Diflunisal (T3D2918)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (7)XML
Targets (7)
Record Information
Version2.0
Creation Date2009-07-21 20:27:51 UTC
Update Date2014-12-24 20:25:53 UTC
Accession NumberT3D2918
Identification
Common NameDiflunisal
ClassSmall Molecule
DescriptionDiflunisal, a salicylate derivative, is a nonsteroidal anti-inflammatory agent (NSAIA) with pharmacologic actions similar to other prototypical NSAIAs. Diflunisal possesses anti-inflammatory, analgesic and antipyretic activity. Though its mechanism of action has not been clearly established, most of its actions appear to be associated with inhibition of prostaglandin synthesis via the arachidonic acid pathway. Diflunisal is used to relieve pain accompanied with inflammation and in the symptomatic treatment of rheumatoid arthritis and osteoarthritis.
Compound Type
  • Anti-Inflammatory Agent, Non-Steroidal
  • Cyclooxygenase Inhibitor
  • Drug
  • Ester
  • Metabolite
  • Organic Compound
  • Organofluoride
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
2',4'-Difluoro-4-hydroxy-3-biphenylcarboxylic acid
2-(Hydroxy)-5-(2,4-difluorophenyl)benzoic acid
5-(2,4-Difluorophenyl)salicylic acid
Anton
Diflunisalum
Dolobid
Chemical FormulaC13H8F2O3
Average Molecular Mass250.198 g/mol
Monoisotopic Mass250.044 g/mol
CAS Registry Number22494-42-4
IUPAC Name5-(2,4-difluorophenyl)-2-hydroxybenzoic acid
Traditional Namediflunisal
SMILESOC(=O)C1=C(O)C=CC(=C1)C1=C(F)C=C(F)C=C1
InChI IdentifierInChI=1S/C13H8F2O3/c14-8-2-3-9(11(15)6-8)7-1-4-12(16)10(5-7)13(17)18/h1-6,16H,(H,17,18)
InChI KeyInChIKey=HUPFGZXOMWLGNK-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as biphenyls and derivatives. These are organic compounds containing to benzene rings linked together by a C-C bond.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassBiphenyls and derivatives
Direct ParentBiphenyls and derivatives
Alternative Parents
Substituents
  • Biphenyl
  • Hydroxybenzoic acid
  • Salicylic acid or derivatives
  • Salicylic acid
  • Benzoic acid or derivatives
  • Benzoic acid
  • Benzoyl
  • 1-hydroxy-2-unsubstituted benzenoid
  • Fluorobenzene
  • Halobenzene
  • Phenol
  • Aryl fluoride
  • Aryl halide
  • Vinylogous acid
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organic oxide
  • Organic oxygen compound
  • Organohalogen compound
  • Organofluoride
  • Organooxygen compound
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
Pathways
NameSMPDB LinkKEGG Link
Diflunisal PathwayNot AvailableNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point210-211°C
Boiling PointNot Available
SolubilityPractically insoluble (14.5 mg/L) at neutral or acidic pH.
LogP4.44
Predicted Properties
PropertyValueSource
Water Solubility0.071 g/LALOGPS
logP3.11ALOGPS
logP3.91ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)2.69ChemAxon
pKa (Strongest Basic)-6.3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area57.53 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity60.86 m³·mol⁻¹ChemAxon
Polarizability22.29 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0pc0-1190000000-37ea5d58644c01ef5b1e2017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-05fr-5019000000-223530358c78521d83132017-10-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0002-2690000000-64056c9dc4e2f14d3c592017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0a4j-5590000000-462ea99995ea9238bf942017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0a4i-5490000000-ec23e03578a95364b7482017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0a4i-9550000000-2fa065aea811fa7b6c5a2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-000t-9000000000-01d2c7c75ab3756b3df72017-09-14View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0udi-0090000000-e1009fb8e100faed20652016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0f89-0090000000-e9bcdf3ba0212ee28f452016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0fc0-1970000000-baed3c5d64825d6b04b22016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-052b-0090000000-6427bf95a0116aa621f12016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-0090000000-83af00a8dd308410951d2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4i-0690000000-a756057c6442130830ef2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0ue9-0090000000-645b3ae2575f112278132021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-001i-0090000000-78fd25facb031cdb643f2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-056r-0940000000-9920437171fca6936f282021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0002-0090000000-3e0ed3bddcaf7a500b102021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-052b-0090000000-4ac100e6866826f4e00a2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0kdi-1930000000-6c51e381123d99125d702021-10-11View Spectrum
MSMass Spectrum (Electron Ionization)splash10-0fai-1690000000-d231ff5a9ac7d9769d2d2014-09-20View Spectrum
Toxicity Profile
Route of ExposureRapidly and completely absorbed following oral administration, with a bioavailability of 80-90%. Peak plasma concentrations are achieved 2 - 3 hours following oral administration.
