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.