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The effect of N-alkyl modification on the antimalarial activity of 3-
hydroxypyridin-4-one oral iron chelators
C Hershko, EN Theanacho, DT Spira, HH Peter, P Dobbin and RC Hider
Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel.
The antimalaria effect of iron chelators is attributed to their interaction
with a labile iron pool within parasitised erythrocytes, and it was
postulated that increased affinity to iron as well as increased
lipophilicity may improve antimalarial activity. In the present study we
have examined the antimalarial effect of 3- hydroxypyridin-4-ones, a family
of bidentate orally effective iron chelators whose lipophilicity may be
modified by altering the length of the R2 substituent on the ring nitrogen.
A significant dose-related suppression of Plasmodium falciparum cultures
was observed with all drugs tested in vitro at concentrations of 5 mumol/L
or higher. In contrast, there was a clear segregation of the in vivo effect
on P berghei in rats (300 mg/kg/d subcutaneous) into two categories:
compounds CP20, 38, and 40 failed to suppress malaria, whereas CP51, 94,
and 96 had a strong antimalarial effect, similar or better than
deferoxamine. There was a close linear correlation between the suppression
of peak parasite counts and the reduction in hepatic nonheme iron induced
by the various drugs tested (r = .9837). The most lipophilic compounds were
also the most effective in suppressing malaria and in depleting hepatic
iron stores. These data indicate that 3-hydroxypyrydin-4-ones are able to
suppress malaria in vivo and in vitro. Because lipid solubility is an
important determinant of antimalarial action, our study provides useful
information regarding the selection of orally effective iron-chelating
compounds that may be suitable for clinical application as antimalarial
agents.
Volume 77,
Issue 3,
pp. 637-643,
02/01/1991
Copyright © 1991 by The American Society of Hematology
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