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Record Information
Version2.0
Creation Date2009-07-05 03:00:49 UTC
Update Date2014-12-24 20:25:42 UTC
Accession NumberT3D2561
Identification
Common NameChloroquine
ClassSmall Molecule
DescriptionChloroquine is only found in individuals that have used or taken this drug. It is a prototypical antimalarial agent with a mechanism that is not well understood. It has also been used to treat rheumatoid arthritis, systemic lupus erythematosus, and in the systemic therapy of amebic liver abscesses. [PubChem]The mechanism of plasmodicidal action of chloroquine is not completely certain. Like other quinoline derivatives, it is thought to inhibit heme polymerase activity. This results in accumulation of free heme, which is toxic to the parasites. nside red blood cells, the malarial parasite must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasite cell.During this process, the parasite produces the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a non-toxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.Chloroquine enters the red blood cell, inhabiting parasite cell, and digestive vacuole by simple diffusion. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form what is known as the FP-Chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-Chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. In essence, the parasite cell drowns in its own metabolic products.
Compound Type
  • Amebicide
  • Amine
  • Antimalarial
  • Antirheumatic Agent
  • Drug
  • Metabolite
  • Organic Compound
  • Organochloride
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Aralen
Artrichin
Bemaphate
Capquin
Chloraquine
Chlorochin
Chlorochine
Chloroquina
Chloroquinium
Chloroquinum
Chlorquin
Clorochina
Cloroquina
Malarex
N(4)-(7-chloro-4-Quinolinyl)-N(1),N(1)-diethyl-1,4-pentanediamine
Nivaquine b
Resochin
Resoquine
Reumachlor
Sanoquin
Chemical FormulaC18H26ClN3
Average Molecular Mass319.872 g/mol
Monoisotopic Mass319.182 g/mol
CAS Registry Number54-05-7
IUPAC Name7-chloro-N-[5-(diethylamino)pentan-2-yl]quinolin-4-amine
Traditional Name7-chloro-N-[5-(diethylamino)pentan-2-yl]quinolin-4-amine
SMILESCCN(CC)CCCC(C)NC1=C2C=CC(Cl)=CC2=NC=C1
InChI IdentifierInChI=1/C18H26ClN3/c1-4-22(5-2)12-6-7-14(3)21-17-10-11-20-18-13-15(19)8-9-16(17)18/h8-11,13-14H,4-7,12H2,1-3H3,(H,20,21)
InChI KeyInChIKey=WHTVZRBIWZFKQO-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as 4-aminoquinolines. These are organic compounds containing an amino group attached to the 4-position of a quinoline ring system.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassQuinolines and derivatives
Sub ClassAminoquinolines and derivatives
Direct Parent4-aminoquinolines
Alternative Parents
Substituents
  • 4-aminoquinoline
  • Haloquinoline
  • Chloroquinoline
  • Aminopyridine
  • Secondary aliphatic/aromatic amine
  • Aryl chloride
  • Aryl halide
  • Pyridine
  • Benzenoid
  • Heteroaromatic compound
  • Tertiary aliphatic amine
  • Tertiary amine
  • Azacycle
  • Secondary amine
  • Amine
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Hydrocarbon derivative
  • Organopnictogen compound
  • Organic nitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite to slightly yellow, crystalline powder (2).
Experimental Properties
PropertyValue
Melting Point289°C
Boiling PointNot Available
Solubility10.6 mg/L
LogP4.63
Predicted Properties
PropertyValueSource
Water Solubility0.018 g/LALOGPS
logP5.28ALOGPS
logP3.93ChemAxon
logS-4.3ALOGPS
pKa (Strongest Basic)10.32ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area28.16 ŲChemAxon
Rotatable Bond Count8ChemAxon
Refractivity96.42 m³·mol⁻¹ChemAxon
Polarizability37.29 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-00di-0009000000-d54119d64cfc341cee7dJSpectraViewer | MoNA
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-00di-0009000000-d54119d64cfc341cee7dJSpectraViewer | MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0pbi-9242000000-6cd79ce1c8a9ada4550dJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00di-0119000000-8f9d4513bf5993f3c9c4JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00dl-3957000000-e533e26da609c9329daeJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00bc-9530000000-646244109f4c47e0c2a6JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-014i-0009000000-d45e56a4f82a2d58657dJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-014i-1229000000-09769326d92e55dd78aaJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00fu-9630000000-f2986e805921cc8d3a37JSpectraViewer
MSMass Spectrum (Electron Ionization)splash10-000i-9320000000-2663c398ede2e502ca34JSpectraViewer | MoNA
Toxicity Profile
Route of ExposureInhalation Completely absorbed from gastrointestinal tract
Mechanism of ToxicityThe mechanism of plasmodicidal action of chloroquine is not completely certain. Like other quinoline derivatives, it is thought to inhibit heme polymerase activity. This results in accumulation of free heme, which is toxic to the parasites. nside red blood cells, the malarial parasite must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasite cell. During this process, the parasite produces the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a non-toxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals. Chloroquine enters the red blood cell, inhabiting parasite cell, and digestive vacuole by simple diffusion. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form what is known as the FP-Chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-Chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. In essence, the parasite cell drowns in its own metabolic products.