Mechanism of ToxicityThe precise mechanism of the analgesic and anti-inflammatory actions of diflunisal is not known. Diflunisal is a prostaglandin synthetase inhibitor. In animals, prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain. Since prostaglandins are known to be among the mediators of pain and inflammation, the mode of action of diflunisal may be due to a decrease of prostaglandins in peripheral tissues.
MetabolismHepatic, primarily via glucuronide conjugation (90% of administered dose). Route of Elimination: The drug is excreted in the urine as two soluble glucuronide conjugates accounting for about 90% of the administered dose. Little or no diflunisal is excreted in the feces. Half Life: 8 to 12 hours
Toxicity ValuesLD50: 392 mg/kg (Oral, Rat) (1) LD50: 439 mg/kg (Oral, Mouse) (1) LD50: 603 mg/kg (Oral, Rabbit) (1)
Lethal DoseThe lowest dose without the presence of other medicines which caused death was 15 grams.
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesUsed to relieve pain, tenderness, swelling and stiffness caused by osteoarthritis (arthritis caused by a breakdown of the lining of the joints) and rheumatoid arthritis (arthritis caused by swelling of the lining of the joints). [L1869]
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsSymptoms of overdose include coma, tachycardia, stupor, and vomiting.
TreatmentIn the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Because of the high degree of protein binding, hemodialysis may not be effective. (3)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00861
HMDB IDHMDB14999
PubChem Compound ID3059
ChEMBL IDCHEMBL898
ChemSpider ID2951
KEGG IDC01691
UniProt IDNot Available
OMIM ID
ChEBI ID39669
BioCyc IDNot Available
CTD IDNot Available
Stitch IDDiflunisal
PDB ID1FL
ACToR IDNot Available
Wikipedia LinkDiflunisal
References
Synthesis Reference

Ruyle, W.V., Jarett, L.H. and Matzuk, A.R. ; U S . Patent 3,714,226; January 30, 1973; assigned to Merck & Co., Inc.

MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Medline Plus. Diflunisal [Link]
  3. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated GenesNot Available

Targets

Target Details
1. Serum albumin
General Function:
Toxic substance binding
Specific Function:
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.
Gene Name:
ALB
Uniprot ID:
P02768
Molecular Weight:
69365.94 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Dissociation1.23 uMNot AvailableBindingDB 50240510
References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Lazaro E, Lowe PJ, Briand X, Faller B: New approach to measure protein binding based on a parallel artificial membrane assay and human serum albumin. J Med Chem. 2008 Apr 10;51(7):2009-17. doi: 10.1021/jm7012826. Epub 2008 Mar 19. [18348514 ]
Target Details
2. Transthyretin
General Function:
Identical protein binding
Specific Function:
Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.
Gene Name:
TTR
Uniprot ID:
P02766
Molecular Weight:
15886.88 Da
References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Tagoe CE, Reixach N, Friske L, Mustra D, French D, Gallo G, Buxbaum JN: In vivo stabilization of mutant human transthyretin in transgenic mice. Amyloid. 2007 Sep;14(3):227-36. [17701470 ]
Target Details
3. Carbonic anhydrase 1
General Function:
Zinc ion binding
Specific Function:
Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea.
