Design and synthesis of new rofecoxib analogs as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of the methanesulfonyl pharmacophore by a N-acetylsulfonamido bioisostere.
Bibliographic record
Abstract
PURPOSE: A group of 3,4-diaryl- 2(5H)furanones were synthesized to determine whether a N-acetylsulfonamido (SO2NHCOCH3) moiety could be used as a bioisosteric replacement for the traditional sulfonamide (SO2NH2) and methanesulfonyl (SO2CH3) COX-2 pharmacophores. METHODS: In vitro COX-1 and COX-2 isozyme inhibition studies were carried out to acquire structure activity relationship data with respect to the point of attachment of the Nacetylsulfonamide moiety at the para and metapositions of the C-4 phenyl ring in conjunction with a variety of substituents (H, F, Cl, Me, OMe) at the para position of the C-3 phenyl ring. RESULTS: COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of COX-2 since no inhibition of COX-1 was observed at a concentration of 100 microM. The relative COX-2 potency, and COX-2 selectivity index, profiles for the C-4 para acetamidophenyl compounds, with respect to the C-3 phenyl parasubstituent was H > F > Cl. The point of attachment of the SO2NHCOCH3 substituent on the C-4 phenyl ring was a determinant of COX-2 potency, and COX-2 selectivity, where the relative activity profile was para acetylsulfonamido > meta acetylsulfonamido. 4-[4-(NAcetylsulfonamido) phenyl]-3-phenyl-2(5H)furanone was identified as a more potent (IC50 = 0.32 microM), and selective (S.I. > 313), COX-2 inhibitor than the parent reference compound rofecoxib (IC50 = 0.43 microM, S.I. > 232). CONCLUSIONS: The SO2NHCOCH3 moiety i) is a novel COX-2 pharmacophore that also has the potential to serve as a prodrug moiety to the traditional SO2NH2 COX-2 pharmacophore, and ii) it could serve as a useful COX-2 pharmacophore to study the structure-function relationship of the COX-2 isozyme in view of its potential to acetylate the NH2 moiety of amino acid residues such as Gln192 or Arg513 that line the pocket of the secondary COX-2 binding site.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".