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Showing drug card for Pyrimethamine (DB00205)

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Version 2.5
Creation Date 2005-06-13 13:24:05
Update Date 2009-06-23 18:06:27
Primary Accession Number DB00205
Secondary Accession Number
  • APRD00599
Name Pyrimethamine
Drug Type
  • Approved
  • Small Molecule
Description One of the folic acid antagonists that is used as an antimalarial or with a sulfonamide to treat toxoplasmosis. [PubChem]
Synonyms
  1. CD
  2. Chloridin
  3. Chloridine
  4. Chloridyn
  5. Diaminopyritamin
  6. Ethylpyrimidine
  7. Pirimetamin
  8. Pirimetamina
  9. Primethamine
  10. Pyremethamine
  11. Pyrimethamin
  12. Pyrimethamine Hcl
Brand Names
  1. Darachlor
  2. Daraclor
  3. Darapram
  4. Daraprim
  5. Daraprime
  6. Disulone
  7. Erbaprelina
  8. Fansidar
  9. Khloridin
  10. Malacid
  11. Malocid
  12. Malocide
  13. Maloprim
  14. Pirimecidan
  15. Tindurin
  16. Tinduring
Brand Mixtures
  1. Fansidar Tablets (Pyrimethamine + Sulfadoxine)
  2. Quinnoxine-S (Pyrimethamine + Sulfaquinoxaline)
  3. Sulfaquinoxaline-S Liq (Pyrimethamine + Sulfaquinoxaline)
Chemical IUPAC Name 5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
Chemical Formula C12H13ClN4
Chemical Structure Structure
CAS Registry Number 58-14-0
InChI Identifier InChI=1/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)/f/h14-15H2
InChI Key WKSAUQYGYAYLPV-KHCWMJRFCQ
KEGG Drug D00488 Link Image
KEGG Compound C07391 Link Image
PubChem Compound 4993 Link Image
PubChem Substance 9595 Link Image
ChEBI ID Not Available
PharmGKB ID PA451193 Link Image
HET ID CP6 Link Image
GenBank ID Not Available
Drug ID Number [DIN] 00004774 Link Image
RxList Link http://www.rxlist.com/cgi/generic/pyrime.htm Link Image
PDRhealth Link Not Available
Wikipedia Link http://en.wikipedia.org/wiki/Pyrimethamine Link Image
FDA Label
Material Safety Data Sheet (MSDS)
Synthesis Reference Russel, Hitchings, J. Am. Chem. Soc. 73, 3763 (1951); Hitchings et al., U.S. pats. 2,576,939; 2,579,259, and 2,602,794 (1951 and 1952 to Burroughs Wellcome); Jacob, U.S. pat 2,680,740 (1954 to Rhone-Poulenc)
Average Molecular Weight 248.7110
Monoisotopic Molecular Weight 248.0829
State Solid
Melting Point 233.5 oC
Experimental Water Solubility 121 mg/L Source: PhysProp
Predicted Water Solubility 1.79e-01 mg/mL Calculated using ALOGPS
Experimental LogP/Hydrophobicity 2.7 Source: PhysProp
Predicted LogP 2.62 Calculated using ALOGPS
Experimental LogS Not Available
Predicted LogS -3.14 Calculated using ALOGPS
Experimental Caco2 Permeability Not Available
pKa/Isoelectric Point 7.34
Mass Spectrum Not Available
MOL File Show Link Image | Download Link Image
SDF File Show Link Image | Download Link Image
PDB File Show Link Image | Download Link Image
2D Structure
3D Structure
Experimental PDB ID 1MVT Link Image
Experimental PDB File Show
Experimental PDB Structure
Isomeric SMILES CCC1=C(C(N)=NC(N)=N1)C1=CC=C(Cl)C=C1
Canonical SMILES CCC1=C(C(N)=NC(N)=N1)C1=CC=C(Cl)C=C1
Drug Category
  • Antimalarials
  • Antiprotozoal Agents
  • Antiprotozoals
  • Folic Acid Antagonists
ATC Codes
AHFS Codes
  • 08:30.08
Indication For the treatment of toxoplasmosis and acute malaria; For the prevention of malaria in areas non-resistant to pyrimethamine
Pharmacology 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
Toxicity Not Available
Protein Binding 87%
Biotransformation Hepatic
Half Life 96 hours
Dosage Forms
Form Route
Tablet Oral
Patient Information Show Link Image
Contraindications Show Link Image
Interactions Show Link Image
Drug Interactions Not Available
Food Interactions
  • Folic acid needs increased.
  • Take with food to reduce irritation.
