Pyrazolobenzotriazinone Derivatives as COX Inhibitors: Synthesis, Biological Activity, and Molecular-Modeling Studies

Pyrazolylbenzotriazinones are endowed with a structural analogy with the COX‐2 selective inhibitor celecoxib. Considering that our research group has long been interested in the 3‐pyrazolyl‐substituted benzotriazinones as anti‐inflammatory agents, six new pyrazolylbenzotriazinone derivatives 16a–c and 18a–c have been prepared by reacting the opportune ethyl 5‐(2‐aminobenzamido)‐1‐(pyridin‐2‐yl)‐1H‐pyrazole‐4‐carboxylate or 5‐(2‐aminobenzamido)‐1‐(pyridin‐2‐yl)‐1H‐pyrazole‐4‐carboxyic acid with sodium nitrite in glacial acetic acid. The biological studies revealed a good pharmacological profile for some pyrazolylbenzotriazinones and, in the case of the ethyl 5‐(4‐oxo‐1,2,3‐benzotriazin‐3(4H)‐yl)‐1‐pyridin‐2‐yl‐1H‐pyrazole‐4‐carboxylate, a good COX‐1/COX‐2 selectivity. Molecular modeling studies confirmed the obtained biological results. Gastrolesivity in all those therapies associated to an inflammatory process calls for the availability of new anti‐inflammatory agents. Therefore, new pyrazolylbenzotriazinones were synthesized and tested for their COX‐1 and COX‐2 inhibitory activities.