Effects of dual combinations of antifolates with atovaquone or dapsone on nucleotide levels in Plasmodium falciparum

Biochemical Pharmacology
A E YeoR I Christopherson

Abstract

The triazine antifolates, cycloguanil and 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[(2,4,5-trichlorophenoxy)propy loxy]-1,3,5-triazine hydrobromide (WR99210), and their parent biguanide compounds, proguanil and N-[3-(2,4,5-trichlorophenoxy)propyloxy]-n-(1-methylethyl)-imido dicarbonimidic-diamine hydrochloride (PS-15), were tested in combination with a series of antimalarial drugs for synergism against Plasmodium falciparum growing in erythrocytic culture. Four synergistic combinations were found: cycloguanil dapsone, WR99210-dapsone, proguanil-atovaquone, and PS-15-atovaquone. Cycloguanil-dapsone or WR99210-dapsone had a profound suppressive effect on the concentration of dTTP in parasites while that of dATP increased. Depletion of dTTP is consistent with cycloguanil or WR99210 inhibiting dihydrofolate reductase and dapsone inhibiting dihydropteroate synthase. For the combinations proguanil-atovaquone and PS-15-atovaquone, the levels of nucleoside triphosphates (NTPs) and dNTPs were generally suppressed, suggesting that inhibition is not through nucleotide pathways but probably through another metabolic mechanism(s). Combinations of two synergistic pairs of antimalarial drugs, (proguanil-atovaquone)-(cycloguanil-dapsone) and (PS...Continue Reading

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Citations

Sep 11, 2007·Biological & Pharmaceutical Bulletin·Joanna BajsaBabu Lal Tekwani
May 27, 2010·Malaria Journal·Sébastien BriolantBruno Pradines
Jul 5, 2005·Expert Opinion on Investigational Drugs·P Winstanley, P Olliaro
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Nov 10, 2006·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·D J Walker, S R Meshnick

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