title: Evaluation of the activities of pyrimethamine analogs against Plasmodium vivax and Plasmodium falciparum dihydrofolate reductase-thymidylate synthase using in vitro enzyme inhibition and bacterial complementation assays.
abstract: Pyrimethamine analogs were examined as potential agents against vivax malaria using a bacterial surrogate system carrying Plasmodium vivax dihydrofolate reductase-thymidylate synthase (PvDHFR-TS), in which the PvDHFR complemented chemically knocked out host dihydrofolate reductase. The system was initially tested with P. falciparum dihydrofolate reductase-thymidylate synthase and was found to have good correlation with the parasite-based system. The 50% inhibitory concentrations derived from PvDHFR-TS-dependent bacteria were correlated with their corresponding inhibition constants (Ki) from an enzyme inhibition assay, pointing to the likelihood that the potent enzyme inhibitors will also have potent antimalarial activities. Active compounds against both wild-type and S58R S117N (SP21) double-mutant P. vivax include analogs with structures which can avert a steric clash with the asparagine (S117N) side chain of the mutant, similar to those found for homologous Plasmodium falciparum mutants, raising the possibility that the same compounds can be developed against both types of antifolate-resistant malaria. This rapid and convenient drug screening system should be useful for development of new antifolates against P. vivax, for which a continuous culture system is not yet available.
authors.affiliation: National Center for Genetic Engineering and Biotechnology, 113 Paholyothin Rd., Klong 1, Klong Luang, Pathumthani 12120, Thailand.
authors.forename: Sasinee
authors.initials: S
authors.lastname: Bunyarataphan
authors.forename: Ubolsree
authors.initials: U
authors.lastname: Leartsakulpanich
authors.forename: Supannee
authors.initials: S
authors.lastname: Taweechai
authors.forename: Bongkoch
authors.initials: B
authors.lastname: Tarnchompoo
authors.forename: Sumalee
authors.initials: S
authors.lastname: Kamchonwongpaisan
authors.forename: Yongyuth
authors.initials: Y
authors.lastname: Yuthavong
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004351:Drug Resistance; D005493:Folic Acid Antagonists; D005816:Genetic Complementation Test; D009154:Mutation / Q000502:physiology; D010957:Plasmids / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D010966:Plasmodium vivax / Q000187:drug effects* / Q000201:enzymology*; D011739:Pyrimethamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects* / Q000235:genetics; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000962:Antimalarials; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D011739:Pyrimethamine