New indomethacin analogs as selective COX‐2 inhibitors: Synthesis, COX‐1/2 inhibitory activity, anti‐inflammatory, ulcerogenicity, histopathological, and docking studies

New indomethacin analogs 4a–g, 5, 6, 8a, and 8b were synthesized to overcome the nonselectivity and ulcer liability of indomethacin. All newly synthesized compounds were more potent against cyclooxygenase 2 (COX‐2; IC50 value range: 0.09–0.4 μМ) as compared with celecoxib (IC50 = 0.89 μМ). Compounds 4a, 4b, 4d, 5, and 6 showed the highest COX‐2 selectivity index (SI range = 4.07–6.33) as compared with indomethacin (SI = 1.14) and celecoxib (SI = 3.52). Additionally, 4a, 4b, 4d, 5, and 7 showed good anti‐inflammatory activity with edema inhibition (79.36–88.8%), relative to celecoxib (78.96%) and indomethacin (90.43%), after 5 h. Also, ulcerogenic effects and histopathological examination were assessed for the most potent analogs, 4b, 4d, 5, and 6, to determine their safety. The results can shed light on indomethacin analog 5 as a remarkable anti‐inflammatory lead compound with a good safety profile (ulcer index = 10.62) close to the nonulcerogenic drug celecoxib (ulcer index = 10.53) and better than indomethacin (ulcer index = 18.50). Docking studies were performed in the COX‐2 active site for the most active compounds, to test their selectivity and to confirm their mechanism of action. Eleven indomethacin analogs were synthesized and evaluated for their cyclooxygenase (COX) inhibitory and anti‐inflammatory activities and ulcerogenic liability. All tested compounds showed a higher COX‐2 selectivity index (1.85–5.5‐fold) than indomethacin and most of them were more selective than celecoxib. Compound 5 showed remarkable anti‐inflammatory activity, with a good safety profile. Molecular docking studies were performed to investigate their binding modes in the COX‐2 active site.