Antimalarial Action of Iron Chelators

Unlike mammalian cells, malaria parasites are uniquely sensitive to the action of iron chelators. By depriving cells of iron, natural and synthetic iron chelators and siderophores of the hydroxamate family, inhibit, among others, nucleic acid synthesis, arrest parasite growth and stop proliferation. Moreover, the chelator induced damage to parasites can often be irreversible, depending on the nature of the drug used and on the developmental stage of the parasite exposed to the drug. The uniqueness of parasite’s susceptibility to iron chelators rests on the parasite’s limited ability for mobilizing iron. However, the fact that most available iron chelators irreversibly affect parasites only at given stages of parasite development, limits their usefulness as prospective therapeutic agents. The aim is to develop iron chelators and treatments which lead to long lasting inhibitory effects on all stages of parasite development. This was accomplished with iron chelators which, in combination, outperformed the sum of single drug treatments. The synergistic properties of chelators herewith reported were obtained in malaria parasites grown in Plasmodium falciparum infected red blood cells. The studies were carried with desferrioxamine (DFO) in combination with various hydrophobic siderophores of the salicylaldehyde-isonicotinoyl or fluorobenzoyl hydrazone family and reversed siderophores.