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 micro M. 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.