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Piperaquine

PubChem CID
122262
Structure
Piperaquine_small.png
Piperaquine_3D_Structure.png
Molecular Formula
Synonyms
  • piperaquine
  • 4085-31-8
  • Piperaquine phosphate
  • Piperaquinoline
  • 1,3-Bis(4-(7-chloroquinolin-4-yl)piperazin-1-yl)propane
Molecular Weight
535.5 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-08-08
  • Modify:
    2025-01-18
Description
Piperaquine is an aminoquinoline that is 1,3-di(piperazin-1-yl)propane in which the nitrogen at position 4 of each of the piperazine moieties is replaced by a 7-chloroquinolin-4-yl group. It has a role as an antimalarial. It is a N-arylpiperazine, an organochlorine compound and an aminoquinoline.
Piperaquine is an antimalarial agent first synthesized in the 1960's and used throughout China. Its use declined in the 1980's as piperaquine resistant strains of *Plasmodium falciparum* appeared and artemisinin derivatives became available. It has come back into use in combination with the artemisinin derivative [DB11638] as part of the combination product Eurartesim. Eurartesim was first authorized for market by the European Medicines Agency in October 2011.
PIPERAQUINE is a small molecule drug with a maximum clinical trial phase of III (across all indications) and has 7 investigational indications.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Piperaquine.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

7-chloro-4-[4-[3-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]propyl]piperazin-1-yl]quinoline
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C29H32Cl2N6/c30-22-2-4-24-26(20-22)32-8-6-28(24)36-16-12-34(13-17-36)10-1-11-35-14-18-37(19-15-35)29-7-9-33-27-21-23(31)3-5-25(27)29/h2-9,20-21H,1,10-19H2
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

UCRHFBCYFMIWHC-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

C1CN(CCN1CCCN2CCN(CC2)C3=C4C=CC(=CC4=NC=C3)Cl)C5=C6C=CC(=CC6=NC=C5)Cl
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C29H32Cl2N6
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 Deprecated CAS

83764-65-2

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 Metabolomics Workbench ID

2.3.10 NCI Thesaurus Code

2.3.11 Nikkaji Number

2.3.12 PharmGKB ID

2.3.13 Pharos Ligand ID

2.3.14 Wikidata

2.3.15 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 1,3-bis(1-(7-chloro-4'-quinolyl)-4'-piperazinyl)propane
  • piperaquine
  • piperaquine phosphate
  • piperaquine phosphate (1:1)
  • piperaquine phosphate (1:4) anhydrous
  • piperaquine tetraphosphate anhydrous
  • piperaquine tetraphosphate tetrahydrate
  • quinoline, 4,4'-(1,3-propanediyldi-4,1-piperazinediyl)bis(7-chloro-)
  • quinoline, 4,4'-(1,3-propanediyldi-4,1-piperazinediyl)bis(7-chloro-, phosphate (1:1)
  • quinoline, 4,4'-(1,3-propanediyldi-4,1-piperazinediyl)bis(7-chloro-, phosphate (1:4)
  • quinoline, 4,4'-(1,3-propanediyldi-4,1-piperazinediyl)bis(7-chloro-, phosphate, hydrate (1:4:4)

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
535.5 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
5.6
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
0
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
6
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
6
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
534.2065504 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
534.2065504 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
38.7 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
37
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
655
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Chemical Classes

3.2.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 13C NMR Spectra

Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
Thumbnail
Thumbnail

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

For the treatment of uncomplicated *Plasmodium falciparum* infection in adults, children, and infants aged 6 months and up weighing over 5 kg. Used in combination with [DB11638].

7.2 Clinical Trials

7.2.1 ClinicalTrials.gov

7.2.2 EU Clinical Trials Register

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Piperaquine inhibits the P. Falciparum parasite's haem detoxification pathway.

8.2 MeSH Pharmacological Classification

Antimalarials
Agents used in the treatment of malaria. They are usually classified on the basis of their action against plasmodia at different stages in their life cycle in the human. (From AMA, Drug Evaluations Annual, 1992, p1585) (See all compounds classified as Antimalarials.)

