Lien DOI – https://doi.org/10.1016/j.isci.2023.105940
iScience 2023 S2589-0042(23)00017-2
Malaria eradication requires the development of new drugs to combat drug-resistant parasites. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus hirsutus that are active against P. falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivatives allowed to identify compound 84 that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35-88nM). Chemical optimisation led to compound 125 with significantly improved preclinical properties. 125 delays the onset of parasitemia in P. berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays), and in vivo using membrane feeding assay in the Anopheles stephensi vector. Compound 125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, by chemical pull-down strategy we characterised 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.