CHLOROQUINE

First approved in 1943

Details

Stereochemistry	RACEMIC
Molecular Formula	C18H26ClN3
Molecular Weight	319.872
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCN(CC)CCCC(C)NC1=CC=NC2=C1C=CC(Cl)=C2

InChI

InChIKey=WHTVZRBIWZFKQO-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Molecular Formula	C18H26ClN3
Molecular Weight	319.872
Charge	0
Count

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 1
E/Z Centers	0
Optical Activity	( + / - )

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/06002slr039_aralen_lbl.pdf | https://www.ncbi.nlm.nih.gov/pubmed/14967191

Chloroquine (brand name Aralen) is indicated for the suppressive treatment and for acute attacks of malaria due to P. vivax, P.malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated for the treatment of extraintestinal amebiasis. In addition, chloroquine is in clinical trials as an investigational antiretroviral in humans with HIV-1/AIDS and as a potential antiviral agent against chikungunya fever. The mechanism of plasmodicidal action of chloroquine is not completely certain. However, is existed theory, that like other quinoline derivatives, it is thought to inhibit heme polymerase activity. 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. 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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Ferriprotoporphyrin IX 41 Target ID: CHEMBL613897 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14967191	Inhibitor 8146
L-lactate dehydrogenase 8 Target ID: P13774 Gene ID: NA Gene Symbol: NA Target Organism: Plasmodium falciparum Sources: https://www.ncbi.nlm.nih.gov/pubmed/10187806	Binding Agent 1037
Plasmodium falciparum 71 Target ID: CHEMBL364 Sources: https://www.ncbi.nlm.nih.gov/pubmed/3279208 \| https://www.ncbi.nlm.nih.gov/pubmed/25016227 \|	Inhibitor 8146
Ferriprotoporphyrin IX 41 Target ID: CHEMBL613897 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14967191	Inhibitor 8146

Conditions

Condition	Modality	Highest Phase	Product
Acute attacks of malaria 8 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/06002slr039_aralen_lbl.pdf	Curative	Approved 8307	ARALEN Approved Use ARALEN is indicated for the suppressive treatment and for acute attacks of malaria due to P. vivax, P.malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated for the treatment of extraintestinal amebiasis. ARALEN does not prevent relapses in patients with vivax or malariae malaria because it is not effective against exoerythrocytic forms of the parasite, nor will it prevent vivax or malariae infection when administered as a prophylactic. It is highly effective as a suppressive agent in patients with vivax or malariae malaria, in terminating acute attacks, and significantly lengthening the interval between treatment and relapse. In patients with falciparum malaria it abolishes the acute attack and effects complete cure of the infection, unless due to a resistant strain of P. falciparum. Launch Date -6.3650883E11
Extraintestinal amebiasis 8 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/06002slr039_aralen_lbl.pdf	Curative	Approved 8307	ARALEN Approved Use ARALEN is indicated for the suppressive treatment and for acute attacks of malaria due to P. vivax, P.malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated for the treatment of extraintestinal amebiasis. ARALEN does not prevent relapses in patients with vivax or malariae malaria because it is not effective against exoerythrocytic forms of the parasite, nor will it prevent vivax or malariae infection when administered as a prophylactic. It is highly effective as a suppressive agent in patients with vivax or malariae malaria, in terminating acute attacks, and significantly lengthening the interval between treatment and relapse. In patients with falciparum malaria it abolishes the acute attack and effects complete cure of the infection, unless due to a resistant strain of P. falciparum. Launch Date -6.3650883E11
HIV-1 infection 145 Sources: https://clinicaltrials.gov/ct2/show/NCT00819390	Primary	Phase II 1133	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
700 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18594802/	5 mg/kg 1 times / day multiple, oral dose: 5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered:		CHLOROQUINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
134087 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18594802/	5 mg/kg 1 times / day multiple, oral dose: 5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered:		CHLOROQUINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
209 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18594802/	5 mg/kg 1 times / day multiple, oral dose: 5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered:		CHLOROQUINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
45% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18594802/	5 mg/kg 1 times / day multiple, oral dose: 5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered:		CHLOROQUINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
3 g single, oral Overdose Dose: 3 g Route: oral Route: single Dose: 3 g Sources: https://pubmed.ncbi.nlm.nih.gov/33722251	unknown, 14 years n = 1 Health Status: unknown Age Group: 14 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/33722251	Other AEs: Cardiac arrest... Other AEs: Cardiac arrest Sources: https://pubmed.ncbi.nlm.nih.gov/33722251
600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30195996	pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: https://pubmed.ncbi.nlm.nih.gov/30195996	Other AEs: Dizziness, Vomiting... Other AEs: Dizziness (19%) Vomiting (17%) Palpitations (5%) Headache (6%) Nausea (5%) Abdominal pain (2%) Sources: https://pubmed.ncbi.nlm.nih.gov/30195996

