2,4-diaminopteridine-based compounds as precursors for de novo synthesis of antifolates: a novel class of antimalarials.
We have tested the hypothesis that 2,4-diamino-6-hydroxymethyl-pteridine (DAP), 2,4-diaminopteroic acid (DAPA), and 2,4 diamino-N10-methyl-pteroic acid (DAMPA) could be converted into aminopterin (from DAP and DAPA) and methotrexate (from DAMPA), both of which are potent inhibitors of dihydrofolate reductase, a proven drug target for Plasmodium falciparum. DAP, DAPA, and DAMPA inhibited parasite growth in the micromolar range; DAMPA was the most active, with 50% inhibitory concentrations in vitro of 446 ng/ml against the antifolate-sensitive strain and 812 ng/ml against the highly resistant strain under physiological folate conditions. DAMPA potentiates the activity of the sulfone dapsone, an inhibitor of dihydropteroate synthase, but not that of chlorcycloguanil, a known inhibitor of dihydrofolate reductase (DHFR). Experiments with a Saccharomyces cerevisiae strain dependent upon the P. falciparum DHFR enzyme showed that DHFR is a target of DAMPA in that system. We hypothesize that DAMPA is converted to methotrexate by the parasite dihydrofolate synthase, which explains the synergy of DAMPA with dapsone but not with chlorcycloguanil. This de novo synthesis will not occur in the host, since it lacks the complete folate pathway. If this hypothesis holds true, the de novo synthesis of the toxic compounds could be used as a framework for the search for novel potent antimalarial antifolates.
Nduati
Eunice
E
Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, Wellcome Trust Research Laboratories, P.O. Box 43640, GPO 00100, Nairobi, Kenya.
Hunt
Sonya
S
Kamau
Eddy M
EM
Nzila
Alexis
A
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D003622:Dapsone / Q000494:pharmacology; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors; D004338:Drug Combinations; D004357:Drug Synergism; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D010961:Plasmodium / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D002727:Proguanil; D011621:Pteridines / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology
C115021:2,4-diaminopteridine; D000962:Antimalarials; D004338:Drug Combinations; D005493:Folic Acid Antagonists; D011621:Pteridines; D014227:Triazines; C026009:cycloguanil; D003622:Dapsone; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D002727:Proguanil