You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameHalofantrine
Accession NumberDB01218  (APRD00419)
TypeSmall Molecule
GroupsApproved
Description

Halofantrine is a drug used to treat malaria. It belongs to the phenanthrene class of compounds that includes quinine and lumefantrine. It appears to inhibit polymerisation of heme molecules (by the parasite enzyme “heme polymerase”), resulting in the parasite being poisoned by its own waste. Halofantrine has been shown to preferentially block open and inactivated HERG channels leading to some degree of cardiotoxicity.

Structure
Thumb
Synonyms
SynonymLanguageCode
HalfanNot AvailableNot Available
HalofantrinaSpanishINN
HalofantrineNot AvailableUSAN
HalofantrinumLatinINN
SaltsNot Available
Brand names
NameCompany
HalfanNot Available
Brand mixturesNot Available
Categories
CAS number69756-53-2
WeightAverage: 500.424
Monoisotopic: 499.165654616
Chemical FormulaC26H30Cl2F3NO
InChI KeyFOHHNHSLJDZUGQ-UHFFFAOYSA-N
InChI
InChI=1S/C26H30Cl2F3NO/c1-3-5-10-32(11-6-4-2)12-9-25(33)23-16-22-21(14-18(27)15-24(22)28)20-13-17(26(29,30)31)7-8-19(20)23/h7-8,13-16,25,33H,3-6,9-12H2,1-2H3
IUPAC Name
3-(dibutylamino)-1-[1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl]propan-1-ol
SMILES
CCCCN(CCCC)CCC(O)C1=C2C=CC(=CC2=C2C=C(Cl)C=C(Cl)C2=C1)C(F)(F)F
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassPhenanthrenes and Derivatives
SubclassNot Available
Direct parentPhenanthrenes and Derivatives
Alternative parentsNaphthalenes; Chlorobenzenes; Aryl Chlorides; Tertiary Amines; Secondary Alcohols; Polyamines; Organochlorides; Organofluorides; Alkyl Fluorides
Substituentsnaphthalene; chlorobenzene; aryl chloride; aryl halide; benzene; secondary alcohol; tertiary amine; polyamine; organofluoride; organohalogen; organochloride; amine; alcohol; organonitrogen compound; alkyl halide; alkyl fluoride
Classification descriptionThis compound belongs to the phenanthrenes and derivatives. These are polycyclic compounds containing a phenanthrene moiety, which is a tricyclic aromatic compound with three non-linearly fused benzene.
Pharmacology
IndicationFor treatment of Severe malaria
PharmacodynamicsHalofantrine is a synthetic antimalarial which acts as a blood schizonticide. It is effective against multi drug resistant (including mefloquine resistant) P. falciparum malaria.
Mechanism of actionThe mechanism of action of Halofantrine may be similar to that of chloroquine, quinine, and mefloquine; by forming toxic complexes with ferritoporphyrin IX that damage the membrane of the parasite.
AbsorptionNot Available
Volume of distributionNot Available
Protein binding60-70%;
Metabolism