AEs

AE	Significance	Dose	Population
Cardiac arrest		3 g single, oral Overdose Dose: 3 g Route: oral Route: single Dose: 3 g Sources: https://pubmed.ncbi.nlm.nih.gov/33722251	unknown, 14 years n = 1 Health Status: unknown Age Group: 14 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/33722251
Vomiting	17%	600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30195996	pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: https://pubmed.ncbi.nlm.nih.gov/30195996
Dizziness	19%	600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30195996	pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: https://pubmed.ncbi.nlm.nih.gov/30195996
Abdominal pain	2%	600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30195996	pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: https://pubmed.ncbi.nlm.nih.gov/30195996
Nausea	5%	600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30195996	pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: https://pubmed.ncbi.nlm.nih.gov/30195996
Palpitations	5%	600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30195996	pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: https://pubmed.ncbi.nlm.nih.gov/30195996
Headache	6%	600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30195996	pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: https://pubmed.ncbi.nlm.nih.gov/30195996

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1532 substrate 1670		inhibitor 1789 substrate 1168	inhibitor 1570

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1410 CYP1A2 1463 CYP2E1 846 MATE1 302 OCT2 630	CYP2C8 670 CYP1A1 344

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 1620	inhibitor 3185 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873674/	no	no (co-administration study) Comment: chloroquine did not affect the activities of CYP1A2, CYP2C19, CYP2E1, CYP3A4 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873674/
CYP2C19 1484	inhibitor 3185 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873674/	no	no (co-administration study) Comment: chloroquine did not affect the activities of CYP1A2, CYP2C19, CYP2E1, CYP3A4 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873674/
CYP2E1 929	inhibitor 3185 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873674/	no	no (co-administration study) Comment: chloroquine did not affect the activities of CYP1A2, CYP2C19, CYP2E1, CYP3A4 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873674/
CYP3A4 1857	inhibitor 3185 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873674/	no	no (co-administration study) Comment: chloroquine did not affect the activities of CYP1A2, CYP2C19, CYP2E1, CYP3A4 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873674/
OCT2 631	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/19002438/	yes [IC50 1096 uM]
MATE1 304	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/21518836/	yes [IC50 2.5 uM]
CYP2D6 1826	inhibitor 3185 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873379/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873674/	yes [Ki 12 uM]	weak (co-administration study) Comment: selective inhibiton; Chloroquine produced a reduction in the metabolism of debrisoquine as evaluated by the debrisoquine recovery ratio, a measure of CYP2D6 activity. This reduction was progressive from the first to the seventh dose. This decrease in metabolism was modest (about 7% after the first dose and about 18% after seven doses) but statistically significant Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873379/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873674/

