Highly N‑Methylated Peptides from the Antarctic Sponge Inflatella coelosphaeroides Are Active against Plasmodium falciparum

Malaria, caused by the parasite Plasmodium falciparum, continues to threaten much of the world’s population, and there is a pressing need for expanding treatment options. Natural products have been a vital source of such drugs, and here we report seven new highly N-methylated linear peptides, friomaramide B (2) and shagamides A–F (3–8) from the marine sponge Inflatella coelosphaeroides, collected in Antarctic waters, which demonstrate activity against three strains of blood-stage P. falciparum. The planar structures of these metabolites were solved by interpreting NMR data, as well as HRESIMS/MS fragmentation patterns, while Marfey’s analysis was used to establish the configurations of the amino acids. Reisolation of the previously reported compound friomaramide A (1) allowed us to revise its structure. The panel of isolated compounds allowed establishing structure/activity relationships and provided information for future structure optimization for this class of P. falciparum inhibitory metabolites.