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Details

Stereochemistry RACEMIC
Molecular Formula C18H26ClN3.2C5H4N2O4
Molecular Weight 632.065
Optical Activity ( + / - )
Defined Stereocenters 0 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of CHLOROQUINE DIOROTATE

SMILES

OC(=O)C1=CC(=O)NC(=O)N1.OC(=O)C2=CC(=O)NC(=O)N2.CCN(CC)CCCC(C)NC3=CC=NC4=CC(Cl)=CC=C34

InChI

InChIKey=IUEFAROUKVNKKL-UHFFFAOYSA-N
InChI=1S/C18H26ClN3.2C5H4N2O4/c1-4-22(5-2)12-6-7-14(3)21-17-10-11-20-18-13-15(19)8-9-16(17)18;2*8-3-1-2(4(9)10)6-5(11)7-3/h8-11,13-14H,4-7,12H2,1-3H3,(H,20,21);2*1H,(H,9,10)(H2,6,7,8,11)

HIDE SMILES / InChI

Molecular Formula C5H4N2O4
Molecular Weight 156.0963
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

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 ( + / - )

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

Curator's Comment: Known to be CNS penetrant in rat. Human data not available.

Originator

Curator's Comment: # Hans Andersag and coworkers at the Bayer laboratories

Approval Year

Targets

Targets

Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Curative
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
Curative
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
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
700 ng/mL
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

AUC

ValueDoseCo-administeredAnalytePopulation
134087 ng × h/mL
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
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
209 h
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
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
45%
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

Doses

DosePopulationAdverse events​
3 g single, oral
Overdose
Dose: 3 g
Route: oral
Route: single
Dose: 3 g
Sources:
unknown, 14 years
n = 1
Health Status: unknown
Age Group: 14 years
Sex: F
Population Size: 1
Sources:
Other AEs: Cardiac arrest...
Other AEs:
Cardiac arrest
Sources:
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:
pregnant, 20.7 years
n = 300
Health Status: pregnant
Condition: malaria
Age Group: 20.7 years
Sex: F
Population Size: 300
Sources:
Other AEs: Dizziness, Vomiting...
Other AEs:
Dizziness (19%)
Vomiting (17%)
Palpitations (5%)
Headache (6%)
Nausea (5%)
Abdominal pain (2%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Cardiac arrest
3 g single, oral
Overdose
Dose: 3 g
Route: oral
Route: single
Dose: 3 g
Sources:
unknown, 14 years
n = 1
Health Status: unknown
Age Group: 14 years
Sex: F
Population Size: 1
Sources:
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:
pregnant, 20.7 years
n = 300
Health Status: pregnant
Condition: malaria
Age Group: 20.7 years
Sex: F
Population Size: 300
Sources:
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:
pregnant, 20.7 years
n = 300
Health Status: pregnant
Condition: malaria
Age Group: 20.7 years
Sex: F
Population Size: 300
Sources:
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:
pregnant, 20.7 years
n = 300
Health Status: pregnant
Condition: malaria
Age Group: 20.7 years
Sex: F
Population Size: 300
Sources:
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:
pregnant, 20.7 years
n = 300
Health Status: pregnant
Condition: malaria
Age Group: 20.7 years
Sex: F
Population Size: 300
Sources:
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:
pregnant, 20.7 years
n = 300
Health Status: pregnant
Condition: malaria
Age Group: 20.7 years
Sex: F
Population Size: 300
Sources:
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:
pregnant, 20.7 years
n = 300
Health Status: pregnant
Condition: malaria
Age Group: 20.7 years
Sex: F
Population Size: 300
Sources:
Overview

