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Identification
Name Pyrimethamine
Accession Number DB00205 (APRD00599)
Type small molecule
Groups approved
Description

One of the folic acid antagonists that is used as an antimalarial or with a sulfonamide to treat toxoplasmosis. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
CD
Chloridin
Chloridine
Chloridyn
Diaminopyritamin
Ethylpyrimidine
Pirimetamin
Pirimetamina
Primethamine
Pyremethamine
Pyrimethamin
Pyrimethamine Hcl
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Salts Not Available
Brand names
Name Company
Darachlor
Daraclor
Darapram
Daraprim
Daraprime
Disulone
Erbaprelina
Fansidar
Khloridin
Malacid
Malocid
Malocide
Maloprim
Pirimecidan
Tindurin
Tinduring
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Brand mixtures
Brand Name Ingredients
Fansidar Tablets Pyrimethamine + Sulfadoxine
Quinnoxine-S Pyrimethamine + Sulfaquinoxaline
Sulfaquinoxaline-S Liq Pyrimethamine + Sulfaquinoxaline
Categories
  • Antiprotozoals
  • Antimalarials
  • Folic Acid Antagonists
  • Antiprotozoal Agents
CAS number 58-14-0
Weight Average: 248.711
Monoisotopic: 248.082874143
Chemical Formula C12H13ClN4
InChI Key InChIKey=WKSAUQYGYAYLPV-UHFFFAOYSA-N
InChI
InChI=1S/C12H13ClN4/c1-2-9-10(11(14)17-12(15)16-9)7-3-5-8(13)6-4-7/h3-6H,2H2,1H3,(H4,14,15,16,17)
Plain Text
IUPAC Name
5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
SMILES
CCC1=C(C(N)=NC(N)=N1)C1=CC=C(Cl)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenylpropenes
Substructures
  • Phenylpropenes
  • Aliphatic and Aryl Amines
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Pyrimidines and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Imines
  • Cyanamides
Pharmacology
Indication For the treatment of toxoplasmosis and acute malaria; For the prevention of malaria in areas non-resistant to pyrimethamine
Pharmacodynamics Pyrimethamine is an antiparasitic compound commonly used as an adjunct in the treatment of uncomplicated, chloroquine resistant, P. falciparum malaria. Pyrimethamine is a folic acid antagonist and the rationale for its therapeutic action is based on the differential requirement between host and parasite for nucleic acid precursors involved in growth. This activity is highly selective against plasmodia and Toxoplasma gondii. Pyrimethamine possesses blood schizonticidal and some tissue schizonticidal activity against malaria parasites of humans. However, the 4-amino-quinoline compounds are more effective against the erythrocytic schizonts. It does not destroy gametocytes, but arrests sporogony in the mosquito. The action of pyrimethamine against Toxoplasma gondii is greatly enhanced when used in conjunction with sulfonamides.
Mechanism of action Pyrimethamine inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver.
Absorption Well absorbed with peak levels occurring between 2 to 6 hours following administration
Volume of distribution Not Available
Protein binding 87%
Metabolism Hepatic
Route of elimination Not Available
Half life 96 hours
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Plasmodium
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Glaxosmithkline llc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Pyrimethamine powder 8.88 USD g
Daraprim 25 mg tablet 0.98 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 233.5 °C PhysProp
water solubility 121 mg/L Not Available
logP 2.69 HANSCH,C ET AL. (1995)
pKa 7.34 (at 20 °C) PERRIN,DD (1972)
Predicted Properties
Property Value Source
water solubility 1.79e-01 g/l ALOGPS
logP 2.62 ALOGPS
logP 2.75 ChemAxon
logS -3.1 ALOGPS
pKa (strongest acidic) 17.22 ChemAxon
pKa (strongest basic) 7.77 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 77.82 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 71.54 ChemAxon
polarizability 25.79 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Gatton ML, Martin LB, Cheng Q: Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum. Antimicrob Agents Chemother. 2004 Jun;48(6):2116-23. Pubmed
  2. Sirichaiwat C, Intaraudom C, Kamchonwongpaisan S, Vanichtanankul J, Thebtaranonth Y, Yuthavong Y: Target guided synthesis of 5-benzyl-2,4-diamonopyrimidines: their antimalarial activities and binding affinities to wild type and mutant dihydrofolate reductases from Plasmodium falciparum. J Med Chem. 2004 Jan 15;47(2):345-54. Pubmed
External Links
Resource Link
KEGG Drug D00488 Link_out
KEGG Compound C07391 Link_out
PubChem Compound 4993 Link_out
PubChem Substance 46505987 Link_out
ChemSpider 4819 Link_out
BindingDB 18512 Link_out
ChEBI 8673 Link_out
ChEMBL 8673 Link_out
Therapeutic Targets Database DAP000633 Link_out
PharmGKB PA451193 Link_out
HET CP6 Link_out
Drug Product Database 4774 Link_out
RxList http://www.rxlist.com/cgi/generic/pyrime.htm Link_out
Drugs.com http://www.drugs.com/cdi/pyrimethamine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Pyrimethamine Link_out
ATC Codes
  • P01BD01
AHFS Codes
  • 08:30.08
PDB Entries
FDA label show (29.7 KB)
MSDS show (74 KB)
Interactions
Drug Interactions
Drug Interaction
Artemether Pyrimethamine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.
Lumefantrine Pyrimethamine may increase the adverse effects of lumefantrine. Combination therapy is contraindicated unless there are no other treatment options.
Tamoxifen Pyrimethamine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.
Tamsulosin Pyrimethamine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Pyrimethamine is initiated, discontinued, or dose changed.
Tramadol Pyrimethamine may decrease the effect of Tramadol by decreasing active metabolite production.
Food Interactions
  • Folic acid needs increased.
  • Take with food to reduce irritation.
Targets