MetabolismCompletely absorbed from gastrointestinal tract. Chloroquine is partially metabolized; the major metabolite is desethylchloroquine. Desethylchloroquine also has antiplasmodial activity, but is slightly less active than chloroquine. Bisdesethylchloroquine, which is a carboxylic acid derivative, and several other unidentified metabolites are also formed in small amounts (3). Route of Elimination: Excretion of chloroquine is quite slow, but is increased by acidification of the urine. Half Life: 1-2 months
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)3, not classifiable as to its carcinogenicity to humans. (6)
Uses/SourcesFor the suppressive treatment and for acute attacks of malaria due to P. vivax, P.malariae, P. ovale, and susceptible strains of P. falciparum, Second-line agent in treatment of Rheumatoid Arthritis (1).
Minimum Risk LevelNot Available
Health EffectsPossible heath effects include an irreversible retinal damage, visual disturbances, nyctalopia; scotomatous vision with field defects of paracentral, pericentral ring types, and typically temporal scotomas, nerve type deafness; tinnitus, reduced hearing in patients with preexisting auditory damage. Other effects include pleomorphic skin eruptions, skeletal muscle myopathy, hypotension, electrocardiographic change as well as neuropsychiatric changes including psychosis, delirium, personality changes and depression (RxList, A308).
SymptomsConvulsive seizures. Mild and transient headache.
TreatmentTreatment is symptomatic and must be prompt with immediate evacuation of the stomach by emesis (at home, before transportation to the hospital) or gastric lavage until the stomach is completely emptied. If finely powdered, activated charcoal is introduced by stomach tube, after lavage, and within 30 minutes after ingestion of the antimalarial, it may inhibit further intestinal absorption of the drug. To be effective, the dose of activated charcoal should be at least five times the estimated dose of chloroquine ingested. Convulsions, if present, should be controlled before attempting gastric lavage. (8)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00608
HMDB IDHMDB14746
PubChem Compound ID2719
ChEMBL IDCHEMBL76
ChemSpider ID2618
KEGG IDC07625
UniProt IDNot Available
OMIM ID
ChEBI ID3638
BioCyc IDNot Available
CTD IDD002738
Stitch IDChloroquine
PDB IDCLQ
ACToR IDNot Available
Wikipedia LinkChloroquine
References
Synthesis Reference

Andersag, H., Breitner, S.and Jung, H.; U S . Patent 2,233,970; March 4,1941; assigned to
Winthrop Chemical Company, Inc.

MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Flanagan JN, Young MV, Persons KS, Wang L, Mathieu JS, Whitlatch LW, Holick MF, Chen TC: Vitamin D metabolism in human prostate cells: implications for prostate cancer chemoprevention by vitamin D. Anticancer Res. 2006 Jul-Aug;26(4A):2567-72. [16886665 ]
  3. Kojima T, Matsumoto M, Togashi H, Tachibana K, Kemmotsu O, Yoshioka M: Fluvoxamine suppresses the long-term potentiation in the hippocampal CA1 field of anesthetized rats: an effect mediated via 5-HT1A receptors. Brain Res. 2003 Jan 3;959(1):165-8. [12480170 ]
  4. Osol A, Hoover JE, et al. (eds) (1975). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co.
  5. McEvoy GK (ed) (2006). American Hospital Formulary Service - Drug Information 2006. Bethesda, MD: American Society of Health-System Pharmacists.
  6. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
  7. Drugs.com [Link]
  8. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Transmembrane signaling receptor activity
Specific Function:
Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Controls lymphocyte response to Helicobacter infection.
Gene Name:
TLR9
Uniprot ID:
Q9NR96
Molecular Weight:
115858.665 Da
References
  1. Trevani AS, Chorny A, Salamone G, Vermeulen M, Gamberale R, Schettini J, Raiden S, Geffner J: Bacterial DNA activates human neutrophils by a CpG-independent pathway. Eur J Immunol. 2003 Nov;33(11):3164-74. [14579285 ]
  2. Rutz M, Metzger J, Gellert T, Luppa P, Lipford GB, Wagner H, Bauer S: Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur J Immunol. 2004 Sep;34(9):2541-50. [15307186 ]
  3. Lenert P: Inhibitory oligodeoxynucleotides - therapeutic promise for systemic autoimmune diseases? Clin Exp Immunol. 2005 Apr;140(1):1-10. [15762869 ]
  4. Huang LY, Ishii KJ, Akira S, Aliberti J, Golding B: Th1-like cytokine induction by heat-killed Brucella abortus is dependent on triggering of TLR9. J Immunol. 2005 Sep 15;175(6):3964-70. [16148144 ]
  5. Merrell MA, Ilvesaro JM, Lehtonen N, Sorsa T, Gehrs B, Rosenthal E, Chen D, Shackley B, Harris KW, Selander KS: Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity. Mol Cancer Res. 2006 Jul;4(7):437-47. [16849519 ]
General Function:
Tumor necrosis factor receptor binding
Specific Function:
Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:22517918).The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.
