Identification

Name
Amodiaquine
Accession Number
DB00613  (APRD00796)
Type
Small Molecule
Groups
Approved, Investigational
Description

A 4-aminoquinoquinoline compound with anti-inflammatory properties.

Structure
Thumb
Synonyms
  • Amodiaquina
  • Amodiaquine
  • Amodiaquinum
External IDs
NSC-13453
Product Ingredients
IngredientUNIICASInChI Key
Amodiaquine dihydrochloride dihydrateK6PW2S574L6398-98-7YVNAYSHNIILOJS-UHFFFAOYSA-N
Amodiaquine hydrochlorideHOE64181MP69-44-3ROEBJVHPINPMKL-UHFFFAOYSA-N
International/Other Brands
Basoquin / Camoquin (Parke Davis) / Flavoquine
Categories
UNII
220236ED28
CAS number
86-42-0
Weight
Average: 355.861
Monoisotopic: 355.145140048
Chemical Formula
C20H22ClN3O
InChI Key
OVCDSSHSILBFBN-UHFFFAOYSA-N
InChI
InChI=1S/C20H22ClN3O/c1-3-24(4-2)13-14-11-16(6-8-20(14)25)23-18-9-10-22-19-12-15(21)5-7-17(18)19/h5-12,25H,3-4,13H2,1-2H3,(H,22,23)
IUPAC Name
4-[(7-chloroquinolin-4-yl)amino]-2-[(diethylamino)methyl]phenol
SMILES
CCN(CC)CC1=C(O)C=CC(NC2=C3C=CC(Cl)=CC3=NC=C2)=C1

Pharmacology

Indication

For treatment of acute malarial attacks in non-immune subjects.

Pharmacodynamics

Amodiaquine, a 4-aminoquinoline similar to chloroquine in structure and activity, has been used as both an antimalarial and an anti-inflammatory agent for more than 40 years. Amodiaquine is at least as effective as chloroquine, and is effective against some chloroquine-resistant strains, although resistance to amodiaquine has been reported. The mode of action of amodiaquine has not yet been determined. 4-Aminoquinolines depress cardiac muscle, impair cardiac conductivity, and produce vasodilatation with resultant hypotension. They depress respiration and cause diplopia, dizziness and nausea.

Mechanism of action

The mechanism of plasmodicidal action of amodiaquine 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. The drug binds the free heme preventing the parasite from converting it to a form less toxic. This drug-heme complex is toxic and disrupts membrane function.

TargetActionsOrganism
AFe(II)-protoporphyrin IX
adduct
Plasmodium falciparum
UHistamine N-methyltransferase
inhibitor
Human
Absorption

Rapidly absorbed following oral administration.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic biotransformation to desethylamodiaquine (the principal biologically active metabolite) is the predominant route of amodiaquine clearance with such a considerable first pass effect that very little orally administered amodiaquine escapes untransformed into the systemic circulation.

Route of elimination
Not Available
Half life

5.2 ± 1.7 (range 0.4 to 5.5) minutes

Clearance
Not Available
Toxicity

LD50 (mouse, intraperitoneal) 225 mg/kg, LD50 (mouse, oral) 550 mg/kg. Symptoms of overdose include headache, drowsiness, visual disturbances, vomiting, hypokalaemia, cardiovascular collapse and cardiac and respiratory arrest. Hypotension, if not treated, may progress rapidly to shock. Electrocardiograms (ECG) may reveal atrial standstill, nodal rhythm, prolonged intraventricular conduction time, broadening of the QRS complex, and progressive bradycardia leading to ventricular fibrillation and/or arrest.

Affected organisms
  • Plasmodium
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Amodiaquine.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Amodiaquine.
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be decreased when combined with Amodiaquine.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Amodiaquine.
AbexinostatThe risk or severity of QTc prolongation can be increased when Amodiaquine is combined with Abexinostat.
AbirateroneThe metabolism of Amodiaquine can be decreased when combined with Abiraterone.
AcebutololThe risk or severity of QTc prolongation can be decreased when Amodiaquine is combined with Acebutolol.
AceclofenacThe metabolism of Aceclofenac can be decreased when combined with Amodiaquine.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Amodiaquine.
AcepromazineThe risk or severity of QTc prolongation can be increased when Amodiaquine is combined with Acepromazine.
Food Interactions
Not Available

References

Synthesis Reference

Burckhalter, J.H., Jones, E.M., Rawlins, A.L., Tendick, F.H, and 2,474,821; July 5,1949; assigned to Parke, Davis & Co.

