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A unique metabolic feature of malaria parasites is their restricted ability to synthesize nucleotides. These parasites are unable to synthesize the purine ring and must therefore obtain preformed purine bases and nucleosides from the host cell, the erythrocyte. On the other hand, pyrimidines must be synthesized de novo because of the inability of the parasites to salvage preformed pyrimidines. Thus, one would anticipate that the blockage of purine salvage or pyrimidine de novo synthesis should adversely affect parasite growth. This premise was tested in vitro with a total of 64 compounds, mostly purine and pyrimidine analogs, known to inhibit one or more steps of nucleotide synthesis. Of the 64 compounds, 22 produced a 50% inhibition of the growth of the human malaria parasite Plasmodium falkiparum at a concentration of 50 ,uM or less. Inhibition of the growth of chloroquine-resistant clones ofP. fakciparum did not differ significantly from that of the growth of chloroquine-susceptible clones. Two of the compounds which effectively inhibited parasite growth, 6-mercaptopurine and 6-thioguanine, were found to be potent competitive inhibitors of a key purine-salvaging enzyme (hypoxanthine-guanine-xanthine phosphoribosyltransferase) of the parasite.The worldwide resurgence of human malaria during the past decade (60) has been due in part to the rapid spread of Plasmodium falciparum strains resistant to chloroquine and other commonly used antimalarial drugs (21, 41). In view of this resurgence, there is currently an urgent need to develop and identify additional safe and effective drugs (47).A rational approach to drug development is to identify drugs which can be directed at unique metabolic targets in the parasite. One such target is the synthesis of purine and pyrimidine nucleotides. Unlike humans, malaria parasites cannot make purines de novo and must therefore obtain purine bases and nucleosides from the erythrocyte host cell and then metabolize these to nucleotides by salvage pathways (54). Another metabolic distinction between these parasites and humans is that P. falciparum relies exclusively on pyrimidine synthesis de novo because of its inability to salvage preformed pyrimidines (54). Thus, drugs capable of blocking either purine salvage or pyrimidine de novo synthesis would be expected to show strong antimalarial activity.In the present study, we measured the in vitro antimalarial activity of 64 compounds known to inhibit one or more aspects of nucleotide or nucleic acid metabolism. A number of these compounds were also tested for their ability to inhibit a key purine-salvaging enzyme (43)

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