Pathways Not Available
General References
  1. 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 Link Image]
  2. 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 Link Image]
  3. Drugs.com Link Image
  4. Wikipedia Link Image
  5. RxList Link Image
Organisms Affected
  • Plasmodium
Targets
  1. Dihydrofolate reductase
  2. Bifunctional dihydrofolate reductase-thymidylate synthase
Drug Target 1 [top]
Target 1 ID 365
Target 1 Name Dihydrofolate reductase
Target 1 Synonyms
  1. EC 1.5.1.3
Target 1 Gene Name DHFR
Target 1 Protein Sequence >Dihydrofolate reductase 
VGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFSI
PEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSSV
YKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKFE
VYEKND
Target 1 Number of Residues 189
Target 1 Molecular Weight 21322
Target 1 Theoretical pI 7.60
Target 1 GO Classification
Function
binding
cofactor binding
coenzyme binding
NADP binding
catalytic activity
oxidoreductase activity
oxidoreductase activity, acting on the CH-NH group of donors
oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor
dihydrofolate reductase activity
Process
nucleobase, nucleoside, nucleotide and nucleic acid metabolism
nucleotide metabolism
nucleotide biosynthesis
physiological process
metabolism
cellular metabolism
amino acid and derivative metabolism
amino acid metabolism
serine family amino acid metabolism
glycine metabolism
glycine biosynthesis
Component
Not Available
Target 1 General Function Coenzyme transport and metabolism
Target 1 Specific Function Not Available
Target 1 Pathways
Name SMPDB Link KEGG Link
Folate biosynthesis map00790 Link Image
One carbon pool by folate SMP00053 Link Image map00670 Link Image
Target 1 Reactions
  • 5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
Target 1 Pfam Domain Function
Target 1 Signals
  • None
Target 1 Transmembrane Regions
  • None
Target 1 Essentiality Non-Essential
Target 1 GenBank ID Protein 182724 Link Image
Target 1 UniProtKB/Swiss-Prot ID P00374 Link Image
Target 1 UniProtKB/Swiss-Prot Entry Name DYR_HUMAN Link Image
Target 1 PDB ID 1MVT Link Image
Target 1 PDB File Show
Target 1 3D Structure
Target 1 Cellular Location Not Available
Target 1 Gene Sequence >564 bp 
ATGGTTGGTTCGCTAAACTGCATCGTCGCTGTGTCCCAGAACATGGGCATCGGCAAGAAC
GGGGACCTGCCCTGGCCACCGCTCAGGAATGAATTCAGATATTTCCAGAGAATGACCACA
ACCTCTTCAGTAGAAGGTAAACAGAATCTGGTGATTATGGGTAAGAAGACCTGGTTCTCC
ATTCCTGAGAAGAATCGACCTTTAAAGGGTAGAATTAATTTAGTTCTCAGCAGAGAACTC
AAGGAACCTCCACAAGGAGCTCATTTTCTTTCCAGAAGTCTAGATGATGCCTTAAAACTT
ACTGAACAACCAGAATTAGCAAATAAAGTAGACATGGTCTGGATAGTTGGTGGCAGTTCT
GTTTATAAGGAAGCCATGAATCACCCAGGCCATCTTAAACTATTTGTGACAAGGATCATG
CAAGACTTTGAAAGTGACACGTTTTTTCCAGAAATTGATTTGGAGAAATATAAACTTCTG
CCAGAATACCCAGGTGTTCTCTCTGATGTCCAGGAGGAGAAAGGCATTAAGTACAAATTT
GAAGTATATGAGAAGAATGATTAA
Target 1 GenBank Gene ID
Target 1 GeneCard ID DHFR Link Image
Target 1 GenAtlas ID DHFR Link Image
Target 1 HGNC ID HGNC:2861 Link Image
Target 1 Chromosome Location 5
Target 1 Locus 5q11.2-q13.2
Target 1 SNPs SNPJam Report Link Image
Target 1 General References
  1. Stockman BJ, Nirmala NR, Wagner G, Delcamp TJ, DeYarman MT, Freisheim JH: Sequence-specific 1H and 15N resonance assignments for human dihydrofolate reductase in solution. Biochemistry. 1992 Jan 14;31(1):218-29. [PubMed Link Image]
  2. Davies JF 2nd, Delcamp TJ, Prendergast NJ, Ashford VA, Freisheim JH, Kraut J: Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate. Biochemistry. 1990 Oct 9;29(40):9467-79. [PubMed Link Image]
