1,2,4-Triazole-based benzothiazole/benzoxazole derivatives: Design, synthesis, p38 alpha MAP kinase inhibition, anti-inflammatory activity and molecular docking studies

Novel N-(benzothiazol/oxazol-2-yl) 2 [(5-(phenoxymethyl)-4-aryl-4H-1,2,4-triazol-3-yethio] acetamide derivatives (5a-n) were synthesized and investigated for in vitro anti-inflammatory activity and p38 alpha MAP kinase inhibition. Compounds showing good in vitro activities (5a, 5b, 5d, 5e, 5i, 5k and 5l) were studied for their in vivo anti-inflammatory activity using carrageenan induced rat paw edema model. Compound 5b emerged as the most active compound with an edema inhibition of 84.43%. It also showed improved GI safety profile with lower ulcer severity index and lipid peroxidation potential. Also, p38 alpha MAP kinase assay of 5b showed superior inhibitory potency (IC50:0.031 +/- 0.14 mu M) than the standard SB 203580 (IC50:0.043 +/- 0.14 mu M). To predict their binding mode compounds were also docked against p38 alpha MAP kinase enzyme. Compound 5b and SB 203580 showed hinge region interaction with MET 109.