Bioactivity Comments

The interaction table below provides data from whole cell assays and gives the antiparasite activity of E209 against a number of Plasmodium lifecycle stages. The results include an evaluation of asexual blood stage activity using a panel of culture-adapted P. falciparum strains, with E209 demonstrating no evidence of reduced potency against drug resistant strains. In addition, the compound exhibited good oral activity when tested in vivo using mice infected with P. berghei (ED50 4 mg kg-1 after 3 doses and 66% cure rate after a single dose of 30 mg kg-1) and in the SCID mouse model of P. falciparum malaria (ED90 of 11.6 mg kg-1) [1].

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 Unknown MOA 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 - - 8.5 pIC50 - 1 ⤷ pIC50 8.5 (IC50 2.9x10-9 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Unknown MOA 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 - - 8.4 pIC50 - 1 ⤷ pIC50 8.4 (IC50 4.2x10-9 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Unknown MOA 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 - - 8.4 pIC50 - 1 ⤷ pIC50 8.4 (IC50 4.2x10-9 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Unknown MOA PfHB3 Plasmodium falciparum HB3 P. falciparum strain HB3 (PfHB3) was cloned from the Honduras I/CDC strain, originally isolated from a patient in Choluteca, Honduras, during an outbreak of urban malaria in January 1980. PfHB3 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be chloroquine sensitive. ✖ Parasite growth inhibition assay - - 8.4 pIC50 - 1 ⤷ pIC50 8.4 (IC50 4.2x10-9 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Unknown MOA Pf3D7 Plasmodium falciparum 3D7 P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1). Pf3D7 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 - - 8.3 pIC50 - 1 ⤷ pIC50 8.3 (IC50 5.1x10-9 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Unknown MOA 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 - - 8.3 pIC50 - 1 ⤷ pIC50 8.3 (IC50 5.2x10-9 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Unknown MOA PfTM90C2B Plasmodium falciparum TM90C2B P. falciparum TM90C2B (PfTM90C2B) is a clinical isolate, first described during a Phase 2 clinical trial to determine atovaquone efficacy in Thailand (PMID:8651372). A point mutation (Y268S) at the Qo site of cytochrome b results in a 3,000-fold loss of atovaquone sensitivity. It is used as a screening tool for the development of new cytochrome b inhibitors. ✖ Parasite growth inhibition assay - - 8.1 pIC50 - 1 ⤷ pIC50 8.1 (IC50 7.3x10-9 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Unknown MOA PfDd2 Plasmodium falciparum Dd2 P. falciparum strain Dd2 (PfDd2) is a clone derived from PfW2, following continuous culture in mefloquine. PfW2 was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfDd2 can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, pyrimethamine and mefloquine. ✖ Parasite growth inhibition assay - - 8.1 pIC50 - 1 ⤷ pIC50 8.1 (IC50 7.7x10-9 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Unknown MOA 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 - - 8.1 pIC50 - 1 ⤷ pIC50 8.1 (IC50 8.5x10-9 M) [3H]-hypoxanthine incorporation [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Unknown MOA 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. ✖ Standard membrane feeding assay (SMFA) - - 7.8 pIC50 - 1 ⤷ pIC50 7.8 (IC50 1.45x10-8 M) determined by the reduction in oocyst mean intensity. A corresponding ~60 and 90% transmission blocking activity (defined as the percentage of mosquitoes with no observed oocysts) was determined at 100nM and 1µM, respectively [1] Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)