Bioactivity Comments

The interaction table below provides data from whole cell assays and gives the antiparasite activity of P218 against a number of Plasmodium lifecycle stages. The results include an evaluation of asexual blood stage activity, with high potency observed against both a wild-type and a clinically relevant pyrimethamine-resistant strain (PfV1/S) [7]. The compound is also active against hepatic schizonts [4] and has transmission blocking potential, inhibiting exflagellation in both wild-type PfNF54 (IC50 of 4 nM) and NF54-4mutPfdhfr, a transgenic strain with quadruple PfDHFR mutations (IC50 of 11 nM) [3].

Whole organism assay data
Key to terms and symbols	Click on species/strain names for details	Click column headers to sort
MOA/likely target Sp. Assay description Type Action Value Parameter Concentration range (M) Reference Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase Pf Plasmodium falciparum P. falciparum (Pf) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pf is responsible for the majority of malaria related deaths and is the most prevalent species in sub-Saharan Africa. ✖ Parasite liver stage assay - - >7.9 pEC50 - 4 ⤷ pEC50 >7.9 (EC50 <1.2x10-8 M) Primary human hepatocyte assay to assess inhibition of hepatic schizonts (prophylactic activity) [4] Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite) Plasmodium falciparum bifunctional dihydrofolate reductase-thymidylate synthase Pv Plasmodium vivax P. vivax (Pv) is one of five protozoan parasite species of the genus Plasmodium that cause malaria in humans. Pv is the second most common cause of malaria in humans, after P. falciparum, and is prevalent in Southeast Asia and Latin America. Pv has a dormant liver stage that can reactivate and lead to clinical symptoms. ✖ Parasite liver stage assay - - 7.3 pEC50 - 4 ⤷ pEC50 7.3 (EC50 4.5x10-8 M) Primary human hepatocyte assay to assess inhibition of hepatic schizonts (prophylactic activity) [4] Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite) 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 exflagellation assay - - 8.4 pIC50 - 3 ⤷ pIC50 8.4 (IC50 4x10-9 M) Induction of male gamete activation (exflagellation) following 48 hour exposure of mature gametocytes to P218 [3] Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite) 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 - - 8.3 pIC50 - 7 ⤷ pIC50 8.3 (IC50 4.6x10-9 M) [3H]-hypoxanthine incorporation [7] 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 - - 7.3 pIC50 - 7 ⤷ pIC50 7.3 (IC50 5.6x10-8 M) [3H]-hypoxanthine incorporation [7] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)