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Record Information
Version2.0
Creation Date2014-09-11 05:16:14 UTC
Update Date2014-12-24 20:26:57 UTC
Accession NumberT3D4779
Identification
Common NamePyrimethamine
ClassSmall Molecule
DescriptionOne of the folic acid antagonists that is used as an antimalarial or with a sulfonamide to treat toxoplasmosis.
Compound Type
  • Amine
  • Antimalarial
  • Antiprotozoal Agent
  • Drug
  • Folic Acid Antagonist
  • Metabolite
  • Organic Compound
  • Organochloride
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
2,4-Diamino-5-(4-chlorophenyl)-6-ethylpyrimidine
2,4-Diamino-5-(P-chlorophenyl)-6-ethylpyrimidine
2,4-Diamino-5-chlorophenyl-6-ethylpyrimidine
5-(4'-Chlorophenyl)-2,4-diamino-6-ethylpyrimidine
5-(4-Chlorophenyl)-6-ethyl-2,4-diaminopyrimidine
5-(4-Chlorophenyl)-6-ethyl-2,4-pyrimidinediamine
CD
Chloridin
Chloridine
Chloridyn
Daraprim
Diaminopyritamin
Ethylpyrimidine
Pirimetamin
Pirimetamina
Primethamine
Pyremethamine
Pyrimethamin
Pyrimethaminum
Chemical FormulaC12H13ClN4
Average Molecular Mass248.711 g/mol
Monoisotopic Mass248.083 g/mol
CAS Registry Number58-14-0
IUPAC Name5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
Traditional Namepyrimethamine
SMILESCCC1=NC(=N)NC(N)=C1C1=CC=C(Cl)C=C1
InChI IdentifierInChI=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)
InChI KeyInChIKey=WKSAUQYGYAYLPV-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as aminopyrimidines and derivatives. These are organic compounds containing an amino group attached to a pyrimidine ring. 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 ParentAminopyrimidines and derivatives
Alternative Parents
Substituents
  • Aminopyrimidine
  • Chlorobenzene
  • Halobenzene
  • Aryl chloride
  • Aryl halide
  • Monocyclic benzene moiety
  • Hydropyrimidine
  • Benzenoid
  • Heteroaromatic compound
  • Azacycle
  • Organochloride
  • Organohalogen compound
  • Amine
  • Hydrocarbon derivative
  • Organopnictogen compound
  • Organonitrogen compound
  • Primary amine
  • Organic nitrogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point233.5°C
Boiling PointNot Available
Solubility121 mg/L
LogP2.69
Predicted Properties
PropertyValueSource
Water Solubility0.18 g/LALOGPS
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 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity71.54 m³·mol⁻¹ChemAxon
Polarizability25.79 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-0002-0090000000-4e966bed391e234a23e3JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - CI-B (Non-derivatized)splash10-0002-0090000000-4e966bed391e234a23e3JSpectraViewer | MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-01pk-0290000000-f67f41257c448ad0d840JSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0002-0090000000-a146b85d59fc9835ed4cJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0002-0090000000-84e4cea277c64351f21bJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0002-0190000000-d931593de00f33f04587JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0059-0980000000-a232e355dd50976aea07JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-005a-0920000000-7d48f7cfecbd7823803aJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0002-0290000000-b6d3f56ade24c0e6984cJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0002-0290000000-415b60a9caab352df184JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0032-2960000000-583d00b81182f34e5a94JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 20V, Positivesplash10-0002-0090000000-84e4cea277c64351f21bJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 10V, Positivesplash10-0002-0090000000-a146b85d59fc9835ed4cJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 40V, Positivesplash10-0059-0980000000-a232e355dd50976aea07JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 30V, Positivesplash10-0002-0190000000-d931593de00f33f04587JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 30V, Positivesplash10-0002-0090000000-a5bd8cb5be16b08fe352JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 45V, Positivesplash10-0002-0090000000-ec976a2cca417c4abd83JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 15V, Positivesplash10-0002-0090000000-142231cbd9fb9d4cd7caJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 50V, Positivesplash10-005a-0920000000-7d48f7cfecbd7823803aJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 90V, Positivesplash10-005a-0910000000-74228f82abe0906b09ddJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 30V, Positivesplash10-0002-0190000000-2277a786baa63a6f391cJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 50V, Positivesplash10-005a-0920000000-aacf5c362f2e7330e364JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 90V, Positivesplash10-005a-0910000000-d01f0a8b6058c2712921JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 40V, Positivesplash10-0059-0980000000-f3fae500644ff74973deJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 75V, Positivesplash10-0059-0950000000-ef36c55d4c28769d604fJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 60V, Positivesplash10-0032-0590000000-60880dda788d5075e682JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0002-0090000000-7cec7981debaccce56c0JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0002-1190000000-3e6ac4ed3d9334756216JSpectraViewer
MSMass Spectrum (Electron Ionization)splash10-0002-2590000000-6434b6f0181741b3ca41JSpectraViewer | MoNA
Toxicity Profile
Route of ExposureWell absorbed with peak levels occurring between 2 to 6 hours following administration
Mechanism of ToxicityPyrimethamine 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.
