Non-steroidal anti-inflammatory drugs: recent advances in the use of synthetic COX-2 inhibitors

Abstract

Cyclooxygenase (COX) enzymes comprise COX-1 and COX-2 isoforms and are responsible for prostaglandin production. Prostaglandins have critical roles in the inflammation pathway and must be controlled by administration of selective nonsteroidal anti-inflammatory drugs (NSAIDs). Selective COX-2 inhibitors have been among the most used NSAIDs during the ongoing coronavirus 2019 pandemic because they reduce pain and protect against inflammation-related diseases. In this framework, the mechanism of action of both COX isoforms (particularly COX-2) as inflammation mediators must be reviewed. Moreover, proinflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-6, IL-1β, and IL-8 must be highlighted due to their major participation in upregulation of the inflammatory reaction. Structural and functional analyses of selective COX-2 inhibitors within the active-site cavity of COXs could enable introduction of lead structures with higher selectivity and potency against inflammation with fewer adverse effects. This review focuses on the biological activity of recently discovered synthetic COX-2, dual COX-2/lipoxygenase, and COX-2/soluble epoxide hydrolase hybrid inhibitors based primarily on the active motifs of related US Food and Drug Administration-approved drugs. These new agents could provide several advantages with regard to anti-inflammatory activity, gastrointestinal protection, and a safer profile compared with those of the NSAIDs celecoxib, valdecoxib, and rofecoxib.

Fig. 1. Inflammation pathways and inhibition by targeting of the enzymes COX-2, 5-LOX, and sEH. Created with BioRender.com.

Fig. 2. Arachidonic acid (AA) cascade. PG = prostaglandin, TX = thromboxane.

Fig. 3. Active-site cavity of COX-1 and COX-2 (schematic). Created with BioRender.com.

Fig. 4. Active site cavity of COX-1 (PDB 3KK6; left) and COX-2 (PDB 3LN1; right) in complex with celecoxib. Figures were generated by Discovery Studio Visualizer v20.1.0.19295.

Fig. 5. Relative COX-1/COX-2 selectivity of NSAIDs. IC₅₀ >1 = higher selectivity for COX-2, IC₅₀ <1 = higher selectivity for COX-1. ASA = aspirin. Reproduced from ref. with permission from Dove Press Ltd, copyright 2021 (https://creativecommons.org/licenses/by-nc/3.0/).

Fig. 6. Chemical structure of the slightly selective and reversible COX inhibitors containing carboxylic acid.

Fig. 7. Chemical structure of piroxicam and paracetamol as non-selective COX inhibitors without a carboxylic acid functional group.

Fig. 8. Chemical structure of diarylheterocycle coxibs.

Fig. 9. Chemical structure of SC-558.

Fig. 10. Thiazole-based derivatives 1, 2, 3, and 4.

Fig. 11. Chalcone-based inhibitors 5 and 6.

Fig. 12. Pyrazole-based inhibitors 7, 8, 9, and 10.

Fig. 13. Docking simulations of the pyrazole–pyrazoline compound 10 (R₁ = OMe, R₂ = H) within the active-site cavity of COX-2. The broken line in green: H-bond interactions; orange lines: π–cation interactions; purple lines: hydrophobic interactions. Reproduced from ref. with permission from Wiley-VCH GmbH, Weinheim, copyright 2021.

Fig. 14. Pyrazole-based inhibitors 11, 12, and 13 comprising amide and urea linkers.

Fig. 15. Benzenesulfonamide derivatives 14.

Fig. 16. Diaryl-based pyrazole and triazole derivatives 15.

Fig. 17. Triazole derivatives 16, 17 and 18.

Fig. 18. Arylidene-based derivatives 19 and 20.

Fig. 19. 1,3,4-Thiadiazole-thiazolidinone hybrids 21.

Fig. 20. Tetrazole-based derivatives 22.

Fig. 21. Oxadiazole-based derivatives 23 and 24.

Fig. 22. N-Substituted pyrrolidine-2,5-dione derivatives 25.

Fig. 23. Ribbon model of the superimposed binding poses of derivatives 25c (R-isomer) inside the active-site cavity of COX-2 (PDB 1CX2). Secondary pocket residues are shown as red spheres. In comparison, some other essential residues are shown as yellow spheres. Reproduced from ref. with permission from MDPI, copyright 2008 (https://creativecommons.org/licenses/by/4.0/).

Fig. 24. Amide indomethacin derivatives 26.

Fig. 25. Fused-ring derivatives 27, 28, and 29.

Fig. 26. Fused-ring derivatives 30 and 31.

Fig. 27. Alignment of docking poses of pyrazoloquinazoline derivatives 30 (line) with SC-558 (stick) inside the active-site cavity of COX-2. Reproduced from ref. with permission from Wiley-VCH GmbH, Weinheim, copyright 2021.

Fig. 28. Semi-synthetic sclerotiorin-based derivatives 32.

Fig. 29. (Top left) Harmaline derivatives 33. (Top right) Stereodiagram of the X-ray co-crystal structure of 33b (R = 6-OMe) bound within the active-site cavity of COX-2 with PDB code 6V3R (this figure is reproduced from ref. with permission from the American Chemical Society, copyright 2020). (Bottom left) Polycyclic polyprenylated acylphloroglucinol analog derivatives 34 (ref. 101). (Bottom right) Docking simulation of compound 34a within the active-site cavity of COX-2 (ref. 101).

Fig. 30. Pyridazine derivatives 35 and isonicotinic acid derivatives 36.

Fig. 31. Naproxen–dehydrodipeptide derivatives 37.

Fig. 32. d-Glucose-derived N-glycopeptides containing derivatives of mefenamic acid 38.

Fig. 33. Mofezolac-spacer-mofezolac derivatives 39a and mofezolac-spacer-AA derivatives 39b. AA = arachidonic acid.

Fig. 34. Proposed 3D binding mode inside the active-site cavity of COX-2. (Top) mof-spacer-mof derivative 39a (spacer = ethane), (bottom) mof-spacer-AA derivative 39b (spacer = biphenyl). Reproduced from ref. with permission from Elsevier, copyright 2021.

Fig. 35. Carborane-based derivatives 40.

Fig. 36. Potential COX-2 inhibitors 41, 42 and 43.

Mohsen Ahmadi

Sander Bekeschus

Klaus-Dieter Weltmann

Thomas von Woedtke

Kristian Wende