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Antimalarial effect of HBED and other phenolic and catecholic iron
chelators
AM Yinnon, EN Theanacho, RW Grady, DT Spira and C Hershko
Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel.
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.
Volume 74,
Issue 6,
pp. 2166-2171,
11/01/1989
Copyright © 1989 by The American Society of Hematology
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