The antimalarial triazine WR99210 and the prodrug PS-15: folate reversal of in vitro activity against Plasmodium falciparum and a non-antifolate mode of action of the prodrug.
We have studied the reversal of activity against Plasmodium falciparum of WR99210, a triazine antimalarial drug, and of the pro-drug PS-15 by folic acid (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, respectively. The activity of pyrimethamine against Kenyan strains M24 and K39 is 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 Kenyan strains, and only partially antagonize the action of WR99210 action against the Southeast Asian strains V1/S and W282. Similarly, FA and FNA exerted weak or no antagonism of the action of PS-15. The inability of folates to antagonize the action of WR99210 can be explained in terms of high drug-enzyme affinity, but this does not account for the inability of FA and FNA to antagonize PS-15. These results suggest that action of PS-15 against P. falciparum is primarily due to a non-folate mechanism.
Kenya Medical Research Institute/Wellcome Trust Collaborative Research Program, Nairobi.
S M
SM
Kinyanjui
E K
EK
Mberu
P A
PA
Winstanley
D P
DP
Jacobus
W M
WM
Watkins
D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D001210:Asia, Southeastern; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005492:Folic Acid / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006397:Hematinics / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007630:Kenya; D002955:Leucovorin / Q000494:pharmacology; D016778:Malaria, Falciparum / Q000188:drug therapy*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development*; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D002727:Proguanil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use
D000931:Antidotes; D000962:Antimalarials; D005493:Folic Acid Antagonists; D006397:Hematinics; D011355:Prodrugs; D014227:Triazines; C082651:PS 15; C006201:BRL 6231; D005492:Folic Acid; D002955:Leucovorin; D002727:Proguanil