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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
Halfan
Halofantrina
Halofantrine
Halofantrinum
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Halfan - Tab 250mgtablet250 mgoralSmithkline Beecham Pharma Division Of Smithkline Beecham Inc1996-07-161999-03-08Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
HalfanNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Halofantrine hydrochloride
ThumbNot applicableDBSALT001186
Categories
UNIIQ2OS4303HZ
CAS number69756-53-2
WeightAverage: 500.424
Monoisotopic: 499.165654616
Chemical FormulaC26H30Cl2F3NO
InChI KeyInChIKey=FOHHNHSLJDZUGQ-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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenanthrenes and derivatives. These are polycyclic compounds containing a phenanthrene moiety, which is a tricyclic aromatic compound with three non-linearly fused benzene.
KingdomOrganic compounds
Super ClassBenzenoids
ClassPhenanthrenes and derivatives
Sub ClassNot Available
Direct ParentPhenanthrenes and derivatives
Alternative Parents
Substituents
  • Phenanthrene
  • Naphthalene
  • 1,3-dichlorobenzene
  • Aralkylamine
  • Chlorobenzene
  • Aryl halide
  • Aryl chloride
  • 1,3-aminoalcohol
  • Tertiary aliphatic amine
  • Tertiary amine
  • Secondary alcohol
  • Hydrocarbon derivative
  • Aromatic alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organochloride
  • Organohalogen compound
  • Amine
  • Alkyl halide
  • Alkyl fluoride
  • Alcohol
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External DescriptorsNot Available
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.
Related Articles
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
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.949
Caco-2 permeable+0.6485
P-glycoprotein substrateSubstrate0.74
P-glycoprotein inhibitor IInhibitor0.6857
P-glycoprotein inhibitor IIInhibitor0.6097
Renal organic cation transporterNon-inhibitor0.5267
CYP450 2C9 substrateNon-substrate0.8426
CYP450 2D6 substrateSubstrate0.8918
CYP450 3A4 substrateSubstrate0.6218
CYP450 1A2 substrateInhibitor0.5513
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorInhibitor0.8931
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorInhibitor0.7959
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5252
Ames testNon AMES toxic0.6185
CarcinogenicityNon-carcinogens0.6485
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6809 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.732
hERG inhibition (predictor II)Inhibitor0.9085
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral250 mg
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP8.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000111 mg/mLALOGPS
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 FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesP01BX01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (84 KB)
MSDSDownload (27.1 KB)
Interactions
Drug Interactions
Drug
AprepitantThe serum concentration of Halofantrine can be increased when it is combined with Aprepitant.
AtazanavirThe serum concentration of Halofantrine can be increased when it is combined with Atazanavir.
BoceprevirThe serum concentration of Halofantrine can be increased when it is combined with Boceprevir.
CeritinibThe serum concentration of Halofantrine can be increased when it is combined with Ceritinib.
ClarithromycinThe serum concentration of Halofantrine can be increased when it is combined with Clarithromycin.
CobicistatThe serum concentration of Halofantrine can be increased when it is combined with Cobicistat.
DarunavirThe serum concentration of Halofantrine can be increased when it is combined with Darunavir.
DelavirdineThe serum concentration of Halofantrine can be increased when it is combined with Delavirdine.
DiltiazemThe serum concentration of Halofantrine can be increased when it is combined with Diltiazem.
FluconazoleThe serum concentration of Halofantrine can be increased when it is combined with Fluconazole.
FosamprenavirThe serum concentration of Halofantrine can be increased when it is combined with Fosamprenavir.
IdelalisibThe serum concentration of Halofantrine can be increased when it is combined with Idelalisib.
ImatinibThe serum concentration of Halofantrine can be increased when it is combined with Imatinib.
IndinavirThe serum concentration of Halofantrine can be increased when it is combined with Indinavir.
IsavuconazoniumThe serum concentration of Halofantrine can be increased when it is combined with Isavuconazonium.
ItraconazoleThe serum concentration of Halofantrine can be increased when it is combined with Itraconazole.
KetoconazoleThe serum concentration of Halofantrine can be increased when it is combined with Ketoconazole.
LanthanumThe serum concentration of Halofantrine can be decreased when it is combined with Lanthanum.
Lanthanum carbonateThe serum concentration of Halofantrine can be decreased when it is combined with Lanthanum carbonate.
MefloquineMefloquine may increase the QTc-prolonging activities of Halofantrine.
NefazodoneThe serum concentration of Halofantrine can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Halofantrine can be increased when it is combined with Nelfinavir.
PosaconazoleThe serum concentration of Halofantrine can be increased when it is combined with Posaconazole.
QuinineThe risk or severity of adverse effects can be increased when Quinine is combined with Halofantrine.
RitonavirThe serum concentration of Halofantrine can be increased when it is combined with Ritonavir.
SaquinavirThe serum concentration of Halofantrine can be increased when it is combined with Saquinavir.
TelaprevirThe serum concentration of Halofantrine can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Halofantrine can be increased when it is combined with Telithromycin.
VerapamilThe serum concentration of Halofantrine can be increased when it is combined with Verapamil.
VoriconazoleThe serum concentration of Halofantrine can be increased when it is combined with Voriconazole.
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
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:17139284 ]
  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:17016423 ]
  3. Blauer G: Interaction of ferriprotoporphyrin IX with the antimalarials amodiaquine and halofantrine. Biochem Int. 1988 Oct;17(4):729-34. [PubMed:3240320 ]
  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:10212997 ]
  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:10403519 ]
  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. doi: 10.1016/j.jinorgbio.2008.04.001. Epub 2008 Apr 20. [PubMed:18508124 ]
  7. Fitch CD: Ferriprotoporphyrin IX, phospholipids, and the antimalarial actions of quinoline drugs. Life Sci. 2004 Mar 5;74(16):1957-72. [PubMed:14967191 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function:
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are r...
Gene Name:
KCNH2
Uniprot ID:
Q12809
Molecular Weight:
126653.52 Da
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:10952689 ]
  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:12176129 ]
Kind
Protein
Organism
Plasmodium falciparum
Pharmacological action
unknown
Actions
inhibitor
General Function:
Aspartic-type endopeptidase activity
Specific Function:
Not Available
Gene Name:
Not Available
Uniprot ID:
P46925
Molecular Weight:
51489.41 Da
References
  1. Friedman R, Caflisch A: Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring. ChemMedChem. 2009 Aug;4(8):1317-26. doi: 10.1002/cmdc.200900078. [PubMed:19472268 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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 antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
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. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-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 performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 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 unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A5
Uniprot ID:
P20815
Molecular Weight:
57108.065 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:
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme...
Gene Name:
CYP2C8
Uniprot ID:
P10632
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 ]
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Drug created on June 13, 2005 07:24 / Updated on September 22, 2015 11:03