MODE OF ACTION OF IRON(III) CHELATORS AS ANTIMALARIALS .3. OVERADDITIVE EFFECTS IN THE COMBINED ACTION OF HYDROXAMATE-BASED AGENTS ON IN-VITRO GROWTH OF PLASMODIUM-FALCIPARUM

Hydroxamate-based iron(lll) chelators exhibit potent antimalarial effe cts on the asexual stages of Plasmodium falciparum grown in vitro. Ant imalarial activity varies with the parasite growth stage and the drug permeation properties. The hydrophilic drug desferrioxamine (DFO) is i neffective on early stages (ring forms) of the parasite due to its poo r permeability but irreversibly blocks the growth of advanced stages o f parasites. On the other hand, hydrophobic reversed siderophores (RSF s) are more membrane permeable and affect all parasite developmental s tages; they affect ring forms irreversibly and trophozoite/schizont fo rms reversibly and at relatively faster rates, compared with DFO. Thes e observations have provided the basis for postulating a possible over additive action of the two, distinctly acting, iron chelator types for enhanced antimalarial activity. This was assessed in this study by us ing novel fast-acting chelators such as RSF derivatives (RSFleum2 and RSFm2) in combination with the relatively slow-acting DFO. Parasite gr owth was assessed in terms of nucleic acid synthesis and parasitemia. The results indicate that, at any molar ratios of the two types of dru gs, the combined inhibitory effect was faster and more potent than the sum of individual effects. The combined drug action showed neither ad ditive nor independent but overadditive properties, as well as sustain ed 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 hand ling by parasites. Iron chelator combinations might be of therapeutic value.