Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites' resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all Plasmodium falciparum strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against Plamodium vinckei petteri in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of Plasmodium falciparum demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound N-acetyl-L-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on P. falciparum are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.New drugs against malaria are urgently needed, and traditional methods of malaria treatment could be a promising source of new antimalarial compounds (5). We have recently initiated several collaborative programs with West African countries aimed at selecting, by ethnopharmacological methods, plants largely used by traditional healers and the local populations for malaria treatment. The in vitro antiplasmodial activities of the crude extracts and fractions (from bioguided fractionation of the promising crude extracts of plants) enabled us to identified ellagic acid as one of the active ingredients. The in vitro antimalarial activity of this molecule was previously reported by other researchers (3,10). In this study, we clarify the high level of in vitro and in vivo antiplasmodial properties of ellagic acid, its antioxidant activity, and its potential pro-oxidant effect and gain a deeper understanding of its mechanisms of action. MATERIALS AND METHODSCompounds. Ellagic acid hydrate (Fig. 1) was obtained from Acros Organics (Belgium), with a molecular weight 302.19 g/mol. The following other reagents were also obtained: chloroquine diphosphate salt (Sigma, France), mefloquine hydrochloride (Hoffmann-La Roche, Switzerland), artesunate (Sanofi-Synthelabo, France), artemisinin (Sigma, Germany), and atovaquone (GlaxoSmithKline, United Kingdom).In vitro antiplasmodial activity. Five strains (W2-Indochina, FcM29-Cameroon, FcB1-Colombia, F32-Tanzania, and D...