Design, synthesis of new anti-inflammatory agents with a pyrazole core: COX-1/COX-2 inhibition assays, anti-inflammatory, ulcerogenic, histopathological, molecular Modeling, and ADME studies

• DOI: 10.1016/j.molstruc.2021.130554
• Publication Date: 2021-05-05T02:43:21Z
• Authors: Khaled R.A. Abdel...; Eman K.A. Abdelall; Heba A.H. Elshemy; Phoebe F. Lamie; Elshaymaa Elnahaas; Dina M.E. Amin
• Keywords: Pyrazole; ADME; Anti-inflammatory

Abstract Novel anti-inflammatory pyrazole derivatives (4a,b, 5a,b, 6a,b, 7a,b, 8a,b, 11a-c, 12a-c, 13a-c and 14a-c) were designed as coxib analogues, synthesized and evaluated for both in vitro and in vivo inhibitory activity. Compounds 4a, 4b, 5a, 6a, 6b, 13a-c and 14a-c were the most COX-2 selective compounds (Selectivity Index) = 242.52, 235.32, 234.50, 462.91 and 334.25, 277.18, 229.07, 243.83, 287.51, 237.03, 236.22 respectively) in comparison with the COX-2 selective reference drug celecoxib (Selectivity Index) = 313.12). Also, compounds 6a and 6b (possess SO2NH2 as selective COX-2 pharmacophore) presented the highest anti-inflammatory activity (ED50 = 136 and 126 µMol/kg, sequentially) in addition, they have the lowest ulcerogenic liability (Ulcer Index = 1.25 and 1.00, respectively) reflecting their expected safe GI profiles. Moreover, the different binding mode of interactions between the synthesized compounds and COX-2 active site were elucidated through molecular docking analysis.