Design, synthesis and biological evaluation of new imidazo[1,2-a]pyridine derivatives as selective COX-2 inhibitors

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Three new series of methylsulfonyl-containing imidazo[1,2-a]pyridines 8a-d, 9a-d and 10a-d were designed and synthesized. Characterization of the chemical structure of these new compounds was performed using spectral and elemental analyses. The synthesized derivatives were tested for their ability to inhibit COX-1 and COX-2 isozymes in addition to their in vivo anti-inflammatory activity. The pyrazoline derivative 9a possessed the highest selectivity index among all compounds regarding COX-2 isozyme (SI = 39) and was almost three folds higher than celecoxib (SI = 13.76) with good in vivo anti-inflammatory activity (% edema inhibition = 11.16–32.64). Compound 10c showed the highest inhibitory activity towards COX-2 isozyme (IC50 = 1.06 µM) and it was the most potent anti-inflammatory derivative (% edema inhibition = 15.04–42.35) with ED50 value of 69.46 µmol/Kg which was approximately one and a half fold more potent than celecoxib (ED50 = 104.88 µmol/Kg). Also, the most potent anti-inflammatory compounds 9a, 9d, 10c and 10d were subjected to ulcerogenic liability and histopathological examinations. Compounds 9d and 10c showed ulcerogenic liability (% ulcerated area = 0.07 and 0.01, respectively) and histopathological changes close to celecoxib. Finally, molecular docking and computational prediction of physicochemical parameters were performed for the prepared compounds to support the biological results.