The antimalarial triazine WR99210 and the prodrug PS-15: Folate reversal of in vitro activity against Plasmodium falciparum and a non-antifolate modeof action of the prodrug

We have studied the reversal of activity against Plasmodium falciparum of W R99210, a triazine antimalarial drug, and of the pro-drug PS-15 by folic ac id (FA) and folinic acid (FNA). Folic acid and FNA inhibit the growth of P. falciparum in vitro at concentrations > 10(-4.5) and 10(-3.5) mol/L, respe ctively. The activity of pyrimethamine against Kenyan strains M24 and K39 i s reduced 10-12-fold by 10(-5) mol/L of FA, and virtually eliminated by 10- 5 mol/L of FNA. Folates do not antagonise the action of WR99210 against Ken yan strains, and only partially antagonize the action of WR99210 action aga inst the Southeast Asian strains V1/S and W282. Similarly, FA and FNA exert ed weak or no antagonism of the action of PS-15. The inability of folates t o antagonize the action of WR99210 can be explained in terms of high drug-e nzyme affinity, but this does not account for the inability of FA and FNA t o antagonize PS-15. These results suggest that action of PS-15 against P. f alciparum is primarily due to a non-folate mechanism.