Bioactivity Comments

FNDR-20123 is a potent inhibitor of both PfHDAC1 (31 nM) and human HDAC (3 nM). The interaction table below provides data from whole cell assays and gives the antiparasite activity of FNDR-20123 against both the sexual and asexual blood stages of the Plasmodium lifecycle. The evaluation of asexual blood stage activity utilized a panel of culture-adapted P. falciparum strains, with FNDR-20123 demonstrating no evidence of reduced potency against drug resistant strains.

Whole organism assay data
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MOA/likely target Sp. Assay description Type Action Value Parameter Concentration range (M) Reference Plasmodium falciparum histone deacetylase 1 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 - - 7.9 pIC50 - 1 ⤷ pIC50 7.9 (IC50 1.326x10-8 M) [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum histone deacetylase 1 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 - - 7.8 pIC50 - 1 ⤷ pIC50 7.8 (IC50 1.436x10-8 M) [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum histone deacetylase 1 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 - - 7.8 pIC50 - 1 ⤷ pIC50 7.8 (IC50 1.75x10-8 M) [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum histone deacetylase 1 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 - - 7.7 pIC50 - 1 ⤷ pIC50 7.7 (IC50 1.905x10-8 M) [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum histone deacetylase 1 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 - - 7.6 pIC50 - 1 ⤷ pIC50 7.6 (IC50 2.527x10-8 M) [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum histone deacetylase 1 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 - - 7.4 pIC50 - 1 ⤷ pIC50 7.4 (IC50 4.1x10-8 M) SYBR Green assay [1] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum histone deacetylase 1 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 dual gamete formation assay (DGFA) - - 6.7 pIC50 - 1 ⤷ pIC50 6.7 (IC50 1.9x10-7 M) Activity against male gametocytes. IC50 values of 190 nM for male and  > 5 µM for female gametocytes [1] Lifecycle stages: Plasmodium sexual blood stage (gametocyte)