Chemoselective halogenation of premarineosin A for next-generation antimalarial development

Premarineosin A undergoes rapid, chemoselective halogenation at C12 under mild conditions, enabling efficient access to brominated, chlorinated, fluorinated, and iodinated analogs without the need for protecting groups or extensive synthetic manipulation. Reaction conditions were optimized to favor selective functionalization of the electron-rich pyrrole ring while preserving the integrity of the macrocyclic scaffold. The resulting halogenated derivatives were readily isolated and characterized by LC-MS/MS and NMR spectroscopy. Biological evaluation revealed that all halogenated analogs retained potent antiplasmodial activity against both chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains. Across the series, the halogenated compounds displayed smaller differences in potency between the chloroquine-sensitive and chloroquine-resistant parasite strains than the parent compound, resulting in reduced resistance indices while maintaining low-nanomolar antiplasmodial activity. Although the molecular target of premarineosin A remains unknown, these findings demonstrate that C12 halogenation is potent in both parasite backgrounds. Collectively, these results establish late-stage C12 halogenation as an operationally efficient strategy for diversifying premarineosin A and demonstrate that subtle halogen substitution can modulate the antimalarial profile of this scaffold, providing a foundation for the future development of premarineosin-derived antiplasmodial agents.