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=C2C=CC(Cl)=CC2=NC=C1

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

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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Ferriprotoporphyrin IX 44 Target ID: CHEMBL613897 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14967191	Inhibitor 8504
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 1076
Plasmodium falciparum 75 Target ID: CHEMBL364 Sources: https://www.ncbi.nlm.nih.gov/pubmed/3279208 \| https://www.ncbi.nlm.nih.gov/pubmed/25016227 \|	Inhibitor 8504

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 8583	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 1949
Extraintestinal amebiasis 8 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/06002slr039_aralen_lbl.pdf	Curative	Approved 8583	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 1949
HIV-1 infection 156 Sources: https://clinicaltrials.gov/ct2/show/NCT00819390	Primary	Phase II 1147	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 Health Status: unknown Age Group: 14 years Sex: F 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 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 Health Status: pregnant Age Group: 20.7 years Sex: F 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 Health Status: unknown Age Group: 14 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/33722251
Vomiting	17%	600 mg 2 times / day multiple, oral 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 Health Status: pregnant Age Group: 20.7 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/30195996
Dizziness	19%	600 mg 2 times / day multiple, oral 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 Health Status: pregnant Age Group: 20.7 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/30195996
Abdominal pain	2%	600 mg 2 times / day multiple, oral 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 Health Status: pregnant Age Group: 20.7 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/30195996
Nausea	5%	600 mg 2 times / day multiple, oral 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 Health Status: pregnant Age Group: 20.7 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/30195996
Palpitations	5%	600 mg 2 times / day multiple, oral 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 Health Status: pregnant Age Group: 20.7 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/30195996
Headache	6%	600 mg 2 times / day multiple, oral 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 Health Status: pregnant Age Group: 20.7 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/30195996

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2252 substrate 1946		inhibitor 2507 substrate 1388	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 2057 CYP1A2 2153 CYP2E1 1060 MATE1 415 OCT2 779	CYP2C8 810 CYP1A1 389

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 2333	inhibitor 4027 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 2141	inhibitor 4027 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 1146	inhibitor 4027 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 2633	inhibitor 4027 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 782	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/19002438/	yes [IC50 1096 uM]
MATE1 416	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/21518836/	yes [IC50 2.5 uM]
CYP2D6 2546	inhibitor 4027 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 389	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/12756207/	yes
CYP2C8 810	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/12756207/	yes
CYP2D6 1388	substrate 4014 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 1946	substrate 4014 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 2263	inhibitor 2237 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
A Comparative Study of Hymenolepicides in Hymenolepis Mana Infestation of Rats.	1962 Jul	17649381
Persisting chloroquine-induced myasthenia?	1991	1665944
Ocular toxicology.	1994 Dec	10172409
Inhibition of the neuronal insulin receptor causes Alzheimer-like disturbances in oxidative/energy brain metabolism and in behavior in adult rats.	1999	10672254
Calcitriol-mediated hypercalcaemia and increased interleukins in a patient with sarcoid myopathy.	1999	10638776
Potential inhibitors of HIV integrase.	1999 Apr-May	10432664
[Neuromuscular complications of long-term treatment of inflammatory diseases. 3 cases].	1999 Dec	10686640
The effect of artesunate combined with standard antimalarials against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum in vitro.	1999 Jul-Aug	10674097
Chloroquine exerts an additive in vitro anti-HIV type 1 effect when associated with didanosine and hydroxyurea.	1999 Sep 20	10505672
Seizures after antimalarial medication in previously healthy persons.	2000 May-Jun	11179947
Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s.	2001 Jan	11124226
Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania.	2001 Oct 13	11675058
High-throughput measurement of the Tp53 response to anticancer drugs and random compounds using a stably integrated Tp53-responsive luciferase reporter.	2002 Jun	12082016
[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
Control of mammary tumor cell growth in vitro by novel cell differentiation and apoptosis agents.	2002 Sep	12243503
[Chloroquine-induced myopathy and neuropathy: progressive tetraparesis with areflexia that simulates a polyradiculoneuropathy. Two case reports].	2003 Mar 16-31	12652413
Differential diagnosis of high serum creatine kinase levels in systemic lupus erythematosus.	2003 Nov	12739036
[Complete auriculoventricular block secondary to cardiac toxicity due to chloroquine].	2006 Feb	16527175
Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases.	2007 May	17202178
Effects of CpG-B ODN on the protein expression profile of swine PBMC.	2007 Nov-Dec	17727805

Patents

Sample Use Guides

In Vivo Use Guide

The dosage of chloroquine phosphate is often expressed in terms of equivalentchloroquine 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.

Name

Type

Language

CHLOROQUINE

Official Name

English

NSC-187208

Preferred 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

CHLOROQUINE [HSDB]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C271