compound 1a [WO2021204952A1]   Click here for help

GtoPdb Ligand ID: 11928

Antimalarial Ligand
Compound class: Synthetic organic
Comment: Compound 1a is from a series of novel tetrahydroisoquinoline derivatives, with antimalarial activity, claimed in patent WO2021204952A1 [1]. Antimalarial potency for this series is predominantly associated with the (+) enantiomer.

The Malaria tab on this ligand page provides additional curator comments of relevance to the Guide to MALARIA PHARMACOLOGY.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 6
Hydrogen bond donors 1
Rotatable bonds 8
Topological polar surface area 95.32
Molecular weight 524.15
XLogP 4.99
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES N#Cc1cc(ccc1F)NC(=O)[C@@H]1[C@@H](c2ccc(nc2)OC2CC2)N(CC(F)(F)F)C(=O)c2c1cccc2
Isomeric SMILES C1CC1Oc1ncc(cc1)[C@@H]1[C@H](c2ccccc2C(=O)N1CC(F)(F)F)C(=O)Nc1cc(c(cc1)F)C#N
InChI InChI=1S/C27H20F4N4O3/c28-21-9-6-17(11-16(21)12-32)34-25(36)23-19-3-1-2-4-20(19)26(37)35(14-27(29,30)31)24(23)15-5-10-22(33-13-15)38-18-7-8-18/h1-6,9-11,13,18,23-24H,7-8,14H2,(H,34,36)/t23-,24+/m0/s1
InChI Key KYICPNWURYGJCB-BJKOFHAPSA-N
Bioactivity Comments
Compound 1a demonstrates activity against the asexual blood stage of the Plasmodium lifecycle and also has transmission-blocking potential [1].
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
Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase 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.
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 Parasite growth inhibition assay - - 7.7 pEC50 - 1
⤷ pEC50 7.7 (EC50 1.9x10-8 M) SYBR Green assay [1]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase 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.
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 Standard membrane feeding assay (SMFA) - - - - - 1
⤷ Relative oocyst intensities, determined using transgenic reporter strain P. falciparum NF54-HGL, show that compound 1a has transmission-blocking potential [1]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)