Iron chelators as antimalarial agents: in vitro activity of dicatecholate against Plasmodium falciparum

• Published in: Journal of antimicrobial chemotherapy Vol. 50; no. 2; pp. 177 - 187
• Main Authors: Pradines, B., Rolain, J. M., Ramiandrasoa, F., Fusai, T., Mosnier, J., Rogier, C., Daries, W., Baret, E., Kunesch, G., Le Bras, J., Parzy, D.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.08.2002; Oxford Publishing Limited (England)
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; Catechols - chemistry; Catechols - pharmacology; Cercopithecus aethiops; Cholates - chemistry; Cholates - pharmacology; Erythrocytes - drug effects; Iron Chelating Agents - chemistry; Iron Chelating Agents - pharmacology; Medical sciences; Pharmacology. Drug treatments; Plasmodium falciparum - drug effects; Plasmodium falciparum - growth & development; Vero Cells; Protozoa; Antimalarial; Apicomplexa; Drug combination; Microorganism growth; Ascorbic acid; Toxicity; Iron II; Ferritin; Vitamin; In vitro; Biological activity; Plasmodium falciparum; Iron III; Structure activity relation; Parasiticid; Chelating agent; Drug interaction
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dkf104

The present study was undertaken to explore the antimalarial effect of a series of dicatecholate iron chelators. They may be made more or less lipophilic by increasing or reducing the length of the R substituent on the nitrogen. In vitro activity against the W2 and 3D7 clones of Plasmodium falciparum, toxicity on Vero cells and toxicity on uninfected erythrocytes by measure of the released haemoglobin were assessed for each compound. These findings were compared with the ability of iron(III), iron(II) and ferritin to reverse the inhibitory effect of catecholates. This study shows that increased lipid solubility of catecholate iron chelators does not lead to improved antimalarial activity. However, their activity is well correlated with their interaction with iron and with their toxicity against Vero cells. This study demonstrates a potent antimalarial effect of FR160 (R = C9H19) on five different strains of P. falciparum in vitro. FR160 inhibited parasite growth with an IC50 between 0.8 and 1.5 µM. The effects of FR160 on mammalian cells were minimal compared with those obtained with malaria parasites. FR160 acted on parasites at considerably higher rates than desferrioxamine, and at all stages of parasite growth. The drug was more effective at the late trophozoite and young schizont stages, although FR160 affected rings and schizonts as well. Ascorbic acid, a free radical scavenger, reduced the activities of FR160 and artesunate. FR160 might induce formation of free radicals, which could explain why FR160 antagonized the effects of artesunate and dihydroartemisinin.