Dimeric polyphenols to pave the way for new antimalarial drugs

Because of the threat of resistant Plasmodium sp. , new orally active antimalarials are urgently needed. Inspired by the structure of ellagic acid, exhibiting potent in vivo and in vitro antiplasmodial effects, polyphenolic structures possessing a similar activity-safety profile were synthesized. Indeed, most exhibited a marked in vitro effect (IC 50 < 4 μM) on resistant P. falciparum , without any detrimental effects reported during the toxicity assays (hemolysis, cytotoxicity, in vivo ). In addition, they possessed a greater hydrosolubility (from 7 μM to 2.7 mM) compared to ellagic acid. Among them, 30 is the most promising for antimalarial purposes since it displayed a significant parasitaemia reduction after oral administration in mice (50 mg kg −1 ) compared to the orally ineffective ellagic acid. In conclusion, our investigations led to the identification of a promising scaffold, which could bring new insights for malaria treatment. A polyphenolic scaffold to develop novel orally active antimalarials against resistant Plasmodium falciparum.