  3. Oefner C, D'Arcy A, Winkler FK: Crystal structure of human dihydrofolate reductase complexed with folate. Eur J Biochem. 1988 Jun 1;174(2):377-85. [PubMed Link Image]
  4. Yang JK, Masters JN, Attardi G: Human dihydrofolate reductase gene organization. Extensive conservation of the G + C-rich 5' non-coding sequence and strong intron size divergence from homologous mammalian genes. J Mol Biol. 1984 Jun 25;176(2):169-87. [PubMed Link Image]
  5. Chen MJ, Shimada T, Moulton AD, Cline A, Humphries RK, Maizel J, Nienhuis AW: The functional human dihydrofolate reductase gene. J Biol Chem. 1984 Mar 25;259(6):3933-43. [PubMed Link Image]
  6. Masters JN, Attardi G: The nucleotide sequence of the cDNA coding for the human dihydrofolic acid reductase. Gene. 1983 Jan-Feb;21(1-2):59-63. [PubMed Link Image]
  7. Cody V, Galitsky N, Luft JR, Pangborn W, Rosowsky A, Blakley RL: Comparison of two independent crystal structures of human dihydrofolate reductase ternary complexes reduced with nicotinamide adenine dinucleotide phosphate and the very tight-binding inhibitor PT523. Biochemistry. 1997 Nov 11;36(45):13897-903. [PubMed Link Image]
Target 1 Drug References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed Link Image]
Drug Target 2 [top]
Target 2 ID 620
Target 2 Name Bifunctional dihydrofolate reductase-thymidylate synthase
Target 2 Synonyms
  1. DHFR-TS
Target 2 Gene Name Not Available
Target 2 Protein Sequence >Bifunctional dihydrofolate reductase-thymidylate synthase 
MMEQVCDVFDIYAICACCKVESKNEGKKNEVFNNYTFRGLGNKGVLPWKCNSLDMKYFRA
VTTYVNESKYEKLKYKRCKYLNKETVDNVNDMPNSKKLQNVVVMGRTNWESIPKKFKPLS
NRINVILSRTLKKEDFDEDVYIINKVEDLIVLLGKLNYYKCFIIGGSVVYQEFLEKKLIK
KIYFTRINSTYECDVFFPEINENEYQIISVSDVYTSNNTTLDFIIYKKTNNKMLNEQNCI
KGEEKNNDMPLKNDDKDTCHMKKLTEFYKNVDKYKINYENDDDDEEEDDFVYFNFNKEKE
EKNKNSIHPNDFQIYNSLKYKYHPEYQYLNIIYDIMMNGNKQSDRTGVGVLSKFGYIMKF
DLSQYFPLLTTKKLFLRGIIEELLWFIRGETNGNTLLNKNVRIWEANGTREFLDNRKLFH
REVNDLGPIYGFQWRHFGAEYTNMYDNYENKGVDQLKNIINLIKNDPTSRRILLCAWNVK
DLDQMALPPCHILCQFYVFDGKLSCIMYQRSCDLGLGVPFNIASYSIFTHMIAQVCNLQP
AQFIHVLGNAHVYNNHIDSLKIQLNRIPYPFPTLKLNPDIKNIEDFTISDFTIQNYVHHE
KISMDMAA
Target 2 Number of Residues 618
Target 2 Molecular Weight 71818
Target 2 Theoretical pI 7.41
Target 2 GO Classification
Function
transferase activity
transferase activity, transferring one-carbon groups
methyltransferase activity
5,10-methylenetetrahydrofolate-dependent methyltransferase activity
thymidylate synthase activity
catalytic activity
oxidoreductase activity
oxidoreductase activity, acting on the CH-NH group of donors
oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor
dihydrofolate reductase activity
Process
pyrimidine nucleotide metabolism
pyrimidine nucleotide biosynthesis
pyrimidine nucleoside monophosphate biosynthesis
pyrimidine deoxyribonucleoside monophosphate biosynthesis
dTMP biosynthesis
nucleobase, nucleoside, nucleotide and nucleic acid metabolism
nucleotide metabolism
nucleotide biosynthesis
amino acid and derivative metabolism
amino acid metabolism
serine family amino acid metabolism
glycine metabolism
glycine biosynthesis
physiological process
metabolism
cellular metabolism
one-carbon compound metabolism
Component
Not Available
Target 2 General Function Nucleotide transport and metabolism
Target 2 Specific Function Not Available
Target 2 Pathways
Name SMPDB Link KEGG Link
One carbon pool by folate SMP00053 Link Image map00670 Link Image
Pyrimidine metabolism SMP00046 Link Image map00240 Link Image
Target 2 Reactions
  • 5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
Target 2 Pfam Domain Function
Target 2 Signals
