Iheyamide A ( 1 ) is an antitrypanosomal linear peptide isolated from aDapissp. marine cyanobacterium by our group in 2020, and based on structure-activity relationships of its natural analogues, the C-terminal pyrrolinone moiety has been identified as the phamacophore for its antiparasitic activity. Further, we isolated this pyrrolinone moiety by itself as a new natural product from the marine cyanobacterium and named it iheyanone ( 2 ). As expected, iheyanone ( 2 ) showed antitrypanosomal activity, but its potency was weaker than iheyamide A ( 1 ). To clarify more detailed structure-activity relationships, we completed a total synthesis of iheyamide A ( 1 ) along with iheyanone ( 2 ) and evaluated the antitrypanosomal activities of several synthetic intermediates. As a result, we found that the longer the peptide chain, the stronger the antitrypanosomal activity. As iheyamide A ( 1 ) showed selective toxicity againstTrypanosoma brucei rhodesiense, these findings can provide design guidelines for antitrypanosomal drugs.
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