Résumé
Molecular interaction between the active site of plasmepsin II and (1-(4-fluoronaphthalen-1-yl)-3–[4–(4-nitro-2-trifluoromethylphenyl) piperazin-1–yl] propanl–1-ol). [Display omitted]
► In this paper, written in collaboration between Southern (Peru and Colombia) and Northern (Spain and France) University teams, we showed that some synthetic piperazine derivatives were able to impair the growth of Plasmodium falciparum in vitro, with low cytotoxicity. ► The most active compound was also able to reduce (moderately) the growth of Plasmodium berghei in mice. ► Finally, we showed (with in silico studies) that the most active compound targets plasmepsin II enzyme.
Piperazine and pyrrolidine derivatives were synthesised and evaluated for their capacity to inhibit the growth of Plasmodium falciparum chloroquine-resistant (FCR-3) strain in culture. The combined presence of a hydroxyl group, a propane chain and a fluor were shown to be crucial for the antiplasmodial activity. Five compounds of the aryl-alcohol series inhibited 50% of parasite growth at doses ⩽10μM. The most active compound 1-(4-fluoronaphthyl)-3-[4-(4-nitro-2-trifluoromethylphenyl)piperazin-1-yl] propan-1-ol was almost 20–40 times more active on P. falciparum (IC50: 0.5μM) than on tumorogenic and non-tumorogenic cells. In vivo it has a very weak effect; inhibiting 35% of parasite growth only, at 10mg/kg/day against Plasmodium berghei infected mice without any impact on survival time. In silico molecular docking study and molecular electrostatic potential calculation revealed that this compound bound to the active site of Plasmodium plasmepsin II enzyme.