Synthesis, biological evaluation and molecular docking studies of 1,3-benzoxazine derivatives as potential anticancer agents

A series of 6 and/or 8-substituted derivatives of 1,3-benzoxazines, having flavone moiety at 3-position, have been synthesized. For synthesis of the compounds, 6 or/and 8-substituted saliscylaldehydes were reacted with aminoflavone followed by reduction, and CHCl₃/HCHO promoted cyclization to give corresponding aminoflavone precursors which provided the desired 1,3-benzoxazine skeleton. Cytotoxic effects of the synthesized compounds were investigated in vitro against human breast cancer (MCF-7) cell lines. Among the compounds tested, methyl (3f and 6f), methoxy (3h, 3i, and 6h), and chloro (3d) derivatives were found to be most potent with IC₅₀ values of 14.3, 14.9, 17.1, 8.03, 12.1, and 12.03 μM, respectively. Molecular docking studies of most active compounds of the series revealed that they bind to a narrow hydrophobic pocket of the N-terminal chain in the ATP binding site of EGFR.