Bioactivity Comments

The interaction table below provides data from whole cell assays and gives the antiparasite activity of ACT-451840 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 ACT-451840 demonstrating no evidence of reduced potency against drug resistant strains. Results from assays measuring the effect of ACT-451840 on the functional viability of mature gametocytes and oocysts of P. falciparum indicate that the transmission-blocking effect is dependent on the gametocytocidal activity of the compound.

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 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 - - 9.7 pIC50 - 7 ⤷ pIC50 9.7 (IC50 2x10-10 M) [3H]-hypoxanthine incorporation [7] 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 - - 9.5 pIC50 - 7 ⤷ pIC50 9.5 (IC50 3x10-10 M) [3H]-hypoxanthine incorporation [7] 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 - - 9.5 pIC50 - 7 ⤷ pIC50 9.5 (IC50 3x10-10 M) [3H]-hypoxanthine incorporation [7] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) 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 - - 9.5 pIC50 - 7 ⤷ pIC50 9.5 (IC50 3x10-10 M) [3H]-hypoxanthine incorporation [7] 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 - - 9.4 pIC50 - 7 ⤷ pIC50 9.4 (IC50 4x10-10 M) [3H]-hypoxanthine incorporation [7] 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 - - 9.3 pIC50 - 7 ⤷ pIC50 9.3 (IC50 5x10-10 M) [3H]-hypoxanthine incorporation [7] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Unknown MOA 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 - - 9.0 pIC50 - 7 ⤷ pIC50 9.0 (IC50 1x10-9 M) [3H]-hypoxanthine incorporation [7] 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 dual gamete formation assay (DGFA) - - 8.2 pIC50 - 7 ⤷ pIC50 8.2 (IC50 5.89x10-9 M) male gamete formation from the gametocyte stage [7] Lifecycle stages: Plasmodium sexual blood stage (gametocyte) Conditions: ACT-451840 had no effect on the functional viability of female gametocytes up to a concentration of 20 μM. 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) - - 7.5 pIC50 - 7 ⤷ pIC50 7.5 (IC50 3x10-8 M) Indirect mode: dose-dependent inhibition of oocyst development in the mosquito was observed. Direct mode: no activity at concentrations up to 1 μM [7] Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)