The Pyrazolobenzothiazine Core as a New Chemotype of p38 Alpha Mitogen-Activated Protein Kinase Inhibitors

The identification, synthesis, biological activity, and binding mode prediction of a series of pyrazolobenzothiazines as novel p38α MAPK inhibitors are reported. Some of these compounds showed interesting activity in both p38α MAPK and TNF‐α release assays. Derivative 6 emerged as the most interesting compound with IC50 (p38α) = 0.457 μm, IC50 (TNF‐α) = 0.5 μm and a promising kinase selectivity profile. The obtained results strongly indicate the pyrazolobenzothiazine core as a new p38α inhibitor chemotype worthy of future chemical optimization efforts directed toward identifying a new generation of anti‐inflammatory agents. A series of pyrazolobenzothiazines has been identified as novel p38α MAPK inhibitors. Hit compound 6 turned out to be an effective inhibitor with a reasonable kinase selectivity profile. The obtained results strongly indicate the pyrazolobenzothiazine core as a new p38α inhibitor chemotype worthy of hit‐to‐lead optimization work.