WM382   Click here for help

GtoPdb Ligand ID: 11162

Antimalarial Ligand
Compound class: Synthetic organic
Comment: WM382 is the drug-like lead for a novel class of antimalarial compounds that are dual inhibitors of P. falciparum plasmepsin IX (PfPMIX) and plasmepsin X (PfPMX). The compound was identified by an optimization study following phenotypic high-throughput screening of an aspartic protease inhibitor library [1].

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 6
Hydrogen bond donors 3
Rotatable bonds 6
Topological polar surface area 103.75
Molecular weight 504.27
XLogP 5.28
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
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Canonical SMILES CCC1(CC)NC(=N)N(C(=O)C1)[C@@H]1CCOc2c1cc(cc2)C(=O)N[C@H]1CC(C)(C)Oc2c1cccc2
Isomeric SMILES CCC1(CC)NC(=N)N(C(=O)C1)[C@@H]1CCOc2c1cc(cc2)C(=O)N[C@H]1CC(C)(C)Oc2c1cccc2
InChI InChI=1S/C29H36N4O4/c1-5-29(6-2)17-25(34)33(27(30)32-29)22-13-14-36-23-12-11-18(15-20(22)23)26(35)31-21-16-28(3,4)37-24-10-8-7-9-19(21)24/h7-12,15,21-22H,5-6,13-14,16-17H2,1-4H3,(H2,30,32)(H,31,35)/t21-,22+/m0/s1
InChI Key ZSZSSSHEMYULPX-FCHUYYIVSA-N
Bioactivity Comments
The interaction table below provides data from whole cell assays and gives the antiparasite activitity of WM382 against a number of Plasmodium lifecycle stages. The compound demonstrates potent in vitro activity against P. falciparum (including multidrug-resistant strains) and P. knowlesi, with parasite development arrested at the late schizont form of the asexual blood stage [1].

Note: PfPMIX is not yet included in the database, with PfPMX tagged as the target for this ligand for data retrieval purposes.
Selectivity at other protein targets
Key to terms and symbols Click on species/strain names for details Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
Plasmodium falciparum plasmepsin X Pf None Inhibition 10.5 pKi - 1
pKi 10.5 (Ki 3.5x10-11 M) [1]
Description: Peptide cleavage assay using recombinant PMX
Whole organism assay data
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MOA/likely target Sp. Assay description Type Action Value Parameter Concentration range (M) Reference
Plasmodium falciparum plasmepsin X Pk Parasite growth inhibition assay - - 9.7 pEC50 - 1
pEC50 9.7 (EC50 1.8x10-10 M) SYBR Green assay [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum plasmepsin X PfDd2 Parasite growth inhibition assay - - 9.6 pEC50 - 1
pEC50 9.6 (EC50 2.6x10-10 M) [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum plasmepsin X Pf3D7 Parasite growth inhibition assay - - 9.2 pEC50 - 1
pEC50 9.2 (EC50 6x10-10 M) Results are for R-WM382 [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum plasmepsin X PfK1 Parasite growth inhibition assay - - 9.2 pEC50 - 1
pEC50 9.2 (EC50 6.5x10-10 M) [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum plasmepsin X Pf Standard membrane feeding assay (SMFA) - - - - - 1
Oocyst count: potent inhibition of oocyst development [1]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)