is classified as a neglected tropical disease (NTD) and is predominantly endemic in South America. Despite advances in modern medicine, more than 10 million people worldwide are currently infected, and approximately 12 000 deaths are reported annually. The World Health Organization (WHO) aims to eliminate Chagas disease by 2030. Although more than 100 years have passed since the discovery of Chagas disease, no effective vaccine has yet been developed. The only available chemotherapeutic agents are nifurtimox and benznidazole, both of which were introduced more than half a century ago and are included in the WHO's list of essential medicines. However, because these drugs are associated with severe adverse effects and are effective only during the early phase of infection, they have not achieved eradication of Chagas disease. In this study, a scalable synthetic method was developed for noncanonical cyclic peptides bearing a rare N-acylindole linkage, a structural motif not typically observed in conventional cyclic peptides. This strategy enabled the synthesis of bulbiferamide A, a potent antitrypanosomal agent reported to be effective against Chagas disease, as well as a variety of related analogues that had previously been difficult to access synthetically.