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Identification
NameChloroquine
Accession NumberDB00608  (APRD00468)
Typesmall molecule
Groupsapproved
Description

The 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]

Structure
Thumb
Synonyms
SynonymLanguageCode
ChloraquineNot AvailableNot Available
ChlorochineNot AvailableNot Available
ChloroquinaNot AvailableNot Available
ChloroquiniumNot AvailableNot Available
ResochinNot AvailableNot Available
Salts
Name/CAS Structure Properties
Chloroquine Phosphate
Thumb
  • InChI Key: AEUAEICGCMSYCQ-UHFFFAOYNA-N
  • Monoisotopic Mass: 417.15842065
  • Average Mass: 417.867
DBSALT000025
Brand names
NameCompany
AralenSanofi
ArtrichinNot Available
BemaphateNot Available
CapquinNot Available
MalarexActavis
Nivaquine BSanofi
ResoquineNot Available
ReumachlorNot Available
SanoquinNot Available
Brand mixturesNot Available
Categories
CAS number54-05-7
WeightAverage: 319.872
Monoisotopic: 319.181525554
Chemical FormulaC18H26ClN3
InChI KeyWHTVZRBIWZFKQO-UHFFFAOYSA-N
InChI
InChI=1S/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)
IUPAC Name
{4-[(7-chloroquinolin-4-yl)amino]pentyl}diethylamine
SMILES
CCN(CC)CCCC(C)NC1=C2C=CC(Cl)=CC2=NC=C1
Mass Specshow(8.47 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassQuinolines and Derivatives
SubclassAminoquinolines and Derivatives
Direct parentAminoquinolines and Derivatives
Alternative parentsAminopyridines and Derivatives; Chlorobenzenes; Aryl Chlorides; Tertiary Amines; Polyamines; Secondary Amines; Organochlorides
Substituentsaminopyridine; chlorobenzene; aryl chloride; aryl halide; pyridine; benzene; tertiary amine; polyamine; secondary amine; amine; organochloride; organohalogen; organonitrogen compound
Classification descriptionThis compound belongs to the aminoquinolines and derivatives. These are organic compounds containing an amino group attached to a quinoline ring system.
Pharmacology
IndicationFor 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
PharmacodynamicsChloroquine is the prototype anti malarial drug, most widely used to treat all types of malaria except for disease caused by chloroquine resistant Plasmodium falciparum. It is highly effective against erythrocytic forms of Plasmodium vivax, Plasmodium ovale and Plasmodium malariae, sensitive strains of Plasmodium falciparum and gametocytes of Plasmodium vivax. Being alkaline, the drug reaches high concentration within the food vacuoles of the parasite and raises its pH. It is found to induce rapid clumping of the pigment. Chloroquine inhibits the parasitic enzyme heme polymerase that converts the toxic heme into non-toxic hemazoin, thereby resulting in the accumulation of toxic heme within the parasite. It may also interfere with the biosynthesis of nucleic acids.
Mechanism of actionThe 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.
AbsorptionCompletely absorbed from gastrointestinal tract
Volume of distributionNot Available
Protein binding~55% of the drug in the plasma is bound to nondiffusible plasma constituents
Metabolism

Hepatic (partially)

Route of eliminationExcretion of chloroquine is quite slow, but is increased by acidification of the urine.
Half life1-2 months
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Plasmodium
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9939
Blood Brain Barrier + 0.7421
Caco-2 permeable + 0.5804
P-glycoprotein substrate Substrate 0.8
P-glycoprotein inhibitor I Inhibitor 0.622
P-glycoprotein inhibitor II Inhibitor 0.7773
Renal organic cation transporter Inhibitor 0.6046
CYP450 2C9 substrate Non-substrate 0.8422
CYP450 2D6 substrate Substrate 0.8804
CYP450 3A4 substrate Substrate 0.6009
CYP450 1A2 substrate Non-inhibitor 0.8586
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9218
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.8308
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5496
Ames test AMES toxic 0.9106
Carcinogenicity Non-carcinogens 0.8374
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.9547 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.6959
hERG inhibition (predictor II) Inhibitor 0.8293
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
  • Impax laboratories inc
  • Ipca laboratories ltd
  • Md pharmaceutical inc
  • Purepac pharmaceutical co
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
  • West ward pharmaceutical corp
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Aralen 500 mg tablet7.85USDtablet
Aralen phosphate 500 mg tablet7.78USDtablet
Chloroquine ph 500 mg tablet5.64USDtablet
Chloroquine Phosphate 500 mg tablet5.42USDtablet
Chloroquine phosphate powdr4.29USDg
Plaquenil 200 mg tablet3.14USDtablet
Chloroquine Phosphate 250 mg tablet2.57USDtablet
Chloroquine ph 250 mg tablet2.49USDtablet
Novo-Chloroquine 250 mg Tablet0.35USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubility10.6 mg/LNot Available
logP4.63HANSCH,C ET AL. (1995)
pKa10.1SANGSTER (1994)
Predicted Properties
PropertyValueSource
water solubility1.75e-02 g/lALOGPS
logP5.28ALOGPS
logP3.93ChemAxon
logS-4.3ALOGPS
pKa (strongest basic)10.32ChemAxon
physiological charge2ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count1ChemAxon
polar surface area28.16ChemAxon
rotatable bond count8ChemAxon
refractivity96.42ChemAxon
polarizability37.29ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
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.

