Synergistic Antimalarial Activity of Dapsone/dihydrofolate Reductase Inhibitors and the Interaction of Antifol, Antipyrimidine and Antipurine Combinations Against Plasmodium Falciparum in Vitro

Using low folate, low p-aminobenzoic acid medium, 2 isolates of Plasmodium falciparum were tested in vitro against a wide range of antimetabolite compounds with known or potential antimalarial activity. ID50 values (the concentration of compound causing 50% inhibition of [3H]hypoxanthine incorporation) were determined for each compound against both isolates. The compounds tested may affect folate, pyrimidine or purine metabolism in malaria parasites and various combinations of compounds were examined for further synergistic antimalarial effects. The combination of any of the dihydrofolate reductase inhibitors cycloguanil, pyrimethamine or WR 99210 with the sulphone drug dapsone demonstrated strongly synergistic antimalarial activity. Combinations of dihydrofolate reductase inhibitors with the antipyrimidine compounds pyrazofurin or menoctone, or with the antipurine compounds tubercidin, bredinin or hadacidin, or with primaquine, failed to demonstrate synergistic activity. Most combinations of an antipurine with an antipyrimidine compound also failed to show any synergistic effect. However, weak synergism was consistently seen in the tubercidin/pyrazofurin and tubercidin/menoctone combinations. Over the 48 h intraerythrocytic cycle using tightly synchronized parasites, tubercidin demonstrated both a cytotoxic and a cytostatic effect.