Mode of action of iron(III) chelators as antimalarials. III. Overadditive effects in the combined action of hydroxamate-based agents on in vitro growth of Plasmodium falciparum

Hydroxamate-based iron(III) chelators exhibit potent antimalarial effects on the asexual stages of Plasmodium falciparum grown in vitro. Antimalarial activity varies with the parasite growth stage and the drug permeation properties. The hydrophilic drug desferrioxamine (DFO) is ineffective on early stages (ring forms) of the parasite due to its poor permeability but irreversibly blocks the growth of advanced stages of parasites. On the other hand, hydrophobic reversed siderophores (RSFs) are more membrane permeable and affect all parasite developmental stages; they affect ring forms irreversibly and trophozoite/schizont forms reversibly and at relatively faster rates, compared with DFO. These observations have provided the basis for postulating a possible overadditive action of the two, distinctly acting, iron chelator types for enhanced antimalarial activity. This was assessed in this study by using novel fast-acting chelators such as RSF derivatives (RSFleum2 and RSFm2) in combination with the relatively slow-acting DFO. Parasite growth was assessed in terms of nucleic acid synthesis and parasitemia. The results indicate that, at any molar ratios of the two types of drugs, the combined inhibitory effect was faster and more potent than the sum of individual effects. The combined drug action showed neither additive nor independent but overadditive properties, as well as sustained inhibition even after drug removal. The potentiating action of RSFs on the long-lasting effects of DFO on parasite growth conformed with the postulated mechanistic model of iron chelator action and iron handling by parasites. Iron chelator combinations might be of therapeutic value.