Capitalizing on an Invasive Species: Micurane Sesquiterpenoids from Micrococca mercurialis with Stage-Specific Antiplasmodial Activity.

Invasive plants pose threats to ecosystems and agriculture but can also serve as reservoirs of bioactive natural products. In an in-house antimalarial screening campaign, the invasive species Micrococca mercurialis was prioritized, leading to the isolation of 19 new sesquiterpenoids (micmeroids A-S, 1-19). Notably, these metabolites were the predominant constituents in the roots, with a substantial total isolation yield of approximately 0.1% (w/w). Their structures, elucidated by extensive spectroscopic analyses, quantum-chemical calculations, chemical derivatization, and single-crystal X-ray diffraction, feature a rare sesquiterpene skeleton named "micurane". Biological evaluation established micurane-type sesquiterpenoids as a new class of antimalarial agents, with micmeroid L (12) exhibiting the most potent antiplasmodial activity (IC50 = 1.47 μM) against the chloroquine-resistant Plasmodium falciparum Dd2 strain. Stage-specific inhibition assays revealed that micmeroid L likely selectively targeted the early ring-to-trophozoite transition of P. falciparum, which may induce irreversible developmental arrest and sustained parasite clearance.