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

Abstract

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.