Mode of action of iron(III) chelators as antimalarials .4. Potentiation of desferal action by benzoyl and isonicotinoyl hydrazone derivatives

The antimalarial action of iron chelators is limited by factors related to drug permeation and parasite susceptibility to metal deprivation. In this study we applied iron-chelating isonicotinoyl and benzoyl hydrazones on Plasmodium falciparum cultures and assessed their antimalarial properties. The agents were used both individually and in combination with deferoxamine (DFO), a clinically approved iron chelator, and with hydroxyethyl-starch-DFO, a macromolecular carrier of DFO. Salicylaldehyde isonicotinoyl hydrazone (SIH) and 2-hydroxy-1-naphthylaldehyde m-fluorobenzoyl hydrazone (HNFBH) were found to be highly efficient in suppressing parasite growth at all developmental stages (IC50 24 +/- 6 mu mol/L and 0.21 +/- 0.04 mu mol/L, respectively, in a 36-to-42 hour test), In combination with impermeant DFO, SIH and HNFBH actions on ring forms were significantly potentiated in terms of speed of drug action and extent of inhibition. The combined effect of the hydrazones with DFO was greater than additive. Based on the capacity of SIH to extract iron from infected cells and to transfer the metal to extracellular DFOs, we propose a mechanism for a synergistic action of permeant hydrazones and impermeant (DFO) iron chelators. The application of a combination of iron chelators as antimalarials might be of therapeutic value.