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP1A1 344	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/12756207/	yes
CYP2C8 670	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/12756207/	yes
CYP2D6 1168	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/12756207/; https://link.springer.com/article/10.2165/00003088-199631040-00003	yes	yes (co-administration study) Comment: Concomitant administration of a single dose of chloroquine and cimetidine daily starting 4 days prior to chloroquine, resulted in a 50% increase in chloroquine half-life, associated with a 50% decrease in its clearance.Since the AUC of desethylchloroquine decreased by 47%, cimetidine probably decreased chloroquine clearance by inhibiting its hepatic desethylation. Sources: https://pubmed.ncbi.nlm.nih.gov/12756207/; https://link.springer.com/article/10.2165/00003088-199631040-00003
CYP3A4 1670	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/12756207/; https://link.springer.com/article/10.2165/00003088-199631040-00003	yes	yes (co-administration study) Comment: Concomitant administration of a single dose of chloroquine and cimetidine daily starting 4 days prior to chloroquine, resulted in a 50% increase in chloroquine half-life, associated with a 50% decrease in its clearance.Since the AUC of desethylchloroquine decreased by 47%, cimetidine probably decreased chloroquine clearance by inhibiting its hepatic desethylation. Sources: https://pubmed.ncbi.nlm.nih.gov/12756207/; https://link.springer.com/article/10.2165/00003088-199631040-00003

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1603	inhibitor 1584 Sources: https://pubmed.ncbi.nlm.nih.gov/14729380/ Page: 44.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:50178	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:50178
ChemicalBook	CB7204393	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7204393
eMolecules	7546431	https://www.emolecules.com/cgi-bin/more?vid=7546431

PubMed

Title	Date	PubMed
Drug-induced haemolysis and renal failure in children with glucose-6-phosphate dehydrogenase deficiency in Central Asia.	1990	1708959
Inhibition of human immunodeficiency virus infectivity by chloroquine.	1990 Apr	1692728
Persisting chloroquine-induced myasthenia?	1991	1665944
Chloroquine related complete heart block with blindness: case report.	1992 Jan	1628552
Involvement of GABAergic mechanisms in chloroquine-induced seizures in mice.	1992 Mar	1639237
The effect of EGb 761 on the doxorubicin cardiomyopathy.	1999	11485048
Calcitriol-mediated hypercalcaemia and increased interleukins in a patient with sarcoid myopathy.	1999	10638776
Multifocal ERG in chloroquine retinopathy: regional variance of retinal dysfunction.	2000 Jan	10664060
[Complete heart block following chronic chloroquine treatment].	2000 May	10874768
Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced release of nitric oxide.	2001 Jul 31	11518563
The additive in vitro anti-HIV-1 effect of chloroquine, when combined with zidovudine and hydroxyurea.	2001 Jun 15	11377382
Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor-alpha.	2001 Oct 1	11543732
[Chloroquine cardiomyopathy revealed by complete atrio-ventricular block. A case report].	2002 Sep	12407800
EGb 761 is a neuroprotective agent against beta-amyloid toxicity.	2002 Sep	12396081
Chloroquine cardiotoxicity: clinicopathologic features in three patients and comparison with three patients with Fabry disease.	2002 Sep-Oct	12361838
Therapy of glioblastoma multiforme improved by the antimutagenic chloroquine.	2003 Feb 15	15727424
Acute neuropharmacologic action of chloroquine on cortical neurons in vitro.	2003 Jan 10	12493616
Heart transplantation in a patient with chloroquine-induced cardiomyopathy.	2004 Feb	14761774
Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells.	2004 Jul	15139008
Skeletal muscle expression of clathrin and mannose 6-phosphate receptor in experimental chloroquine-induced myopathy.	2005 Apr	15712280
Images in cardiovascular medicine. Contrast-enhanced magnetic resonance imaging of a patient with chloroquine-induced cardiomyopathy confirmed by endomyocardial biopsy.	2006 Aug 22	16923761
[Cytochrome P-450 and the response to antimalarial drugs].	2006 Jan	16536934
Frequency of high-risk use of QT-prolonging medications.	2006 Jun	16178046
[Complete auriculoventricular block during chloroquine treatment].	2007 Feb	17150283
Crystal structure of an FIV/HIV chimeric protease complexed with the broad-based inhibitor, TL-3.	2007 Jan 9	17212810
Effect of chloroquine on gene expression of Plasmodium yoelii nigeriensis during its sporogonic development in the mosquito vector.	2007 Jul 2	17605769
Assessment of chloroquine as a modulator of immune activation to improve CD4 recovery in immune nonresponding HIV-infected patients receiving antiretroviral therapy.	2015 Jan	24889179

