Hemisynthetic alkaloids derived from trilobine are antimalarials with sustained activity in multidrug-resistant .

Malaria eradication requires the development of new drugs to combat drug-resistant parasites. We identified bisbenzylisoquinoline alkaloids isolated from that are active against blood stages. Synthesis of a library of 94 hemi-synthetic derivatives allowed to identify compound that kills multi-drug resistant clinical isolates in the nanomolar range (median IC ranging from 35 to 88 nM). Chemical optimization led to compound with significantly improved preclinical properties. delays the onset of parasitemia in infected mice and inhibits transmission stages (culture assays), and using membrane feeding assay in the vector. Compound also impairs development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, by chemical pull-down strategy, we characterized the parasite interactome with trilobine derivatives, identifying protein partners belonging to metabolic pathways that are not targeted by the actual antimalarial drugs or implicated in drug-resistance mechanisms.