  • None
Target 2 Transmembrane Regions
  • None
Target 2 Essentiality Essential
Target 2 GenBank ID Protein 160260 Link Image
Target 2 UniProtKB/Swiss-Prot ID P13922 Link Image
Target 2 UniProtKB/Swiss-Prot Entry Name DRTS_PLAFK Link Image
Target 2 PDB ID 1J3K Link Image
Target 2 PDB File Show
Target 2 3D Structure
Target 2 Cellular Location Not Available
Target 2 Gene Sequence >1827 bp 
ATGATGGAACAAGTCTGCGACGTTTTCGATATTTATGCCATATGTGCATGTTGTAAGGTT
GAAAGCAAAAATGAGGGGAAAAAAAATGAGGTTTTTAATAACTACACATTTAGAGGTCTA
GGAAATAAAGGAGTATTACCATGGAAATGTAATTCCCTAGATATGAAATATTTTCGTGCA
GTTACAACATATGTGAATGAATCAAAATATGAAAAATTGAAATATAAGAGATGTAAATAT
TTAAACAAAGAAACTGTGGATAATGTAAATGATATGCCTAATTCTAAAAAATTACAAAAT
GTTGTAGTTATGGGAAGAACAAACTGGGAAAGCATTCCAAAAAAATTTAAACCTTTAAGC
AATAGGATAAATGTTATATTGTCTAGAACCTTAAAAAAAGAAGATTTTGATGAAGATGTT
TATATCATTAACAAAGTTGAAGATCTAATAGTTTTACTTGGGAAATTAAATTACTATAAA
TGTTTTATTATAGGAGGTTCCGTTGTTTATCAAGAATTTTTAGAAAAGAAATTAATAAAA
AAAATATATTTTACTAGAATAAATAGTACATATGAATGTGATGTATTTTTTCCAGAAATA
AATGAAAATGAGTATCAAATTATTTCTGTTAGCGATGTATATACTAGTAACAATACAACA
TTGGATTTTATCATTTATAAGAAAACGAATAATAAAATGTTAAATGAACAAAATTGTATA
AAAGGAGAAGAAAAAAATAATGATATGCCTTTAAAGAATGATGACAAAGATACATGTCAT
ATGAAAAAATTAACAGAATTTTACAAAAATGTAGACAAATATAAAATTAATTATGAAAAT
GATGATGATGATGAAGAAGAAGATGATTTTGTTTATTTTAATTTTAATAAAGAAAAAGAA
GAGAAAAATAAAAATTCTATACATCCAAATGATTTTCAAATATATAATAGCTTGAAATAT
AAATATCATCCTGAATACCAATATTTAAATATTATTTATGATATTATGATGAATGGAAAT
AAACAAAGTGATCGAACGGGAGTAGGTGTTTTAAGTAAATTCGGATATATTATGAAATTT
GATTTAAGTCAATATTTCCCATTATTAACTACGAAGAAATTATTTTTAAGAGGAATTATT
GAAGAATTGCTTTGGTTTATTAGAGGAGAAACAAATGGTAATACGTTGTTAAATAAGAAT
GTAAGGATATGGGAAGCTAATGGTACTAGGGAATTTTTAGATAATAGAAAATTATTTCAT
AGAGAAGTTAACGATTTAGGACCTATTTATGGTTTTCAATGGAGACATTTCGGTGCTGAA
TATACAAATATGTATGATAATTATGAAAATAAAGGAGTGGATCAATTAAAAAATATAATA
AATTTAATTAAAAATGATCCTACAAGTAGAAGAATTCTTTTGTGTGCATGGAATGTAAAA
GATCTTGACCAAATGGCATTACCTCCTTGTCATATTTTATGTCAGTTTTATGTTTTCGAT
GGGAAATTATCATGTATTATGTATCAAAGATCATGTGATTTAGGGCTAGGAGTACCTTTT
AATATTGCTTCTTATTCTATTTTTACTCATATGATTGCACAAGTCTGTAATTTGCAACCT
GCGCAGTTCATACACGTTTTAGGAAATGCACATGTTTATAATAATCACATTGATAGTTTA
AAAATTCAACTTAACAGAATACCCTATCCATTCCCAACACTTAAATTAAATCCAGATATT
AAAAATATTGAAGATTTTACAATTTCGGATTTTACAATACAAAATTATGTTCATCATGAA
AAAATTTCAATGGATATGGCTGCTTAA
Target 2 GenBank Gene ID
Target 2 GeneCard ID Not Available
Target 2 GenAtlas ID Not Available
Target 2 HGNC ID Not Available
Target 2 Chromosome Location Not Available
Target 2 Locus Not Available
Target 2 SNPs Not Available
Target 2 General References
  1. Snewin VA, England SM, Sims PF, Hyde JE: Characterisation of the dihydrofolate reductase-thymidylate synthetase gene from human malaria parasites highly resistant to pyrimethamine. Gene. 1989 Mar 15;76(1):41-52. [PubMed Link Image]
  2. 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 Link Image]
  3. Bzik DJ, Li WB, Horii T, Inselburg J: Molecular cloning and sequence analysis of the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8360-4. [PubMed Link Image]
  4. Cowman AF, Morry MJ, Biggs BA, Cross GA, Foote SJ: Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9109-13. [PubMed Link Image]
Target 2 Drug References
  1. 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 Link Image]
  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 Link Image]
  3. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed Link Image]
  4. 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 Link Image]
  5. 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 Link Image]

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