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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
SynonymLanguageCode
HalfanNot AvailableNot Available
HalofantrinaSpanishINN
HalofantrineNot AvailableUSAN
HalofantrinumLatinINN
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
HalfanNot Available
Brand mixturesNot Available
SaltsNot 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
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.
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 substrateNon-inhibitor0.9071
CYP450 2D6 substrateInhibitor0.8931
CYP450 2C19 substrateNon-inhibitor0.9025
CYP450 3A4 substrateInhibitor0.7959
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
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
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 ReferenceNot Available
External Links
ATC CodesP01BX01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (84 KB)
MSDSDownload (27.1 KB)
Interactions
Drug Interactions
Drug
AbirateroneCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
AprepitantCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
ArtemetherLumefantrine may enhance the QTc-prolonging effect of Halofantrine.
AtazanavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
BicalutamideCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
BiotinCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
BoceprevirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
CimetidineCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
ClarithromycinCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
ClotrimazoleCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
ConivaptanCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
DarunavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
DelavirdineCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
DesipramineCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
DiltiazemCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
FosamprenavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
FosaprepitantCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
IndinavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
IsavuconazoniumCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
ItraconazoleCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
Lanthanum carbonateLanthanum may decrease the serum concentration of Halofantrine.
LomitapideCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
LopinavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
LumefantrineLumefantrine may enhance the QTc-prolonging effect of Halofantrine.
MefloquineMefloquine may enhance the QTc-prolonging effect of Halofantrine.
NefazodoneCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
NelfinavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
NorfloxacinCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
PosaconazoleCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
QuinineQuiNINE may enhance the adverse/toxic effect of Halofantrine. QuiNINE may increase the serum concentration of Halofantrine.
RitonavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
SaquinavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
TelaprevirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
TelithromycinCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
TetracyclineCYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.
VoriconazoleCYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine.
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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13