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Design, synthesis, and biological evaluation of N-acetyl-2-carboxybenzenesulfonamides: a novel class of cyclooxygenase-2 (COX-2) inhibitors
- Source :
- Bioorganicmedicinal chemistry. 13(7)
- Publication Year :
- 2004
-
Abstract
- N -Acetyl-2-carboxybenzenesulfonamide ( 11 ), and a group of analogues possessing an appropriately substituted-phenyl substituent (4-F, 2,4-F 2 , 4-SO 2 Me, 4-OCHMe 2 ) attached to its C-4, or C-5 position, were synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 inhibition studies showed that 11 is a more potent inhibitor (COX-1 IC 50 = 0.06 μM; COX-2 IC 50 = 0.25 μM) than aspirin (COX-1 IC 50 = 0.35 μM; COX-2 IC 50 = 2.4 μM), and like aspirin [COX-2 selectivity index (S.I.) = 0.14], 11 is a nonselective COX-2 inhibitor (COX-2 S.I. = 0.23). Regioisomers having a 2,4-difluorophenyl substituent attached to the C-4 (COX-2 IC 50 = 0.087 μM; COX-2 S.I. >1149), or C-5 (COX-2 IC 50 = 0.77 μM, SI > 130), position of 11 exhibited the most potent and selective COX-2 inhibitory activity relative to the reference drug celecoxib (COX-1 IC 50 = 33.1 μM; COX-2 IC 50 = 0.07 μM; COX-2 S.I. = 472). N -Acetyl-2-carboxybenzenesulfonamide ( 11 , ED 50 = 49 mg/kg), and its C-4 2,4-difluorophenyl derivative (ED 50 = 91 mg/kg), exhibited superior antiinflammatory activity (oral dosing) in a carrageenan-induced rat paw edema assay compared to aspirin (ED 50 = 129 mg/kg). These latter compounds exhibited comparable analgesic activity to the reference drug diflunisal, and superior analgesic activity compared to aspirin, in a 4% NaCl-induced abdominal constriction assay. A molecular modeling (docking) study indicated that the SO 2 NHCOCH 3 substituent present in N -acetyl-2-carboxy-4-(2,4-fluorophenyl)benzenesulfonamide, like the acetoxy substituent in aspirin, is suitably positioned to acetylate the Ser 530 hydroxyl group in the COX-2 primary binding site. The results of this study indicate that the SO 2 NHCOCH 3 pharmacophore present in N -acetyl-2-carboxybenzenesulfonamides is a suitable bioisostere for the acetoxy (OCOMe) group in aspirin.
- Subjects :
- Models, Molecular
Stereochemistry
Clinical Biochemistry
Substituent
Pharmaceutical Science
Diflunisal
Sodium Chloride
Crystallography, X-Ray
Biochemistry
Chemical synthesis
chemistry.chemical_compound
Structure-Activity Relationship
Drug Discovery
medicine
Animals
Cyclooxygenase Inhibitors
Molecular Biology
Inflammation
Aspirin
Sulfonamides
biology
Cyclooxygenase 2 Inhibitors
Molecular Structure
Organic Chemistry
Membrane Proteins
Rats
chemistry
Enzyme inhibitor
Docking (molecular)
Cyclooxygenase 2
Prostaglandin-Endoperoxide Synthases
Drug Design
biology.protein
Cyclooxygenase 1
Molecular Medicine
Biological Assay
Cyclooxygenase
Bioisostere
medicine.drug
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 13
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry
- Accession number :
- edsair.doi.dedup.....e853ca9ff4098ddee9e832ffdc395b3d