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Synthesis and biological evaluation of linear phenylethynylbenzenesulfonamide regioisomers as cyclooxygenase-1/-2 (COX-1/-2) inhibitors
- Source :
- Bioorganicmedicinal chemistry. 14(15)
- Publication Year :
- 2006
-
Abstract
- A group of regioisomeric phenylethynylbenzenesulfonamides possessing a COX-2 SO2NH2 pharmacophore at the para-, meta- or ortho-position of the C-1 phenyl ring, in conjunction with a C-2 substituted-phenyl (H, OMe, OH, Me, F) group, were synthesized and evaluated as inhibitors of the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isozymes. The target 1,2-diphenylacetylenes were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction. In vitro COX-1/-2 isozyme inhibition structure-activity data showed that COX-1/-2 inhibition and the COX selectivity index (SI) are sensitive to the regioisomeric placement of the COX-2 SO2NH2 pharmacophore where the COX-2 potency order for the benzenesulfonamide regioisomers was generally meta>para and ortho. Among this group of compounds, the in vitro COX-1/-2 isozyme inhibition studies identified 3-(2-phenylethynyl)benzenesulfonamide (10a) as a COX-2 inhibitor (COX-2 IC50=0.45 microM) with a good COX-2 selectivity (COX-2 SI=70). In contrast, 2-[2-(3-fluorophenyl)ethynyl]benzenesulfonamide (11c) possessing a SO2NH2 COX-2 pharmacophore at the ortho-position of the C-1 phenyl ring exhibited COX-1 inhibition and selectivity (COX-1 IC50=3.6 microM). A molecular modeling study where 10a was docked in the binding site of COX-2 shows that the meta-SO2NH2 COX-2 pharmacophore was inserted inside the COX-2 secondary pocket (Arg513, Phe518, Val523, and His90). Similar docking of 10a within the COX-1 binding site shows that the meta-SO2NH2 pharmacophore is unable to interact with the respective amino acid residues in COX-1 that correspond to those near the secondary pocket in COX-2 due to the presence of the larger Ile523 in COX-1 that replaces Val523 in COX-2.
- Subjects :
- Models, Molecular
Molecular model
Stereochemistry
Clinical Biochemistry
Drug Evaluation, Preclinical
Pharmaceutical Science
Administration, Oral
Stereoisomerism
In Vitro Techniques
Crystallography, X-Ray
Biochemistry
Chemical synthesis
Structure-Activity Relationship
Drug Discovery
Structure–activity relationship
Animals
Cyclooxygenase Inhibitors
Molecular Biology
Sulfonamides
Sheep
biology
Molecular Structure
Chemistry
Organic Chemistry
Anti-Inflammatory Agents, Non-Steroidal
Hindlimb
Rats
Docking (molecular)
Enzyme inhibitor
Cyclooxygenase 2
biology.protein
Cyclooxygenase 1
Molecular Medicine
Pharmacophore
Selectivity
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 14
- Issue :
- 15
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry
- Accession number :
- edsair.doi.dedup.....dfbe78e29e4edfaa31a20e42e2798a0c