Following invasion of the human erythrocyte by the
malaria parasite, Plasmodium falciparum, there appear in the parasitized cell new, high-capacity permeation pathways that transport a diverse range of low-molecular-mass solutes. In this study a series of 16 arylaminobenzoates, analogues of the Cl- channel blocker
5-nitro-2-(3-phenylpropylamino)benzoic acid (
NPPB), were tested for their effects on the transport of
choline, a univalent
cation, into
malaria-infected cells. A number of the arylaminobenzoates were found to be potent inhibitors of
malaria-induced
choline transport and to be similarly effective at blocking the induced transport of the uncharged
pyrimidine nucleoside thymidine and the univalent
anion lactate. The data are consistent with the hypothesis that much of the induced transport of
cations,
anions and non-
electrolytes into parasitized cells is via broad-specificity,
anion-selective pathways of a single type. A comparison of the effects of the arylaminobenzoates on
malaria-induced transport with their effects on a number of representative
anion transport systems in normal mammalian cells suggests that it is possible to identify pharmacological agents that block the
malaria-induced pathway while not significantly affecting important transport mechanisms in host tissues. The most potent of the induced-transport inhibitors identified were shown to inhibit [3H]
hypoxanthine incorporation in in vitro parasite growth assays. These data support the view that the induced-transport pathway may be a viable pharmacological target.