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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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Halofantrina [INN-Spanish]
Halofantrine [Usan]
Halofantrinum [INN-Latin]
Salts Not Available
Brand names
Name Company
Halfan
Brand mixtures Not Available
Categories
  • Antiprotozoals
  • Antimalarials
CAS number 69756-53-2
Weight Average: 500.424
Monoisotopic: 499.165654616
Chemical Formula C26H30Cl2F3NO
InChI Key InChIKey=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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenanthrenes
Substructures
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Naphthalenes
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Aliphatic and Aryl Amines
  • Phenanthrenes
  • Aromatic compounds
  • Phenylpropylamines
  • Alcohols and Polyols
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.
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
Pharmacoeconomics
Manufacturers
  • Glaxosmithkline
Packagers Not Available
Dosage forms Not Available
Prices Not Available
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
logP 8.9 Not Available
Predicted Properties
Property Value Source
water solubility 1.11e-04 g/l ALOGPS
logP 7.34 ALOGPS
logP 8.06 ChemAxon
logS -6.7 ALOGPS
pKa (strongest acidic) 14.47 ChemAxon
pKa (strongest basic) 10.05 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 2 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 23.47 ChemAxon
rotatable bond count 11 ChemAxon
refractivity 131.66 ChemAxon
polarizability 51.53 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Compound C07634 Link_out
PubChem Compound 37393 Link_out
PubChem Substance 46506753 Link_out
ChemSpider 34303 Link_out
BindingDB 50096846 Link_out
Therapeutic Targets Database DAP000953 Link_out
PharmGKB PA449839 Link_out
Drug Product Database 2162857 Link_out
Drugs.com http://www.drugs.com/cdi/halofantrine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Halofantrine Link_out
ATC Codes
  • P01BX01
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (84 KB)
MSDS show (27.1 KB)
Interactions
Drug Interactions
Drug Interaction
Artemether Halofantrine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.
Bicalutamide CYP3A4 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).
Clotrimazole CYP3A4 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).
Conivaptan CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Concurrent use of orally inhaled fluticasone with strong CYP3A4 inhibitors is not recommended.
Lumefantrine Halofantrine 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.
Mefloquine Increased risk of cardiac toxicity
Mesoridazine Increased risk of cardiotoxicity and arrhythmias
Posaconazole Contraindicated co-administration
Quinupristin This combination presents an increased risk of toxicity
Tacrolimus Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Telithromycin Telithromycin 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.
Thioridazine Increased risk of cardiotoxicity and arrhythmias
Thiothixene May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
Toremifene Additive 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.
Trimipramine Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Verapamil Verapamil, 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.
Voriconazole Voriconazole 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.
Vorinostat Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Ziprasidone Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy should be avoided.
Zuclopenthixol Additive 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. Ferriprotoporphyrin IX

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
  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

Pharmacological action: yes
Actions: inhibitor

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). Isoform 3 has no channel activity by itself, but modulates channel characteristics when associated with isoform 1

Organism class: human
UniProt ID: Q12809 Link_out
Gene: KCNH2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: inhibitor

Hydrolysis of the bonds linking certain hydrophobic residues in hemoglobin or globin. Also cleaves small molecules substrates such as Ala-Leu-Glu-Arg-Thr-Phe-|-Phe(NO(2))- Ser-Phe-Pro-Thr

Organism class: parasitic
UniProt ID: P46925 Link_out
Protein Sequence: FASTA

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

Actions: substrate, inhibitor

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

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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 responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:20