Patents

Sample Use Guides

In Vivo Use Guide

The dosage of chloroquine phosphate is often expressed in terms of equivalent chloroquine base. Each 500 mg tablet of ARALEN (chloroquine phosphate) contains the equivalent of 300 mg chloroquine base. In infants and children the dosage is preferably calculated by body weight. Malaria: Suppression—Adult Dose: 500 mg (= 300 mg base) on exactly the same day of each week. Pediatric Dose: The weekly suppressive dosage is 5 mg calculated as base, per kg of body weight, but should not exceed the adult dose regardless of weight. If circumstances permit, suppressive therapy should begin two weeks prior to exposure. However, failing this in adults, an initial double (loading) dose of 1 g (= 600 mg base), or in children 10 mg base/kg may be taken in two divided doses, six hours apart. The suppressive therapy should be continued for eight weeks after leaving the endemic area. For Treatment of Acute Attack. Adults: An initial dose of 1 g (=600 mg base) followed by an additional 500 mg (= 300 mg base) after six to eight hours and a single dose of 500 mg (= 300 mg base) on each of two consecutive days. This represents a total dose of 2.5 g chloroquine phosphate or 1.5 g base in three days. The dosage for adults of low body weight and for infants and children should be determined as follows: First dose: 10 mg base per kg (but not exceeding a single dose of 600 mg base) Second dose: (6 hours after first dose) 5 mg base per kg (but not exceeding a single dose of 300 mg base) Third dose: (24 hours after first dose) 5mg base per kg Fourth dose: (36 hours after first dose) 5 mg base per kg For radical cure of vivax and malariae malaria concomitant therapy with an 8-aminoquinoline compound is necessary. Extraintestinal Amebiasis: Adults, 1 g (600 mg base) daily for two days, followed by 500 mg (300 mg base) daily for at least two to three weeks. Treatment is usually combined with an effective intestinal amebicide.

Route of Administration: Oral

In Vitro Use Guide

Chloroquine inhibited mouse colon cancer cell line CT26 cells proliferation by concentration- and time-dependent manner. This effect was associated with apoptosis induction and decreased level of phosphorylated p42/44 mitogen-activated protein kinase and phosphorylated Akt. The cytotoxicity of chloroquine on CT26 cells was determined by the MTT assay. Cells were seeded in 96-well plates at the density of 2000/well and cultured for 24 hr, followed by chloroquine treatment (100, 50, 25, 12.5, 6.25, and 3.125 μ mol/L) for 24, 48, and 72 hr, respectively.

Substance Class	Chemical Created by `admin` on `Fri Dec 16 16:15:41 UTC 2022` Edited by `admin` on `Fri Dec 16 16:15:41 UTC 2022`
Record UNII	886U3H6UFF
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

CHLOROQUINE

Official Name

English

CHLOROQUINE [MI]

Common Name

English

chloroquine [INN]

Common Name

English

CHLOROQUINE [USP IMPURITY]

Common Name

English

CHLOROQUINE [VANDF]

Common Name

English

1,4-PENTANEDIAMINE, N(SUP 4)-(7-CHLORO-4-QUINOLINYL)-N(SUP 1),N (SUP 1)-DIETHYL-

Common Name

English

7-Chloro-4-[[4-(diethylamino)-1-methylbutyl]amino]quinoline

Systematic Name

English

CHLOROQUINE [USP MONOGRAPH]

Common Name

English

CHLOROQUINE [MART.]

Common Name

English

Chloroquine [WHO-DD]

Common Name

English

NSC-187208

Code

English

CHLOROQUINE [HSDB]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C271