T3DB: Diflunisal

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Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (7)XML

Targets (7)

Record Information

Version

2.0

Creation Date

2009-07-21 20:27:51 UTC

Update Date

2014-12-24 20:25:53 UTC

Accession Number

T3D2918

Identification

Common Name

Diflunisal

Class

Small Molecule

Description

Diflunisal, 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

MOL SDF PDB SMILES InChI

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 Formula

C₁₃H₈F₂O₃

Average Molecular Mass

250.198 g/mol

Monoisotopic Mass

250.044 g/mol

CAS Registry Number

22494-42-4

IUPAC Name

5-(2,4-difluorophenyl)-2-hydroxybenzoic acid

Traditional Name

diflunisal

SMILES

OC(=O)C1=C(O)C=CC(=C1)C1=C(F)C=C(F)C=C1

InChI Identifier

InChI=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 Key

InChIKey=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.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Biphenyls and derivatives

Direct Parent

Biphenyls 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 Framework

Aromatic homomonocyclic compounds

External Descriptors

organofluorine compound (CHEBI:39669 )
monohydroxybenzoic acid (CHEBI:39669 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Extracellular
Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Name	SMPDB Link	KEGG Link
Diflunisal Pathway	Not Available	Not Available

Applications

Biological Roles

non-narcotic analgesic

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	210-211°C
Boiling Point	Not Available
Solubility	Practically insoluble (14.5 mg/L) at neutral or acidic pH.
LogP	4.44

Predicted Properties

Property	Value	Source
Water Solubility	0.071 g/L	ALOGPS
logP	3.11	ALOGPS
logP	3.91	ChemAxon
logS	-3.6	ALOGPS
pKa (Strongest Acidic)	2.69	ChemAxon
pKa (Strongest Basic)	-6.3	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	57.53 Å²	ChemAxon
Rotatable Bond Count	2	ChemAxon
Refractivity	60.86 m³·mol⁻¹	ChemAxon
Polarizability	22.29 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0pc0-1190000000-37ea5d58644c01ef5b1e	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positive	splash10-05fr-5019000000-223530358c78521d8313	2017-10-06	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0002-2690000000-64056c9dc4e2f14d3c59	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0a4j-5590000000-462ea99995ea9238bf94	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0a4i-5490000000-ec23e03578a95364b748	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0a4i-9550000000-2fa065aea811fa7b6c5a	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-000t-9000000000-01d2c7c75ab3756b3df7	2017-09-14	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0udi-0090000000-e1009fb8e100faed2065	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0f89-0090000000-e9bcdf3ba0212ee28f45	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0fc0-1970000000-baed3c5d64825d6b04b2	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-052b-0090000000-6427bf95a0116aa621f1	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0a4i-0090000000-83af00a8dd308410951d	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0a4i-0690000000-a756057c6442130830ef	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0ue9-0090000000-645b3ae2575f11227813	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-001i-0090000000-78fd25facb031cdb643f	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-056r-0940000000-9920437171fca6936f28	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0002-0090000000-3e0ed3bddcaf7a500b10	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-052b-0090000000-4ac100e6866826f4e00a	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0kdi-1930000000-6c51e381123d99125d70	2021-10-11	View Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-0fai-1690000000-d231ff5a9ac7d9769d2d	2014-09-20	View Spectrum

Toxicity Profile

Route of Exposure

Rapidly 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 Toxicity

The 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.

Metabolism

Hepatic, 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 Values

LD50: 392 mg/kg (Oral, Rat) (1) LD50: 439 mg/kg (Oral, Mouse) (1) LD50: 603 mg/kg (Oral, Rabbit) (1)

Lethal Dose

The 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/Sources

Used 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 Level

Not Available

Health Effects

Not Available

Symptoms

Symptoms of overdose include coma, tachycardia, stupor, and vomiting.

Treatment

In 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

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

39669

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Diflunisal

PDB ID

1FL

ACToR ID

Not Available

Wikipedia Link

Diflunisal

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.

MSDS

Link

General References

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 ]
Medline Plus. Diflunisal [Link]
RxList: The Internet Drug Index (2009). [Link]

Gene Regulation

Up-Regulated Genes

Gene	Gene Symbol	Gene ID	Interaction	Chromosome	Details

Down-Regulated Genes

Not 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

Type	Value	Assay Type	Assay Source
Dissociation	1.23 uM	Not Available	BindingDB 50240510

References

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 ]
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

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 ]
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

Type	Value	Assay Type	Assay Source
Inhibitory	8.45 uM	Not Available	BindingDB 50240510
IC50	3.38 uM	Not Available	BindingDB 50240510

References

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

Type	Value	Assay Type	Assay Source
Inhibitory	9.37 uM	Not Available	BindingDB 50240510
IC50	2.7 uM	Not Available	BindingDB 50240510

References

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

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

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

Type	Value	Assay Type	Assay Source
IC50	0.85 uM	Not Available	BindingDB 50240510

References

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 ]

Diflunisal (T3D2918)

Structure for T3D2918: Diflunisal

Targets

Binding/Activity Constants

References

References

Binding/Activity Constants

References

Binding/Activity Constants

References

References

References

Binding/Activity Constants

References