Green MCR‐Based Synthesis, In Vitro COX Inhibition, and Molecular Docking Studies of Novel Triazolo–Thiadiazine–Oxepine Hybrids

ABSTRACT A novel series of 2‐((6‐(p‐substituted phenyl)‐7 H ‐1,2,4triazolo3,4‐ b 1,3,4thiadiazin‐3‐yl)methyl)dibenzo b,e oxepin‐11(6 H )‐one derivatives ( 6a–6j ) was synthesized via conventional multi‐step and in situ one‐pot strategies as potential anti‐inflammatory agents. The synthetic procedure was optimized to enhance yield and purity while incorporating green chemistry principles through reduced solvent usage. Structural elucidation was confirmed by IR, 1 H NMR, 13 C NMR, and APT NMR spectral analyses. The synthesized compounds were evaluated for in vitro cyclooxygenase‐1 (COX‐1) inhibitory activity, exhibiting IC 50 values in the range of 9.10–31.47 mM. Among them, compound 6j (unsubstituted phenyl, H) showed the most potent inhibition with an IC 50 value of 9.10 mM. Molecular docking studies further supported these findings, revealing that 6j possessed the highest binding affinity (−11 kJ/mol) and formed two hydrogen bonds with GLN B:289 and THR B:212 within the COX‐1 active site. Compounds bearing small alkyl substituents, such as 6f (4─CH 3 ) and 6g (4─C 2 H 5 ), also demonstrated significant activity, whereas halogenated and highly polar derivatives exhibited weaker inhibition. Comparative analysis with standard drugs indicated promising COX‐1 inhibitory potential for selected derivatives.