Gene Name:
TNF
Uniprot ID:
P01375
Molecular Weight:
25644.15 Da
References
  1. Jang CH, Choi JH, Byun MS, Jue DM: Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes. Rheumatology (Oxford). 2006 Jun;45(6):703-10. Epub 2006 Jan 17. [16418198 ]
  2. Rachmilewitz D, Karmeli F, Shteingart S, Lee J, Takabayashi K, Raz E: Immunostimulatory oligonucleotides inhibit colonic proinflammatory cytokine production in ulcerative colitis. Inflamm Bowel Dis. 2006 May;12(5):339-45. [16670522 ]
  3. Wozniacka A, Lesiak A, Narbutt J, McCauliffe DP, Sysa-Jedrzejowska A: Chloroquine treatment influences proinflammatory cytokine levels in systemic lupus erythematosus patients. Lupus. 2006;15(5):268-75. [16761500 ]
  4. Lim EJ, Lee SH, Lee JG, Chin BR, Bae YS, Kim JR, Lee CH, Baek SH: Activation of toll-like receptor-9 induces matrix metalloproteinase-9 expression through Akt and tumor necrosis factor-alpha signaling. FEBS Lett. 2006 Aug 7;580(18):4533-8. Epub 2006 Jul 17. [16870179 ]
  5. Dias-Melicio LA, Calvi SA, Bordon AP, Golim MA, Peracoli MT, Soares AM: Chloroquine is therapeutic in murine experimental model of paracoccidioidomycosis. FEMS Immunol Med Microbiol. 2007 Jun;50(1):133-43. Epub 2007 Apr 23. [17456179 ]
General Function:
Oxygen transporter activity
Specific Function:
Involved in oxygen transport from the lung to the various peripheral tissues.
Gene Name:
HBA1
Uniprot ID:
P69905
Molecular Weight:
15257.405 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
  3. Stoller TJ, Shields D: The propeptide of preprosomatostatin mediates intracellular transport and secretion of alpha-globin from mammalian cells. J Cell Biol. 1989 May;108(5):1647-55. [2565905 ]
  4. Mockenhaupt FP, May J, Bergqvist Y, Meyer CG, Falusi AG, Bienzle U: Evidence for a reduced effect of chloroquine against Plasmodium falciparum in alpha-thalassaemic children. Trop Med Int Health. 2001 Feb;6(2):102-7. [11251905 ]
General Function:
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function:
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation.
Gene Name:
KCNH2
Uniprot ID:
Q12809
Molecular Weight:
126653.52 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC502.5 uMNot AvailableBindingDB 22985
References
  1. Du LP, Tsai KC, Li MY, You QD, Xia L: The pharmacophore hypotheses of I(Kr) potassium channel blockers: novel class III antiarrhythmic agents. Bioorg Med Chem Lett. 2004 Sep 20;14(18):4771-7. [15324906 ]
  2. O'Neill PM, Park BK, Shone AE, Maggs JL, Roberts P, Stocks PA, Biagini GA, Bray PG, Gibbons P, Berry N, Winstanley PA, Mukhtar A, Bonar-Law R, Hindley S, Bambal RB, Davis CB, Bates M, Hart TK, Gresham SL, Lawrence RM, Brigandi RA, Gomez-delas-Heras FM, Gargallo DV, Ward SA: Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century. J Med Chem. 2009 Mar 12;52(5):1408-15. doi: 10.1021/jm8012618. [19222165 ]
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50350 uMNot AvailableBindingDB 22985
References
  1. Roy K, Pratim Roy P: Comparative chemometric modeling of cytochrome 3A4 inhibitory activity of structurally diverse compounds using stepwise MLR, FA-MLR, PLS, GFA, G/PLS and ANN techniques. Eur J Med Chem. 2009 Jul;44(7):2913-22. doi: 10.1016/j.ejmech.2008.12.004. Epub 2008 Dec 16. [19128860 ]
General Function:
Glutathione transferase activity
Specific Function:
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
Gene Name:
GSTA2
Uniprot ID:
P09210
Molecular Weight:
25663.675 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]