OverviewOther

Other InhibitorOther SubstrateOther Inducer







Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no (co-administration study)
Comment: chloroquine did not affect the activities of CYP1A2, CYP2C19, CYP2E1, CYP3A4
no
no (co-administration study)
Comment: chloroquine did not affect the activities of CYP1A2, CYP2C19, CYP2E1, CYP3A4
no
no (co-administration study)
Comment: chloroquine did not affect the activities of CYP1A2, CYP2C19, CYP2E1, CYP3A4
no
no (co-administration study)
Comment: chloroquine did not affect the activities of CYP1A2, CYP2C19, CYP2E1, CYP3A4
yes [IC50 1096 uM]
yes [IC50 2.5 uM]
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
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
yes
yes
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.
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.
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Drug-induced haemolysis and renal failure in children with glucose-6-phosphate dehydrogenase deficiency in Central Asia.
1990
Amrinone for refractory cardiogenic shock following chloroquine poisoning.
1991
Persisting chloroquine-induced myasthenia?
1991
Occurrence of chloroquine-induced psychotic manifestations in children with malaria.
1992
The effect of EGb 761 on the doxorubicin cardiomyopathy.
1999
Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travellers: a randomised, double-blind study. Malarone International Study Team.
2000 Dec 2
[Unexpected occurrence of cardiac arrest during chloroquine preventive therapy].
2000 Jun
Seizures after antimalarial medication in previously healthy persons.
2000 May-Jun
Induction of glutathione synthesis in human keratinocytes by Ginkgo biloba extract (EGb761).
2001
Effect of primaquine standard dose (15 mg/day for 14 days) in the treatment of vivax malaria patients in Thailand.
2001 Dec
The anti-HIV-1 activity of chloroquine.
2001 Feb
Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s.
2001 Jan
Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced release of nitric oxide.
2001 Jul 31
The additive in vitro anti-HIV-1 effect of chloroquine, when combined with zidovudine and hydroxyurea.
2001 Jun 15
Cardiac toxicity secondary to long term treatment with chloroquine.
2001 Mar
Chloroquine-induced neuronal cell death is p53 and Bcl-2 family-dependent but caspase-independent.
2001 Oct
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
Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania.
2001 Oct 13
Syncope following oral chloroquine administration in a hypertensive patient controlled on amlodipine.
2002 Apr
Cardiac damage from chronic use of chloroquine: a case report and review of the literature.
2002 Jul
High-throughput measurement of the Tp53 response to anticancer drugs and random compounds using a stably integrated Tp53-responsive luciferase reporter.
2002 Jun
[Many travellers suffer of side-effects of malaria prophylaxis].
2002 Jun 27
The first molecular evidence that autophagy relates rimmed vacuole formation in chloroquine myopathy.
2002 May
Side effects of and compliance with malaria prophylaxis in children.
2002 Nov-Dec
[Chloroquine cardiomyopathy revealed by complete atrio-ventricular block. A case report].
2002 Sep
EGb 761 is a neuroprotective agent against beta-amyloid toxicity.
2002 Sep
Chloroquine cardiotoxicity: clinicopathologic features in three patients and comparison with three patients with Fabry disease.
2002 Sep-Oct
Therapy of glioblastoma multiforme improved by the antimutagenic chloroquine.
2003 Feb 15
Chloroquine-induced phospholipidosis of the kidney mimicking Fabry's disease: case report and review of the literature.
2003 Mar
[Chloroquine-induced myopathy and neuropathy: progressive tetraparesis with areflexia that simulates a polyradiculoneuropathy. Two case reports].
2003 Mar 16-31
Increased CSF protein in chloroquine-induced axonal polyneuropathy and myopathy.
2003 Sep
Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data.
2003 Sep
[Infectious diseases in 2003].
2004
The ability of chloroquine to prevent tat-induced cytokine secretion by monocytes is implicated in its in vivo anti-human immunodeficiency virus type 1 activity.
2004 Nov
Seizure associated with chloroquine therapy in a patient with systemic lupus erythematosus.
2004 Sep
Chloroquine-induced cardiomyopathy-echocardiographic features.
2005 Apr
Skeletal muscle expression of clathrin and mannose 6-phosphate receptor in experimental chloroquine-induced myopathy.
2005 Apr
Enhanced anticryptococcal activity of chloroquine in phosphatidylserine-containing liposomes in a murine model.
2005 Feb
cAMP has distinct acute and chronic effects on aquaporin-5 in lung epithelial cells.
2005 Feb 4
[Acute hydroxychloroquine poisoning. The danger of rapid or excessive correction of initial hypokalemia].
2005 Jul 23
Protective effects of different antioxidants and amrinone on vancomycin-induced nephrotoxicity.
2005 Nov
Images in cardiovascular medicine. Contrast-enhanced magnetic resonance imaging of a patient with chloroquine-induced cardiomyopathy confirmed by endomyocardial biopsy.
2006 Aug 22
CpG-B oligodeoxynucleotide promotes cell survival via up-regulation of Hsp70 to increase Bcl-xL and to decrease apoptosis-inducing factor translocation.
2006 Dec 15
Frequency of high-risk use of QT-prolonging medications.
2006 Jun
Antimalarial myopathy: an underdiagnosed complication? Prospective longitudinal study of 119 patients.
2006 Mar
Cardiomyopathy related to antimalarial therapy with illustrative case report.
2007
Effect of chloroquine on gene expression of Plasmodium yoelii nigeriensis during its sporogonic development in the mosquito vector.
2007 Jul 2
Chloroquine-induced recurrent psychosis.
2007 Jul-Aug
Effects of CpG-B ODN on the protein expression profile of swine PBMC.
2007 Nov-Dec
A randomised controlled trial to assess the efficacy of dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Peru.
2007 Oct 31
Patents

