DSM421   Click here for help

GtoPdb Ligand ID: 10020

PDB Ligand Antimalarial Ligand
Compound class: Synthetic organic
Comment: DSM421 was being developed as a backup compound to DSM265, the clinical lead for the triazolopyrimidine structural class of antimalarial compounds, but it has not been progressed due to unpredicted off-target toxicity [1,3].

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 5
Hydrogen bond donors 1
Rotatable bonds 4
Topological polar surface area 68
Molecular weight 358.1
XLogP 2.83
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES Cc1cc(Nc2ccc(nc2)C(F)(F)F)n2c(n1)nc(n2)C(F)(F)C
Isomeric SMILES Cc1cc(Nc2ccc(nc2)C(F)(F)F)n2c(n1)nc(n2)C(F)(F)C
InChI InChI=1S/C14H11F5N6/c1-7-5-10(22-8-3-4-9(20-6-8)14(17,18)19)25-12(21-7)23-11(24-25)13(2,15)16/h3-6,22H,1-2H3
InChI Key HDLFZCDEGAWEFX-UHFFFAOYSA-N
Bioactivity Comments
DSM421 exhibits improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265 [3]. Its excellent efficacy in the SCID mouse model of P. falciparum malaria suggests that of a dose of <200 mg will be effective in humans. Notably, DSM421 is equally activity against field isolates of both P. falciparum and P. vivax, which is in contrast to DSM265 which is more active against P. falciparum. In addition, DSM421 has improved species selectivity relative to DSM265 (i.e. it inhibits mouse and rat DHODH less potently) meaning that toxicological studies in these species will be unhindered.
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
dihydroorotate dehydrogenase (quinone) Hs Inhibitor Inhibition <4.0 pIC50 - 3
pIC50 <4.0 (IC50 >1x10-4 M) [3]
Description: Steady-state kinetic analysis performed to measure recombinant enzyme inhibition.
dihydroorotate dehydrogenase (quinone) Mm Inhibitor Inhibition <4.0 pIC50 - 3
pIC50 <4.0 (IC50 >1x10-4 M) [3]
Description: Steady-state kinetic analysis performed to measure recombinant enzyme inhibition.
dihydroorotate dehydrogenase (quinone) Rn Inhibitor Inhibition <4.0 pIC50 - 3
pIC50 <4.0 (IC50 >1x10-4 M) [3]
Description: Steady-state kinetic analysis performed to measure recombinant enzyme inhibition.
Selectivity at other protein targets
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
Plasmodium falciparum dihydroorotate dehydrogenase Primary target of this compound Pf Inhibitor Inhibition 7.3 pIC50 - 3
pIC50 7.3 (IC50 5.3x10-8 M) [3]
Description: Steady-state kinetic analysis of recombinant enzyme inhibition.
Plasmodium falciparum dihydroorotate dehydrogenase Primary target of this compound Pv Inhibitor Inhibition 7.0 pIC50 - 3
pIC50 7.0 (IC50 9.4x10-8 M) [3]
Description: Steady-state kinetic analysis of recombinant enzyme inhibition.
Whole organism assay data
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MOA/likely target Sp. Assay description Type Action Value Parameter Concentration range (M) Reference
Plasmodium falciparum dihydroorotate dehydrogenase Pf3D7 Parasite growth inhibition assay - - 7.4 – 7.8 pEC50 - 3
pEC50 7.8 (EC50 1.4x10-8 M) SYBR Green incorporation (72h assay) [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
pEC50 7.4 (EC50 4.3x10-8 M) SYBR Green incorporation (48h assay) [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum dihydroorotate dehydrogenase Pv Blood-stage: schizont maturation assay using P. vivax field isolates. - - 6.7 pEC50 - 3
pEC50 6.7 (EC50 1.8x10-7 M) [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)