Antimalarial effect of HBED and other phenolic and catecholic iron chelators

Previous studies showed that deferoxamine inhibits malaria by interacting with a labile iron pool within parasitized erythrocytes. Consequently, we studied the antimalarial properties of other iron-chelating drugs such as 2,3-dihydroxybenzoic acid (2,3-DHB) and its methyl ester as well as two polyanionic amines, N.N'-bis (o-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED) and N,N'-ethylenebis(o-hydroxyphenylglycine) (EHPG) in rats infected with Plasmodium berghei. All drugs were delivered by subcutaneous injection at 8-hour intervals, 40 mg per animal per day. All animals receiving N,N'-ethylenebis(o-hydroxyphenylglycine) died of drug toxicity between days 6 and 11. Peak parasitemia on day 11 of infection was 32.8% in control animals; 25.3% with methyl 2,3-DHB, 15.5% with 2,3-DHB, 8.0% with deferoxamine, and 0.9% with HBED. Subsequent studies of HBED and deferoxamine in P falciparum cultures in human erythrocytes showed a marked suppression of parasite counts by both drugs at concentrations of greater than 5 mumol/L. At all concentrations tested, HBED was four to five times more effective than deferoxamine in suppressing parasite counts. The superior antimalarial activity of HBED is attributed to its increased lipophilicity and higher affinity to ferric iron. These findings indicate that selective iron deprivation by interaction with an intracellular chelator may represent a novel approach to antimalarial drug development, and that systematic screening of available iron-chelating drugs may result in identification of potentially useful antimalarial compounds.