Gene Name:
CA1
Uniprot ID:
P00915
Molecular Weight:
28870.0 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory8.45 uMNot AvailableBindingDB 50240510
IC503.38 uMNot AvailableBindingDB 50240510
References
  1. Bayram E, Senturk M, Kufrevioglu OI, Supuran CT: In vitro inhibition of salicylic acid derivatives on human cytosolic carbonic anhydrase isozymes I and II. Bioorg Med Chem. 2008 Oct 15;16(20):9101-5. doi: 10.1016/j.bmc.2008.09.028. Epub 2008 Sep 13. [18819808 ]
Target Details
4. Carbonic anhydrase 2
General Function:
Zinc ion binding
Specific Function:
Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye. Contributes to intracellular pH regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption. Stimulates the chloride-bicarbonate exchange activity of SLC26A6.
Gene Name:
CA2
Uniprot ID:
P00918
Molecular Weight:
29245.895 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory9.37 uMNot AvailableBindingDB 50240510
IC502.7 uMNot AvailableBindingDB 50240510
References
  1. Bayram E, Senturk M, Kufrevioglu OI, Supuran CT: In vitro inhibition of salicylic acid derivatives on human cytosolic carbonic anhydrase isozymes I and II. Bioorg Med Chem. 2008 Oct 15;16(20):9101-5. doi: 10.1016/j.bmc.2008.09.028. Epub 2008 Sep 13. [18819808 ]
Target Details
5. Prostaglandin G/H synthase 1
General Function:
Prostaglandin-endoperoxide synthase activity
Specific Function:
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells.
Gene Name:
PTGS1
Uniprot ID:
P23219
Molecular Weight:
68685.82 Da
References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
Target Details
6. Prostaglandin G/H synthase 2
General Function:
Prostaglandin-endoperoxide synthase activity
Specific Function:
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, phenotypic changes, resistance to apoptosis and tumor angiogenesis. In cancer cells, PTGS2 is a key step in the production of prostaglandin E2 (PGE2), which plays important roles in modulating motility, proliferation and resistance to apoptosis.
Gene Name:
PTGS2
Uniprot ID:
P35354
Molecular Weight:
68995.625 Da
References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
Target Details
7. Solute carrier family 22 member 6
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one molecule of endogenous dicarboxylic acid (glutarate, ketoglutarate, etc). Mediates the sodium-independent uptake of 2,3-dimercapto-1-propanesulfonic acid (DMPS) (By similarity). Mediates the sodium-independent uptake of p-aminohippurate (PAH), ochratoxin (OTA), acyclovir (ACV), 3'-azido-3-'deoxythymidine (AZT), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), hippurate (HA), indoleacetate (IA), indoxyl sulfate (IS) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), cidofovir, adefovir, 9-(2-phosphonylmethoxyethyl) guanine (PMEG), 9-(2-phosphonylmethoxyethyl) diaminopurine (PMEDAP) and edaravone sulfate. PAH uptake is inhibited by p-chloromercuribenzenesulphonate (PCMBS), diethyl pyrocarbonate (DEPC), sulindac, diclofenac, carprofen, glutarate and okadaic acid (By similarity). PAH uptake is inhibited by benzothiazolylcysteine (BTC), S-chlorotrifluoroethylcysteine (CTFC), cysteine S-conjugates S-dichlorovinylcysteine (DCVC), furosemide, steviol, phorbol 12-myristate 13-acetate (PMA), calcium ionophore A23187, benzylpenicillin, furosemide, indomethacin, bumetamide, losartan, probenecid, phenol red, urate, and alpha-ketoglutarate.
Gene Name:
SLC22A6
Uniprot ID:
Q4U2R8
Molecular Weight:
61815.78 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.85 uMNot AvailableBindingDB 50240510
References
  1. Mulato AS, Ho ES, Cihlar T: Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1. J Pharmacol Exp Ther. 2000 Oct;295(1):10-5. [10991954 ]