MetabolismHepatic Half Life: 96 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)3, not classifiable as to its carcinogenicity to humans. (3)
Uses/SourcesFor the treatment of toxoplasmosis and acute malaria; For the prevention of malaria in areas non-resistant to pyrimethamine
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00205
HMDB IDHMDB14350
PubChem Compound ID4993
ChEMBL IDCHEMBL36
ChemSpider ID4819
KEGG IDC07391
UniProt IDNot Available
OMIM ID
ChEBI ID8673
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDCP6
ACToR IDNot Available
Wikipedia LinkPyrimethamine
References
Synthesis Reference

DrugSyn.org

MSDSLink
General References
  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. [15155209 ]
  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. [14711307 ]
  3. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Nadph binding
Specific Function:
Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.
Gene Name:
DHFR
Uniprot ID:
P00374
Molecular Weight:
21452.61 Da
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. [12951104 ]
  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. [9380737 ]
  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. [9108546 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
General Function:
Zinc ion binding
Specific Function:
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Regulates expression of target genes in a ligand-dependent manner by recruiting chromatin complexes containing KMT2E/MLL5. Mediates retinoic acid-induced granulopoiesis.
Gene Name:
RARA
Uniprot ID:
P10276
Molecular Weight:
50770.805 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.432 uMATG_RARa_TRANSAttagene
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Monoamine transmembrane transporter activity
Specific Function:
Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:
SLC6A3
Uniprot ID:
Q01959
Molecular Weight:
68494.255 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.544 uMNVS_TR_hDATNovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Transcriptional activator activity, rna polymerase ii distal enhancer sequence-specific binding
Specific Function:
Transcription activator that binds to antioxidant response (ARE) elements in the promoter regions of target genes. Important for the coordinated up-regulation of genes in response to oxidative stress. May be involved in the transcriptional activation of genes of the beta-globin cluster by mediating enhancer activity of hypersensitive site 2 of the beta-globin locus control region.
Gene Name:
NFE2L2
Uniprot ID:
Q16236
Molecular Weight:
67825.9 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC502.05 uMATG_NRF2_ARE_CISAttagene
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Norepinephrine:sodium symporter activity
Specific Function:
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:
SLC6A2
Uniprot ID:
P23975
Molecular Weight:
69331.42 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC502.08 uMNVS_TR_hNETNovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Zinc ion binding
Specific Function:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.
Gene Name:
AR
Uniprot ID:
P10275
Molecular Weight:
98987.9 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC502.53 uMTox21_AR_LUC_MDAKB2_AgonistTox21/NCGC
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Thioesterase binding
Specific Function:
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol.
Gene Name:
ADRA2A
Uniprot ID:
P08913
Molecular Weight:
48956.275 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC505.09 uMNVS_GPCR_hAdra2ANovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
G-protein coupled amine receptor activity
Specific Function:
Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.
Gene Name:
DRD1
Uniprot ID:
P21728
Molecular Weight:
49292.765 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC505.36 uMNVS_GPCR_hDRD1Novascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Serotonin receptor activity
Specific Function:
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase.
Gene Name:
HTR7
Uniprot ID:
P34969
Molecular Weight:
53554.43 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC505.39 uMNVS_GPCR_h5HT7Novascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Not Available
Specific Function:
Not Available
Gene Name:
TP53
Uniprot ID:
P04637
Molecular Weight:
43652.79 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC509.710075617 uMAPR_p53Act_72h_upApredica
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]