In this paper, we have developed a new, non-hazardous and eco-friendly access route for the synthesis of a novel Schiff bases containing 2-oxo-3H-benzoxazole scaffold 4(a-f) by lemon juice as natural catalyzed acid under solvent-free conditions. The chemical structures of the new synthesized compounds were elucidated on the basis of the FT-IR, 1 H and 13 C-NMR spectroscopic techniques and all molecules were isolated with moderate yields after shorter reaction times. Furthermore, a preliminary study on the in vitro antioxidant activity of some synthesized compounds was investigated. The biological activity results revealed that highest DPPH radical-scavenging activity was observed for compound 4e with an IC 50 of 2.13 μg.mL −1 , more active than the standard ascorbic acid (IC 50 = 2.16 μg.mL −1). In-silico studies based on density functional theory (DFT) were realized to rationalize the biological activity with the structural and electronic properties of the 6-imino-2-oxo-3H-benzoxazoles. We using the molecular docking simulation to study the affinity and the possible binding mode of complexed ligand-protein. The synthesized molecules were tested to cross the clinical test by the ADMET prediction, these results indicated that the compounds 4(a-f) have excellent drug-likeness properties.