cipargamin   Click here for help

GtoPdb Ligand ID: 9721

Synonyms: KAE609 | NITD609
Antimalarial Ligand
Compound class: Synthetic organic
Comment: Cipargamin is an antimalarial drug candidate, under clinical development. It is the optimised lead for the spiroindolones, a novel class of compounds identified from a phenotypic screen as having antimalarial activity [2,7] and awarded MMV Project of the Year (2009).
The active enantiomer is shown here, with the 1R,3S configuration essential for antimalarial activity [2].

The Malaria tab on this ligand page provides additional curator comments of relevance to the Guide to MALARIA PHARMACOLOGY.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 3
Hydrogen bond donors 3
Rotatable bonds 0
Topological polar surface area 56.92
Molecular weight 389.05
XLogP 4.62
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES CC1Cc2c3cc(F)c(cc3[nH]c2C2(N1)C(=O)Nc1c2cc(Cl)cc1)Cl
Isomeric SMILES C[C@H]1Cc2c3cc(F)c(cc3[nH]c2[C@@]2(N1)C(=O)Nc1c2cc(Cl)cc1)Cl
InChI InChI=1S/C19H14Cl2FN3O/c1-8-4-11-10-6-14(22)13(21)7-16(10)23-17(11)19(25-8)12-5-9(20)2-3-15(12)24-18(19)26/h2-3,5-8,23,25H,4H2,1H3,(H,24,26)/t8-,19+/m0/s1
InChI Key CKLPLPZSUQEDRT-WPCRTTGESA-N
Bioactivity Comments
The interaction table below provides data from whole cell assays and gives the antiparasite activitity of cipargamin 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 cipargamin demonstrating no evidence of reduced potency against drug resistant strains. In addition, ex vivo testing of field-isolates from regions with known chloroquine resistance has shown potent asexual blood stage activity for both P. falciparum and P. vivax (IC50 <10nM) [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 ATPase4 PfNF54 Parasite growth inhibition assay - - 9.3 pIC50 - 2
pIC50 9.3 (IC50 5x10-10 M) [3H]-hypoxanthine incorporation assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum ATPase4 PfTM90C2A Parasite growth inhibition assay - - 9.3 pIC50 - 2
pIC50 9.3 (IC50 5x10-10 M) [3H]-hypoxanthine incorporation assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum ATPase4 PfK1 Parasite growth inhibition assay - - 9.2 pIC50 - 2
pIC50 9.2 (IC50 6x10-10 M) [3H]-hypoxanthine incorporation assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum ATPase4 Pf3D7 Parasite growth inhibition assay - - 9.1 pIC50 - 2
pIC50 9.1 (IC50 7x10-10 M) [3H]-hypoxanthine incorporation assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum ATPase4 PfW2 Parasite growth inhibition assay - - 9.1 pIC50 - 2
pIC50 9.1 (IC50 9x10-10 M) [3H]-hypoxanthine incorporation assay [2]
Plasmodium falciparum ATPase4 PfTM91C235 Parasite growth inhibition assay - - 9.1 pIC50 - 2
pIC50 9.1 (IC50 9x10-10 M) [3H]-hypoxanthine incorporation assay [2]
Plasmodium falciparum ATPase4 PfD6 Parasite growth inhibition assay - - 9.0 pIC50 - 2
pIC50 9.0 (IC50 1x10-9 M) [3H]-hypoxanthine incorporation assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum ATPase4 Pf7G8 Parasite growth inhibition assay - - 8.9 pIC50 - 2
pIC50 8.9 (IC50 1.2x10-9 M) [3H]-hypoxanthine incorporation assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum ATPase4 PfV1/S Parasite growth inhibition assay - - 8.9 pIC50 - 2
pIC50 8.9 (IC50 1.4x10-9 M) [3H]-hypoxanthine incorporation assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum ATPase4 PfNF54 Parasite early stage (I–II) gametocyte assay - - - - - 5
Giemsa-stained blood film counts: dose-dependent, significant inhibition of stage II gametocyte development [5]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Plasmodium falciparum ATPase4 PfNF54 Parasite late stage (III–V) gametocyte assay - - - - - 5
Giemsa-stained blood film counts: dose-dependent, inhibition of stage V gametocyte development [5]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
Plasmodium falciparum ATPase4 PfNF54 Standard membrane feeding assay (SMFA) - - - - - 5
Oocyst count: significantly reduced count observed with the addition of cipargamin when compared to control feeds [5]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)