Synthesis, p38α MAP kinase inhibition, anti-inflammatory activity, and molecular docking studies of...

Recent studies have demonstrated that inhibition of p38α MAP kinase could effectively inhibit pro-inflammatory cytokines including TNF-α and interleukins. Thus, inhibition of this enzyme can prove greatly beneficial in the therapy of chronic inflammatory diseases. A new series of N-[3-(substituted-4H-1,2,4-triazol-4-yl)]-benzo[d]thiazol-2-amines (4a-n) were synthesized and subjected to in vitro evaluation for anti-inflammatory activity (BSA anti-denaturation assay) and p38α MAPK inhibition. Among the compounds selected for in vivo screening of anti-inflammatory activity (4b, 4c, 4f, 4g, 4j, 4m, and 4n), compound 4f was found to be the most active with an in vivo anti-inflammatory efficacy of 85.31% when compared to diclofenac sodium (83.68%). It was also found to have a low ulcerogenic risk and a protective effect on lipid peroxidation. The p38α MAP kinase inhibition of this compound (IC₅₀  = 0.036 ± 0.12 μM) was also found to be superior to the standard SB203580 (IC₅₀  = 0.043 ± 0.27 μM). Furthermore, the in silico binding mode of the compound on docking against p38α MAP kinase exemplified stronger interactions than those of SB203580.