fosmidomycin   Click here for help

GtoPdb Ligand ID: 9739

Synonyms: FR-31564
PDB Ligand Antimalarial Ligand
Compound class: Natural product
Comment: Fosmidomycin was first identified as antibacterial but also has antimalarial activity.

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 Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). 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 4
Hydrogen bond donors 3
Rotatable bonds 5
Topological polar surface area 107.88
Molecular weight 183.03
XLogP -2.24
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
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.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES O=CN(CCCP(=O)(O)O)O
Isomeric SMILES O=CN(CCCP(=O)(O)O)O
InChI InChI=1S/C4H10NO5P/c6-4-5(7)2-1-3-11(8,9)10/h4,7H,1-3H2,(H2,8,9,10)
InChI Key GJXWDTUCERCKIX-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
No information available.
Summary of Clinical Use Click here for help
Concerns regarding recrudescence rates, when the compound is used as a monotherapy, have focused clinical evaluation on fosmidomycin-based combination therapies (click here to view fosmidomycin trials registered with ClinicalTrials.gov). Fosmidomycin-clindamycin combined therapy shows promising results, progressing to Phase 3 (NCT00214643). In combination with piperaquine, fosmidomycin provides rapid parasitemia clearance, clinical recovery and post-treatment prophylaxis, with good safety and tolerance despite prolongation of the QT interval in a subset of participants (findings from Phase 2 trial NCT02198807)[3].
Mechanism Of Action and Pharmacodynamic Effects Click here for help
The exact mechanism of action of fosmidomycin is not fully understood, however it is believed to act on the non-mevalonate pathway of isoprenoid biosynthesis. Inhibition of the second enzyme in the pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) has been demonstrated using recombinant P. falciparum enzyme [1]. There is evidence that fosmidomycin may have indirect activity on 2-C-methyl-D-erythritol 4-phosphate cytidyltransferase (IspD), an enzyme further downstream in the non-mevalonate pathway [4].
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT00214643 Efficacy of Fosmidomycin-Clindamycin for Treating Malaria in Gabonese Children Phase 3 Interventional Albert Schweitzer Hospital
NCT02198807 Evaluation of Fosmidomycin and Piperaquine in the Treatment of Acute Falciparum Malaria Phase 2 Interventional Jomaa Pharma GmbH