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Identification
NamePyrimethamine
Accession NumberDB00205  (APRD00599)
TypeSmall Molecule
GroupsApproved
Description

One of the folic acid antagonists that is used as an antimalarial or with a sulfonamide to treat toxoplasmosis. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
2,4-Diamino-5-(4-chlorophenyl)-6-ethylpyrimidineNot AvailableNot Available
2,4-Diamino-5-(P-chlorophenyl)-6-ethylpyrimidineNot AvailableNot Available
2,4-Diamino-5-chlorophenyl-6-ethylpyrimidineNot AvailableNot Available
5-(4-Chlorophenyl)-6-ethyl-2,4-diaminopyrimidineNot AvailableNot Available
5-(4-Chlorophenyl)-6-ethyl-2,4-pyrimidinediamineNot AvailableNot Available
5-(4'-Chlorophenyl)-2,4-diamino-6-ethylpyrimidineNot AvailableNot Available
CDNot AvailableNot Available
ChloridineNot AvailableNot Available
ChloridynNot AvailableNot Available
DiaminopyritaminNot AvailableNot Available
EthylpyrimidineNot AvailableNot Available
PirimetaminaNot AvailableINN
PrimethamineNot AvailableNot Available
PyrimethaminumNot AvailableNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Daraprimtablet25 mgoralKAISER FOUNDATION HOSPITALS2011-04-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Daraprimtablet25 mgoralAmedra Pharmaceuticals LLC1953-01-23Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Daraprimtablet25 mgoralREMEDYREPACK INC.2013-02-26Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixtures
Brand NameIngredients
Fansidar TabletsPyrimethamine + Sulfadoxine
Quinnoxine-SPyrimethamine + Sulfaquinoxaline
Sulfaquinoxaline-S LiqPyrimethamine + Sulfaquinoxaline
Salts
Name/CASStructureProperties
Pyrimethamine Hydrochloride
19085-09-7
Thumb
  • InChI Key: JZCLIFPQURTYFA-UHFFFAOYSA-N
  • Monoisotopic Mass: 284.059551882
  • Average Mass: 285.172
DBSALT000385
Categories
CAS number58-14-0
WeightAverage: 248.711
Monoisotopic: 248.082874143
Chemical FormulaC12H13ClN4
InChI KeyWKSAUQYGYAYLPV-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)
IUPAC Name
5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
SMILES
CCC1=C(C(N)=NC(N)=N1)C1=CC=C(Cl)C=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylpyrimidines. These are polycyclic aromatic compounds containing a benzene ring linked to a pyrimidine ring through a CC or CN bond. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazines
Sub ClassPyrimidines and pyrimidine derivatives
Direct ParentPhenylpyrimidines
Alternative Parents
Substituents
  • 5-phenylpyrimidine
  • Halobenzene
  • Chlorobenzene
  • Aminopyrimidine
  • Imidolactam
  • Benzenoid
  • Primary aromatic amine
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl chloride
  • Heteroaromatic compound
  • Azacycle
  • Hydrocarbon derivative
  • Primary amine
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of toxoplasmosis and acute malaria; For the prevention of malaria in areas non-resistant to pyrimethamine
PharmacodynamicsPyrimethamine 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 actionPyrimethamine 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.
AbsorptionWell absorbed with peak levels occurring between 2 to 6 hours following administration
Volume of distributionNot Available
Protein binding87%
Metabolism

Hepatic

Route of eliminationNot Available
Half life96 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Plasmodium
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9973
Blood Brain Barrier+0.9383
Caco-2 permeable+0.6217
P-glycoprotein substrateNon-substrate0.5822
P-glycoprotein inhibitor INon-inhibitor0.8643
P-glycoprotein inhibitor IINon-inhibitor0.9045
Renal organic cation transporterNon-inhibitor0.7451
CYP450 2C9 substrateNon-substrate0.8103
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.6582
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 substrateNon-inhibitor0.9071
CYP450 2D6 substrateInhibitor0.8932
CYP450 2C19 substrateNon-inhibitor0.9026
CYP450 3A4 substrateNon-inhibitor0.7586
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6667
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.8016
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.7833 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9337
hERG inhibition (predictor II)Non-inhibitor0.8586
Pharmacoeconomics
Manufacturers
  • Glaxosmithkline llc
Packagers
Dosage forms
FormRouteStrength
Tabletoral25 mg
Prices
Unit descriptionCostUnit
Pyrimethamine powder8.88USD g
Daraprim 25 mg tablet0.98USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point233.5 °CPhysProp
water solubility121 mg/LNot Available
logP2.69HANSCH,C ET AL. (1995)
pKa7.34 (at 20 °C)PERRIN,DD (1972)
Predicted Properties
PropertyValueSource
Water Solubility0.179 mg/mLALOGPS
logP2.62ALOGPS
logP2.75ChemAxon
logS-3.1ALOGPS
pKa (Strongest Acidic)17.22ChemAxon
pKa (Strongest Basic)7.77ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area77.82 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity71.54 m3·mol-1ChemAxon
Polarizability25.79 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraMS
References
Synthesis Reference

DrugSyn.org

US2576939
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
ATC CodesP01BD01
AHFS Codes
  • 08:30.08
PDB Entries
FDA labelDownload (29.7 KB)
MSDSDownload (74 KB)
Interactions
Drug Interactions
Drug
ArtemetherPyrimethamine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.
LumefantrinePyrimethamine may increase the adverse effects of lumefantrine. Combination therapy is contraindicated unless there are no other treatment options.
TamoxifenPyrimethamine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.
TamsulosinPyrimethamine, 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.
TramadolPyrimethamine 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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Dihydrofolate reductase P00374 Details

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

Kind: protein

Organism: Plasmodium falciparum (isolate K1 / Thailand)

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Bifunctional dihydrofolate reductase-thymidylate synthase P13922 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. 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 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 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

2. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 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
  2. Lexicomp

3. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

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 October 08, 2013 14:25