Identification

Name
Halofantrine
Accession Number
DB01218  (APRD00419)
Type
Small Molecule
Groups
Approved
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
  • Halofantrina
  • Halofantrine
  • Halofantrinum
Product Ingredients
IngredientUNIICASInChI Key
Halofantrine hydrochlorideH77DL0Y63036167-63-2WANGFTDWOFGECH-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
HalfanTablet250 mg/1OralGlaxoSmithKline2006-09-20Not applicableUs
Halfan - Tab 250mgTablet250 mgOralSmithkline Beecham Pharma Division Of Smithkline Beecham Inc1996-07-161999-03-08Canada
International/Other Brands
Halfan
Categories
UNII
Q2OS4303HZ
CAS number
69756-53-2
Weight
Average: 500.424
Monoisotopic: 499.165654616
Chemical Formula
C26H30Cl2F3NO
InChI Key
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

Pharmacology

Indication

For treatment of Severe malaria

Pharmacodynamics

Halofantrine 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 action

The 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.

TargetActionsOrganism
AFe(II)-protoporphyrin IX
antagonist
Plasmodium falciparum
APotassium voltage-gated channel subfamily H member 2
inhibitor
Human
UPlasmepsin-2
inhibitor
Plasmodium falciparum
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

60-70%;

Metabolism

Hepatic

Route of elimination
Not Available
Half life

6-10 days

Clearance
Not Available
Toxicity

Side effects incldue coughing noisy, rattling, troubled breathing, loss of appetite, aches and pain in joints, indigestion,and skin itching or rash.

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

Interactions

Drug Interactions
DrugInteraction
AbirateroneThe serum concentration of Halofantrine can be increased when it is combined with Abiraterone.
AcepromazineThe serum concentration of Acepromazine can be increased when it is combined with Halofantrine.
AceprometazineThe serum concentration of Aceprometazine can be increased when it is combined with Halofantrine.
AcetazolamideThe metabolism of Halofantrine can be decreased when combined with Acetazolamide.
Acetyl sulfisoxazoleThe serum concentration of Halofantrine can be increased when it is combined with Acetyl sulfisoxazole.
AlbendazoleThe metabolism of Halofantrine can be decreased when combined with Albendazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Halofantrine.
AlfentanilThe metabolism of Alfentanil can be decreased when combined with Halofantrine.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Halofantrine.
AlimemazineThe risk or severity of QTc prolongation can be increased when Halofantrine is combined with Alimemazine.
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.

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0015349
KEGG Compound
C07634
PubChem Compound
37393
PubChem Substance
46506753
ChemSpider
34303
BindingDB
79214
ChEBI
94392
ChEMBL
CHEMBL1107
Therapeutic Targets Database
DAP000953
PharmGKB
PA449839
Drugs.com
Drugs.com Drug Page
Wikipedia
Halofantrine
ATC Codes
P01BX01 — Halofantrine
FDA label
Download (84 KB)
MSDS
Download (27.1 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral250 mg/1
TabletOral250 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
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 FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

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

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenanthrenes and derivatives
Sub Class
Not Available
Direct Parent
Phenanthrenes and derivatives
Alternative Parents
Chloronaphthalenes / Aralkylamines / Aryl chlorides / 1,3-aminoalcohols / Trialkylamines / Secondary alcohols / Organopnictogen compounds / Organofluorides / Organochlorides / Hydrocarbon derivatives
show 2 more
Substituents
Phenanthrene / Chloronaphthalene / Naphthalene / Aralkylamine / Aryl chloride / Aryl halide / 1,3-aminoalcohol / Tertiary aliphatic amine / Tertiary amine / Secondary alcohol
show 15 more
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
Not Available

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 ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
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
Uniprot Name
Plasmepsin-2
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
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. Halliday RC, Jones BC, Smith DA, Kitteringham NR, Park BK: An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: studies with human liver microsomes and heterologous enzyme expression systems. Br J Clin Pharmacol. 1995 Oct;40(4):369-78. [PubMed:8554939]
  3. 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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
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 un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
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]
  2. Baune B, Flinois JP, Furlan V, Gimenez F, Taburet AM, Becquemont L, Farinotti R: Halofantrine metabolism in microsomes in man: major role of CYP 3A4 and CYP 3A5. J Pharm Pharmacol. 1999 Apr;51(4):419-26. [PubMed:10385214]
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 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]

Drug created on June 13, 2005 07:24 / Updated on October 09, 2018 20:34