Bioactivity Comments

The whole organism assay data in the interactions table below, provides an evaluation of the antimalarial (asexual blood stage) activity of pyrimethamine using a panel of culture-adapted P. falciparum strains. Pyrimethamine demonstrates reduced potency against drug resistant strains.

Selectivity at transporters
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Target Sp. Type Action Value Parameter Concentration range (M) Reference Multidrug and toxin extrusion Hs Inhibitor Inhibition 7.1 pKi - 2 ⤷ pKi 7.1 (Ki 7.7x10-8 M) [2] MATE2 Mm Inhibitor Inhibition 6.3 pKi - 2 ⤷ pKi 6.3 (Ki 4.6x10-7 M) [2]

Whole organism assay data
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MOA/likely target Sp. Assay description Type Action Value Parameter Concentration range (M) Reference Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase PfD6 Plasmodium falciparum D6 P. falciparum strain D6 (PfD6) was collected in Sierra Leone. PfD6 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is generally considered drug sensitive with minor mefloquine resistance. ✖ Parasite growth inhibition assay - - 8.3 pIC50 - 1 ⤷ pIC50 8.3 (IC50 4.6x10-9 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase PfNF54 Plasmodium falciparum NF54 P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands. PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖ Parasite growth inhibition assay - - 7.8 pIC50 - 1 ⤷ pIC50 7.8 (IC50 1.7x10-8 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase PfTM4 Plasmodium falciparum TM4 P. falciparum strain TM4 (PfTM4) was isolated from a patient at the Tropical Medical Hospital, Bangkok, Thailand in 1985. ✖ Parasite growth inhibition assay - - 7.2 pIC50 - 5 ⤷ pIC50 7.2 (IC50 5.8x10-8 M) [3H]-hypoxanthine incorporation assay using wild-type P. falciparum (TM4) [5] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase Pf7G8 Plasmodium falciparum 7G8 P. falciparum strain 7G8 (Pf7G8) was subcloned from the IMTM22 strain by limiting dilution. The original IMTM22 strain was isolated from a 12 year old male near Manaus, Brazil in 1980. Pf7G8 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4). This strain is a gametocyte producer and is reported to be chloroquine-sensitive and pyrimethamine-resistant. ✖ Parasite growth inhibition assay - - 5.2 pIC50 - 1 ⤷ pIC50 5.2 (IC50 6.689x10-6 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase PfTM90C2A Plasmodium falciparum TM90C2A P. falciparum TM90C2A (PfTM90C2A) is a clinical isolate, first described during a Phase 2 clinical trial to determine atovaquone efficacy in Thailand (PMID:8651372). PfTM90C2A is sensitive to atovaquone. ✖ Parasite growth inhibition assay - - 5.1 pIC50 - 1 ⤷ pIC50 5.1 (IC50 8.231x10-6 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase PfK1 Plasmodium falciparum K1 P. falciparum strain K1 (PfK1) was isolated in Kanchanaburi, Thailand in 1979. PfK1 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be a multidrug-resistant strain. ✖ Parasite growth inhibition assay - - <5.0 pIC50 - 1 ⤷ pIC50 <5.0 (IC50 >1x10-5 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase PfW2 Plasmodium falciparum W2 P. falciparum strain W2 (PfW2) was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfW2 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and susceptible to mefloquine. ✖ Parasite growth inhibition assay - - <5.0 pIC50 - 1 ⤷ pIC50 <5.0 (IC50 >1x10-5 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase PfV1/S Plasmodium falciparum V1/S P. falciparum strain V1/S (PfV1/S) is an in vitro culture-adapted clone of V1, that originated in Vietnam. PfV1/S can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and quinine. ✖ Parasite growth inhibition assay - - <4.0 – 5.0 pIC50 - 1,5 ⤷ pIC50 <5.0 (IC50 >1x10-5 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) pIC50 <4.0 (IC50 >1x10-4 M) [3H]-hypoxanthine incorporation assay using quadruple mutant P. falciparum (V1/S) [5] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)