1. Dihydrofolate reductase

Pharmacological action: yes
Actions: inhibitor
Organism class: human
UniProt ID: P00374 Link_out
Gene: DHFR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Rastelli G, Pacchioni S, Parenti MD: Structure of Plasmodium vivax dihydrofolate reductase determined by homology modeling and molecular dynamics refinement. Bioorg Med Chem Lett. 2003 Oct 6;13(19):3257-60. Pubmed
  2. Fidock DA, Wellems TE: Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10931-6. Pubmed
  3. Wooden JM, Hartwell LH, Vasquez B, Sibley CH: Analysis in yeast of antimalaria drugs that target the dihydrofolate reductase of Plasmodium falciparum. Mol Biochem Parasitol. 1997 Mar;85(1):25-40. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Bifunctional dihydrofolate reductase-thymidylate synthase

Pharmacological action: yes
Actions: inhibitor
Organism class: parasitic
UniProt ID: P13922 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA

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. Fohl LM, Roos DS: Fitness effects of DHFR-TS mutations associated with pyrimethamine resistance in apicomplexan parasites. Mol Microbiol. 2003 Nov;50(4):1319-27. Pubmed
  4. McKie JH, Douglas KT, Chan C, Roser SA, Yates R, Read M, Hyde JE, Dascombe MJ, Yuthavong Y, Sirawaraporn W: Rational drug design approach for overcoming drug resistance: application to pyrimethamine resistance in malaria. J Med Chem. 1998 Apr 23;41(9):1367-70. Pubmed
  5. Zolg JW, Plitt JR, Chen GX, Palmer S: Point mutations in the dihydrofolate reductase-thymidylate synthase gene as the molecular basis for pyrimethamine resistance in Plasmodium falciparum. Mol Biochem Parasitol. 1989 Oct;36(3):253-62. Pubmed
  6. Zhang K, Rathod PK: Divergent regulation of dihydrofolate reductase between malaria parasite and human host. Science. 2002 Apr 19;296(5567):545-7. Pubmed
Enzymes

1. Cytochrome P450 2C9

Actions: inhibitor

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. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
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

2. Cytochrome P450 2D6

Actions: 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. 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 2C8

Actions: inhibitor

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 16:19