Sample Use Guides

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
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 15 17:46:21 GMT 2023
Edited
by admin
on Fri Dec 15 17:46:21 GMT 2023
Record UNII
1RO28BA0DO
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
CHLOROQUINE DIOROTATE
WHO-DD  
Common Name English
1,4-PENTANEDIAMINE, N4-(7-CHLORO-4-QUINOLINYL)-N1,N1-DIETHYL-, BIS(1,2,3,6-TETRAHYDRO-2,6-DIOXO-4-PYRIMIDINECARBOXYLATE)
Common Name English
Chloroquine diorotate [WHO-DD]
Common Name English
1,2,3,6-TETRAHYDRO-2,6-DIOXO-4-PYRIMIDINECARBOXYLIC ACID COMPD. WITH N4-(7-CHLORO-4-QUINOLINYL)-N1,N1-DIETHYL-1,4-PENTANEDIAMINE (2:1)
Systematic Name English
4-PYRIMIDINECARBOXYLIC ACID, 1,2,3,6-TETRAHYDRO-2,6-DIOXO-, COMPD. WITH N4-(7-CHLORO-4-QUINOLINYL)-N1,N1-DIETHYL-1,4-PENTANEDIAMINE (2:1)
Common Name English
Code System Code Type Description
EPA CompTox
DTXSID00936779
Created by admin on Fri Dec 15 17:46:21 GMT 2023 , Edited by admin on Fri Dec 15 17:46:21 GMT 2023
PRIMARY
PUBCHEM
83835
Created by admin on Fri Dec 15 17:46:21 GMT 2023 , Edited by admin on Fri Dec 15 17:46:21 GMT 2023
PRIMARY
MESH
C000660
Created by admin on Fri Dec 15 17:46:21 GMT 2023 , Edited by admin on Fri Dec 15 17:46:21 GMT 2023
PRIMARY
CAS
16301-30-7
Created by admin on Fri Dec 15 17:46:21 GMT 2023 , Edited by admin on Fri Dec 15 17:46:21 GMT 2023
PRIMARY
EVMPD
SUB01236MIG
Created by admin on Fri Dec 15 17:46:21 GMT 2023 , Edited by admin on Fri Dec 15 17:46:21 GMT 2023
PRIMARY
FDA UNII
1RO28BA0DO
Created by admin on Fri Dec 15 17:46:21 GMT 2023 , Edited by admin on Fri Dec 15 17:46:21 GMT 2023
PRIMARY
SMS_ID
100000084716
Created by admin on Fri Dec 15 17:46:21 GMT 2023 , Edited by admin on Fri Dec 15 17:46:21 GMT 2023
PRIMARY
ECHA (EC/EINECS)
240-389-6
Created by admin on Fri Dec 15 17:46:21 GMT 2023 , Edited by admin on Fri Dec 15 17:46:21 GMT 2023
PRIMARY
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