Synthesis, characterization and molecular docking of novel lonazolac analogues 3-(3-hydroxy-5-methyl-1H-pyrazol-4-yl)-3-arylpropanoic acid derivatives: Highly potential COX-1/COX-2, matrix metalloproteinase and protein denaturation inhibitors

• Published in: Journal of molecular structure 2022-07, Vol.1260, p.132782, Article 132782
• Main Authors: Pawar, Varsha, Shastri, Lokesh A., Gudimani, Parashuram, Joshi, Shrinivas, Sunagar, Vinay
• Format: Article
• Language: English
• Subjects: Arachidonic acid; Lonazolac, Phenybutazone; MMP'S; NSAIDs; Prostaglandins
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2022.132782

•A simple, economic, eco-friendly acid catalysed pyran ring opening led to single isomer of novel lonazolac analogous, 3-(3‑hydroxy-5-methyl-1H-pyrazol-4-yl)−3-arylpropanoic acid derivatives with exceptional yields and high purity.•All the tested compounds exerted splendid activity against both COX-1 and COX-2 enzymes.•All the targets emerged as good inhibitors of both MMP2 and MMP9 and compound 2l is an excellent inhibitor of both MMP2 and MMP9. Whereas, compound 2i exhibited manifesting activity against heat induced protein denaturation.•Molecular docking has been performed to recognize best way of interaction of the targets with the ligand and are successfully match with the experimental results. The present article involves the design, synthesis, characterization, docking studies and anti-inflammatory activity of two new series of lonazolac analogue: 2a-p. Among the synthesized series, compounds 2b, 2c, 2e, 2f, 2 g, 2j, 2k, 2 m, 2n and 2o were screened for their in vitro COX-1 and COX-2 inhibition. All the screened targets exhibited excellent COX-1 and COX-2 inhibitory activity with low IC50 values compared to standard aspirin. Compound 2n showed excellent COX-1 inhibitory activity (IC50 = 127.00 µl/ml) while compound 2g was an excellent COX-2 inhibitor (IC50 = 5.83 µl/ml). Both 2n and 2g have superior selective index values of 19.53 and 29.41, respectively. The synthesized compounds 2a-2p, were screened against MMP-2 and MMP-9, anti-inflammatory activity comparable to that of tetracycline, as shown by gelatin zymography. Among the tested compounds, 2l showed excellent anti-inflammatory activity against both MMPs. On the other hand, the protein denaturation technique indicates that most of the molecules are beneficially active. A molecular docking study was performed to rationalize the anti-inflammatory activity of the synthesized compounds against standard celecoxib and aspirin, the results obtained are much better than the standard. [Display omitted]