8.3 Absorption, Distribution and Excretion

Absorption
Piperaquine is slowly absorbed and exhibits multiple peaks in its plasma concentration curve suggestive of enterohepatic recycling occurring alongside the absorption process. Due to this complication there is no discreet value for bioavailability but piperaquine is highly absorbed into systemic circulation. When taken with food, Cmax increases by 217% and mean exposure increases by 177%. Tmax is not affected by food and remains around 5 h. Piperaquine has been observed to accumulate more in females to a degree of 30-50% more than males. It also collects in red blood cells similar to [DB11638].
Route of Elimination
Piperaquine is mainly excreted in the feces with a negligible amount in the urine.
Volume of Distribution
Piperaquine is thought to distribute into a central compartment with an apparent volume of 26.7 L/kg, and two peripheral compartments with apparent volumes of 76.8 L/kg and 617 L/kg. These combine for a total volume of distribution of 720.5 L/kg.
Clearance
The mean apparent total clearance has been observed to be 1.12 L/h/kg in adult malaria patients.

8.4 Metabolism / Metabolites

Piperaquine undergoes N-dealkylation, separating its aliphatic bridge from one of the nitrogen-containing rings. The resulting aldehyde is then oxidized to a carboxylic acid to form metabolite 1 (M1). The same nitrogen-containing rings can also undergo hydroxylation at one of two sites to form M3 or M4. M2 is formed via N-oxidation of one of the nitrogens in the quinoline groups at either side of the molecule. M5 results when both of these nitrogens are oxidized. M1 and M2 are the major metabolism products. Each of these metabolites were observed in the urine.

8.5 Biological Half-Life

The terminal elimination half-life was observed to be 576h or 24 days. This is thought to be due to the extensive distribution of piperaquine.

8.6 Mechanism of Action

The mechanism of piperaquine inhibition of the haem detoxification pathway is unknown but is expected to be similar to that of [DB00608].

9 Toxicity

9.1 Toxicological Information

9.1.1 Acute Effects

9.1.2 Protein Binding

Piperaquine's binding to plasma proteins is considered to be virtually complete. It has been measured to be >99% in humans, rats, and dogs.

10 Associated Disorders and Diseases

11 Literature

11.1 Consolidated References

11.2 NLM Curated PubMed Citations

11.3 Springer Nature References

11.4 Chemical Co-Occurrences in Literature

11.5 Chemical-Gene Co-Occurrences in Literature

11.6 Chemical-Disease Co-Occurrences in Literature

12 Patents

12.1 Depositor-Supplied Patent Identifiers

12.2 WIPO PATENTSCOPE

12.3 Chemical Co-Occurrences in Patents

12.4 Chemical-Disease Co-Occurrences in Patents

12.5 Chemical-Gene Co-Occurrences in Patents

13 Interactions and Pathways

13.1 Chemical-Target Interactions

13.2 Drug-Drug Interactions

14 Biological Test Results

14.1 BioAssay Results

15 Classification

15.1 MeSH Tree

15.2 NCI Thesaurus Tree

15.3 ChEBI Ontology

15.4 ChemIDplus

15.5 ChEMBL Target Tree

15.6 NORMAN Suspect List Exchange Classification

15.7 EPA DSSTox Classification

15.8 MolGenie Organic Chemistry Ontology

16 Information Sources

  1. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
    Quinoline, 4,4′-(1,3-propanediyldi-4,1-piperazinediyl)bis[7-chloro-
    https://commonchemistry.cas.org/detail?cas_rn=4085-31-8
  2. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  4. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  6. ChEBI
  7. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  8. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  9. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  10. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  11. EU Clinical Trials Register
  12. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  13. Japan Chemical Substance Dictionary (Nikkaji)
  14. Metabolomics Workbench
  15. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  16. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    Piperaquine
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  17. Therapeutic Target Database (TTD)
  18. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  19. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  20. SpectraBase
    PIPERAQUINE;1,3-BIS-[4-(7-CHLOROQUINOLYL-4)-PIPERAZINYL-1]-PROPANE
    https://spectrabase.com/spectrum/DeGkcT1PkEJ
  21. Springer Nature
  22. Wikidata
  23. Wikipedia
  24. PubChem
  25. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
  26. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  27. PATENTSCOPE (WIPO)
  28. NCBI
CONTENTS