US2233970
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD02366
KEGG CompoundC07625
PubChem Compound2719
PubChem Substance46506925
ChemSpider2618
BindingDB22985
ChEBI3638
ChEMBLCHEMBL76
Therapeutic Targets DatabaseDAP001357
PharmGKBPA448948
HETCLQ
Drug Product Database21261
RxListhttp://www.rxlist.com/cgi/generic2/hquine2.htm
Drugs.comhttp://www.drugs.com/cdi/chloroquine.html
WikipediaChloroquine
ATC CodesP01BA01P01BA02
AHFS Codes
  • 08:30.08
PDB Entries
FDA labelshow(153 KB)
MSDSshow(74.9 KB)
Interactions
Drug Interactions
Drug
AluminiumThe antiacid decreases the absorption of chloroquine
ArtemetherChloroquine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.
AtomoxetineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
AttapulgiteThe antiacid decreases the absorption of chloroquine
CalciumThe antiacid decreases the absorption of chloroquine
CyclosporineChloroquine may increase the therapeutic and adverse effects of cyclosporine.
DihydroxyaluminiumThe antiacid decreases the absorption of chloroquine
KaolinThe antiacid decreases the absorption of chloroquine
LumefantrineChloroquine may increase the adverse effects of lumefantrine. Combination therapy is contraindicated unless there are no other treatment options.
MagnesiumThe antiacid decreases the absorption of chloroquine
Magnesium oxideThe antiacid decreases the absorption of chloroquine
MesoridazineIncreased risk of cardiotoxicity and arrhythmias
PraziquantelMarkedly lower praziquantel levels
TamoxifenChloroquine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.
TamsulosinChloroquine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Chloroquine is initiated, discontinued, or dose changed.
TelithromycinTelithromycin may reduce clearance of Chloroquine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Chloroquine if Telithromycin is initiated, discontinued or dose changed.
TerbinafineTerbinafine may reduce the metabolism and clearance of Chloroquine. Consider alternate therapy or monitor for therapeutic/adverse effects of Chloroquine if Terbinafine is initiated, discontinued or dose changed.
ThioridazineIncreased risk of cardiotoxicity and arrhythmias
TramadolChloroquine may decrease the effect of Tramadol by decreasing active metabolite production.
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of chloroquine by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of chloroquine if voriconazole is initiated, discontinued or dose changed.
Food Interactions
  • Take with food to reduce irritation and increase bioavailability.

Targets

1. Fe(II)-protoporphyrin IX

Kind: small molecule

Organism: Plasmodium falciparum

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details

References:

  1. Fitch CD: Ferriprotoporphyrin IX, phospholipids, and the antimalarial actions of quinoline drugs. Life Sci. 2004 Mar 5;74(16):1957-72. Pubmed
  2. Dorn A, Vippagunta SR, Matile H, Jaquet C, Vennerstrom JL, Ridley RG: An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerisation by quinoline antimalarials. Biochem Pharmacol. 1998 Mar 15;55(6):727-36. Pubmed
  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. Pubmed
  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. Pubmed

2. Glutathione S-transferase A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Glutathione S-transferase A2 P09210 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Tumor necrosis factor

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Tumor necrosis factor P01375 Details

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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed

4. Toll-like receptor 9

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Toll-like receptor 9 Q9NR96 Details

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. Pubmed
  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. Pubmed
  3. Lenert P: Inhibitory oligodeoxynucleotides – therapeutic promise for systemic autoimmune diseases? Clin Exp Immunol. 2005 Apr;140(1):1-10. Pubmed
  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. Pubmed
  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. Pubmed

5. Glutathione S-transferase

Kind: protein

Organism: Plasmodium falciparum

Pharmacological action: unknown

Components

Name UniProt ID Details
Glutathione S-transferase Q8MU52 Details

References:

  1. Hiller N, Fritz-Wolf K, Deponte M, Wende W, Zimmermann H, Becker K: Plasmodium falciparum glutathione S-transferase—structural and mechanistic studies on ligand binding and enzyme inhibition. Protein Sci. 2006 Feb;15(2):281-9. Epub 2005 Dec 29. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 1A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS: Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001 Nov;299(2):620-8. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on April 04, 2014 09:44