General References
  1. Jewell H, Maggs JL, Harrison AC, O'Neill PM, Ruscoe JE, Park BK: Role of hepatic metabolism in the bioactivation and detoxication of amodiaquine. Xenobiotica. 1995 Feb;25(2):199-217. [PubMed:7618347]
  2. Harrison AC, Kitteringham NR, Clarke JB, Park BK: The mechanism of bioactivation and antigen formation of amodiaquine in the rat. Biochem Pharmacol. 1992 Apr 1;43(7):1421-30. [PubMed:1567466]
External Links
Human Metabolome Database
HMDB0014751
KEGG Drug
D02922
KEGG Compound
C07626
PubChem Compound
2165
PubChem Substance
46506940
ChemSpider
2080
BindingDB
50041457
ChEBI
2674
ChEMBL
CHEMBL682
Therapeutic Targets Database
DAP000699
PharmGKB
PA448404
HET
CQA
Wikipedia
Amodiaquine
ATC Codes
P01BF03 — Artesunate and amodiaquineP01BA06 — Amodiaquine
PDB Entries
2aou / 4fgz / 4mwz

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceMalaria caused by Plasmodium falciparum1
1CompletedTreatmentPlasmodium Infections1
1, 2CompletedTreatmentPlasmodium Infections1
1, 2RecruitingTreatmentDrug Combination / Healthy Volunteers / Pharmacokinetics1
2CompletedPreventionPlasmodium Infections1
2CompletedTreatmentPlasmodium Infections3
2CompletedTreatmentPlasmodium Infections / Severe Malaria1
2, 3CompletedPreventionPlasmodium Infections3
2, 3CompletedTreatmentPlasmodium Infections1
3CompletedPreventionIntermittent Preventive Treatment / Plasmodium Infections1
3CompletedPreventionMalaria caused by Plasmodium falciparum1
3CompletedPreventionPlasmodium Infections2
3CompletedPreventionPlasmodium Infections / Respiratory Tract Infections (RTI)1
3CompletedTreatmentMalaria caused by Plasmodium falciparum / Malaria caused by plasmodium vivax / Plasmodium Infections1
3CompletedTreatmentPlasmodium Infections6
3CompletedTreatmentPlasmodium Infections / Pregnancy1
3Unknown StatusTreatmentUncomplicated Malaria1
4CompletedTreatmentMalaria caused by Plasmodium falciparum2
4CompletedTreatmentPlasmodium Infections2
4CompletedTreatmentUncomplicated Malaria1
4Not Yet RecruitingPreventionAnemias / Malaria caused by Plasmodium falciparum1
4SuspendedNot AvailablePlasmodium Infections1
Not AvailableCompletedNot AvailableHuman Immunodeficiency Virus (HIV) Infections / Plasmodium Infections1
Not AvailableCompletedBasic ScienceAnemias1
Not AvailableCompletedTreatmentMalaria caused by Plasmodium falciparum1
Not AvailableCompletedTreatmentPlasmodium Infections1

Pharmacoeconomics

Manufacturers
  • Parke davis div warner lambert co
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)206-208Burckhalter, J.H., Jones, E.M., Rawlins, A.L., Tendick, F.H, and 2,474,821; July 5,1949; assigned to Parke, Davis & Co.
logP3.7Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0088 mg/mLALOGPS
logP4.83ALOGPS
logP3.76ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)9.12ChemAxon
pKa (Strongest Basic)10.23ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area48.39 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity103.29 m3·mol-1ChemAxon
Polarizability38.89 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9818
Blood Brain Barrier+0.7306
Caco-2 permeable+0.5966
P-glycoprotein substrateSubstrate0.7168
P-glycoprotein inhibitor INon-inhibitor0.8782
P-glycoprotein inhibitor IIInhibitor0.8387
Renal organic cation transporterNon-inhibitor0.5943
CYP450 2C9 substrateNon-substrate0.7898
CYP450 2D6 substrateSubstrate0.8919
CYP450 3A4 substrateNon-substrate0.5136
CYP450 1A2 substrateInhibitor0.8347
CYP450 2C9 inhibitorNon-inhibitor0.5836
CYP450 2D6 inhibitorInhibitor0.7582
CYP450 2C19 inhibitorInhibitor0.5416
CYP450 3A4 inhibitorNon-inhibitor0.7203
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9202
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.8452
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.4801 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7619
hERG inhibition (predictor II)Inhibitor0.7306
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0570-3940000000-2d4500c74767ebc68cf0
MS/MS Spectrum - , positiveLC-MS/MSsplash10-001i-1390000000-e476bc93f0f2236bccdc

Taxonomy

Description
This compound 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Aminoquinolines and derivatives
Direct Parent
4-aminoquinolines
Alternative Parents
Chloroquinolines / p-Aminophenols / Phenylmethylamines / Aniline and substituted anilines / Benzylamines / 1-hydroxy-2-unsubstituted benzenoids / Aminopyridines and derivatives / Aralkylamines / Aryl chlorides / Heteroaromatic compounds
show 7 more
Substituents
Chloroquinoline / Haloquinoline / 4-aminoquinoline / Aminophenol / P-aminophenol / Phenylmethylamine / Benzylamine / Aniline or substituted anilines / Aminopyridine / Phenol
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
quinolines, phenols (CHEBI:2674) / a small molecule (CPD-10889)

