Novel 1,2,3‐Triazole‐Functionalized 1,2‐Benzothiazine 1,1‐Dioxide Derivatives: Regioselective Synthesis, Biological Evaluation and Docking Studies

A series of novel 1,2‐benzothiazine‐1,1‐dioxide derivatives (Z)‐3‐hydroxy‐1‐(4‐hydroxy‐2‐methyl‐1,1‐dioxido‐2H‐benzo[e][1, 2]thiazin‐3‐yl)‐3‐phenyl substituted prop‐2‐en‐1‐one (6 a‐d) were synthesized starting from sodium salt of saccharin 1 in series of steps via 3‐acetyl‐2‐methyl‐1,1‐dioxido‐2H‐benzo[e][1, 2]thiazin‐4‐yl substituted benzoates (5 a‐d). Compound 6 e was obtained alternately from 1‐(4‐Hydroxy‐2‐methyl‐1,1‐dioxo‐1,2‐dihydro‐1λ6‐benzo[e][1, 2]thiazin‐3‐yl)‐ethanone (4). Compounds 6 a‐e were further reacted with aromatic azides to form (4‐hydroxy‐2‐methyl‐1,1‐dioxido‐2H‐benzo[e][1, 2]thiazin‐3‐yl)(1‐substitutedphenyl)‐5‐ substituted pheny or methyl‐1H‐1,2,3‐triazol‐4‐yl)methanone derivatives (7 a‐o) by regioselective cyclization. All the compounds were evaluated for anti‐inflammatory and anti‐cancer activities. Compounds 5 a‐b, 6 a‐b, 7 a, 7 c‐d, 7 i and 7 k‐l which showed significant anti‐inflammatory activity at micro molar concentration have been identified. Also screened for cytotoxic activity against four human cancer cells and one normal cell such as prostate cancer (PC‐3), breast adenocarcinoma (MDA‐MB‐231), liver hepatocellular carcinoma (Hep G2), cervical cancer (HeLa) and normal umbilical vein endothelial cell (HUVEC). Compounds 6 a, 7 g, 7 h and 7 k have been identified as promising candidates. Further, anti‐inflammatory activity is also validated by docking studies and compounds 5 a, 5 b and 7 d found to show good interactions when docked with IL‐1β signaling complex. A series of novel 1,2,3‐triazole functionalized 1,2‐benzothiazine‐1,1‐dioxide derivatives 7 a‐o synthesized by regio‐selective cyclization. All the compounds were evaluated for anti‐inflammatory and anti‐cancer activities. Compounds 5 b and 7 h found to show high anti‐inflammatory and anticancer activity respectively. Further, anti‐inflammatory activity is also validated by docking studies and compounds 5 a, 5 b and 7 d revealed good interactions when docked with IL‐1β signaling complex (4DEP protein).