Hepatic

SubstrateEnzymesProduct
Halofantrine
N-debutylhalofantrineDetails
Route of eliminationNot Available
Half life6-10 days
ClearanceNot Available
ToxicitySide effects incldue coughing noisy, rattling, troubled breathing, loss of appetite, aches and pain in joints, indigestion,and skin itching or rash.
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 + 1.0
Blood Brain Barrier + 0.949
Caco-2 permeable + 0.6485
P-glycoprotein substrate Substrate 0.74
P-glycoprotein inhibitor I Inhibitor 0.6857
P-glycoprotein inhibitor II Inhibitor 0.6097
Renal organic cation transporter Non-inhibitor 0.5267
CYP450 2C9 substrate Non-substrate 0.8426
CYP450 2D6 substrate Substrate 0.8918
CYP450 3A4 substrate Substrate 0.6218
CYP450 1A2 substrate Inhibitor 0.5513
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Inhibitor 0.8931
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Inhibitor 0.7959
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5252
Ames test Non AMES toxic 0.6185
Carcinogenicity Non-carcinogens 0.6485
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.6809 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.732
hERG inhibition (predictor II) Inhibitor 0.9085
Pharmacoeconomics
Manufacturers
  • Glaxosmithkline
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP8.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000111ALOGPS
logP7.34ALOGPS
logP8.06ChemAxon
logS-6.7ALOGPS
pKa (Strongest Acidic)14.47ChemAxon
pKa (Strongest Basic)10.05ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area23.47 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity131.66 m3·mol-1ChemAxon
Polarizability51.53 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
KEGG CompoundC07634
PubChem Compound37393
PubChem Substance46506753
ChemSpider34303
BindingDB50096846
Therapeutic Targets DatabaseDAP000953
PharmGKBPA449839
Drug Product Database2162857
Drugs.comhttp://www.drugs.com/cdi/halofantrine.html
WikipediaHalofantrine
ATC CodesP01BX01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(84 KB)
MSDSshow(27.1 KB)
Interactions
Drug Interactions
Drug
ArtemetherHalofantrine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.
BicalutamideCYP3A4 Inhibitors like bicalutamide may increase the serum concentration of halofantrine. Extreme caution, with possibly increased monitoring of cardiac status (e.g., ECG), should be used with concurrent use of halofantrine with any moderate CYP3A4 inhibitor(s).
ClotrimazoleCYP3A4 Inhibitors (Moderate) such as clotrmazole may increase the serum concentration of halofantrine. Extreme caution, with possibly increased monitoring of cardiac status (e.g., ECG), should be used with concurrent use of halofantrine with any moderate CYP3A4 inhibitor(s).
ConivaptanCYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Concurrent use of orally inhaled fluticasone with strong CYP3A4 inhibitors is not recommended.
LumefantrineHalofantrine may increase the adverse effects of lumefantrine. Additive QTc-prolongation may occur. Combination therapy is contraindicated and therapies should not be administered within one month of each other due to the long half-life of lumefantrine.
MefloquineIncreased risk of cardiac toxicity
MesoridazineIncreased risk of cardiotoxicity and arrhythmias
PosaconazoleContraindicated co-administration
QuinupristinThis combination presents an increased risk of toxicity
TacrolimusAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
TelithromycinTelithromycin may reduce clearance of Halofantrine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Halofantrine if Telithromycin is initiated, discontinued or dose changed.
ThioridazineIncreased risk of cardiotoxicity and arrhythmias
ThiothixeneMay cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
ToremifeneAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
TrimipramineAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
VerapamilVerapamil, a moderate CYP3A4 inhibitor, may increase the serum concentration of Halofantrine by decreasing its metabolism. Extreme caution with increased cardiac status monitoring should be used during concomitant therapy.
VoriconazoleVoriconazole may increase the serum concentration of halofantrine by decreasing its metabolism by CYP3A4. Concomitant therapy should be avoided due to the concentration-dependent risk of QTc prolongation related to halofantrine.
VorinostatAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
ZiprasidoneAdditive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy should be avoided.
ZuclopenthixolAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Food Interactions
  • Take on an empty stomach, bioavailability is 6 times higher when drug is taken with high fat meals. Risks of cardiac toxicity are then increased.

Targets

1. Fe(II)-protoporphyrin IX

Kind: small molecule

Organism: Plasmodium falciparum

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Blauer G: Interaction of ferriprotoporphyrin IX with the antimalarials amodiaquine and halofantrine. Biochem Int. 1988 Oct;17(4):729-34. Pubmed
  4. Egan TJ, Hempelmann E, Mavuso WW: Characterisation of synthetic beta-haematin and effects of the antimalarial drugs quinidine, halofantrine, desbutylhalofantrine and mefloquine on its formation. J Inorg Biochem. 1999 Jan-Feb;73(1-2):101-7. Pubmed
  5. Famin O, Krugliak M, Ginsburg H: Kinetics of inhibition of glutathione-mediated degradation of ferriprotoporphyrin IX by antimalarial drugs. Biochem Pharmacol. 1999 Jul 1;58(1):59-68. Pubmed
  6. 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. Epub 2008 Apr 20. Pubmed
  7. Fitch CD: Ferriprotoporphyrin IX, phospholipids, and the antimalarial actions of quinoline drugs. Life Sci. 2004 Mar 5;74(16):1957-72. Pubmed

2. Potassium voltage-gated channel subfamily H member 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Potassium voltage-gated channel subfamily H member 2 Q12809 Details

References:

  1. Tie H, Walker BD, Singleton CB, Valenzuela SM, Bursill JA, Wyse KR, Breit SN, Campbell TJ: Inhibition of HERG potassium channels by the antimalarial agent halofantrine. Br J Pharmacol. 2000 Aug;130(8):1967-75. Pubmed
  2. Mbai M, Rajamani S, January CT: The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels. Cardiovasc Res. 2002 Sep;55(4):799-805. Pubmed

3. Plasmepsin-2

Kind: protein

Organism: Plasmodium falciparum

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Plasmepsin-2 P46925 Details

References:

  1. Friedman R, Caflisch A: Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring. ChemMedChem. 2009 Aug;4(8):1317-26. Pubmed

Enzymes

1. 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. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. 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 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

3. 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

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

Comments
comments powered by Disqus
Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13