Targets

1. Fe(II)-protoporphyrin IX
Kind
Small molecule
Organism
Plasmodium falciparum
Pharmacological action
Yes
Actions
Adduct
References
  1. de Villiers KA, Marques HM, Egan TJ: The crystal structure of halofantrine-ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials. J Inorg Biochem. 2008 Aug;102(8):1660-7. doi: 10.1016/j.jinorgbio.2008.04.001. Epub 2008 Apr 20. [PubMed:18508124]
  2. Weissbuch I, Leiserowitz L: Interplay between malaria, crystalline hemozoin formation, and antimalarial drug action and design. Chem Rev. 2008 Nov;108(11):4899-914. doi: 10.1021/cr078274t. [PubMed:19006402]
  3. Sullivan DJ Jr, Gluzman IY, Russell DG, Goldberg DE: On the molecular mechanism of chloroquine's antimalarial action. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11865-70. [PubMed:8876229]
  4. Schwedhelm KF, Horstmann M, Faber JH, Reichert Y, Bringmann G, Faber C: The novel antimalarial compound dioncophylline C forms a complex with heme in solution. ChemMedChem. 2007 Apr;2(4):541-8. [PubMed:17315144]
  5. Egan TJ, Ncokazi KK: Effects of solvent composition and ionic strength on the interaction of quinoline antimalarials with ferriprotoporphyrin IX. J Inorg Biochem. 2004 Jan;98(1):144-52. [PubMed:14659643]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Histamine n-methyltransferase activity
Specific Function
Inactivates histamine by N-methylation. Plays an important role in degrading histamine and in regulating the airway response to histamine.
Gene Name
HNMT
Uniprot ID
P50135
Uniprot Name
Histamine N-methyltransferase
Molecular Weight
33294.765 Da
References
  1. Yokoyama A, Mori S, Takahashi HK, Kanke T, Wake H, Nishibori M: Effect of amodiaquine, a histamine N-methyltransferase inhibitor, on, Propionibacterium acnes and lipopolysaccharide-induced hepatitis in mice. Eur J Pharmacol. 2007 Mar 8;558(1-3):179-84. Epub 2006 Nov 22. [PubMed:17222819]
  2. Nowak JZ, Zandarowska E: Effect of amodiaquine on histamine level and histamine-methyltransferase activity in the rat brain. Arch Immunol Ther Exp (Warsz). 1980;28(6):927-30. [PubMed:6789797]
  3. Barth H, Lorenz W, Troidl H: Effect of amodiaquine on gastric histamine methyltransferase and on histamine-stimulated gastric secretion. Br J Pharmacol. 1975 Nov;55(3):321-7. [PubMed:1203620]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Li XQ, Bjorkman A, Andersson TB, Ridderstrom M, Masimirembwa CM: Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J Pharmacol Exp Ther. 2002 Feb;300(2):399-407. [PubMed:11805197]
  3. Walsky RL, Obach RS: Validated assays for human cytochrome P450 activities. Drug Metab Dispos. 2004 Jun;32(6):647-60. [PubMed:15155557]
  4. Backman JT, Filppula AM, Niemi M, Neuvonen PJ: Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev. 2016 Jan;68(1):168-241. doi: 10.1124/pr.115.011411. [PubMed:26721703]
  5. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d 24-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 oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
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 oxidizes a variety of structurally un...
Gene Name
CYP1B1
Uniprot ID
Q16678
Uniprot Name
Cytochrome P450 1B1
Molecular Weight
60845.33 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Details
4. Cytochrome P450 2D6
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Wennerholm A, Nordmark A, Pihlsgard M, Mahindi M, Bertilsson L, Gustafsson LL: Amodiaquine, its desethylated metabolite, or both, inhibit the metabolism of debrisoquine (CYP2D6) and losartan (CYP2C9) in vivo. Eur J Clin Pharmacol. 2006 Jul;62(7):539-46. doi: 10.1007/s00228-006-0121-3. Epub 2006 Jun 17. [PubMed:16783563]
  3. Bapiro TE, Egnell AC, Hasler JA, Masimirembwa CM: Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5. [PubMed:11124226]
Details
5. Cytochrome P450 2C9
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Data based on 1 in vivo study.
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Wennerholm A, Nordmark A, Pihlsgard M, Mahindi M, Bertilsson L, Gustafsson LL: Amodiaquine, its desethylated metabolite, or both, inhibit the metabolism of debrisoquine (CYP2D6) and losartan (CYP2C9) in vivo. Eur J Clin Pharmacol. 2006 Jul;62(7):539-46. doi: 10.1007/s00228-006-0121-3. Epub 2006 Jun 17. [PubMed:16783563]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Senarathna SM, Page-Sharp M, Crowe A: The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation. PLoS One. 2016 Apr 5;11(4):e0152677. doi: 10.1371/journal.pone.0152677. eCollection 2016. [PubMed:27045516]
  2. A Chemical Approach Towards Understanding the Mechanism and Reversal of Drug Resistance in Plasmodium falciparum: Is it Viable? [File]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 09:11