A series of eleven flavone derivatives were synthesized. The synthesized compounds were characterized structurally by various techniques using spectral analyses. All of the synthesized compounds were subjected to MTT proliferation assay to investigate their in-vitro cytotoxic activity. Among all the studied compounds, compounds, VIi, VIh, VId and VIk revealed moderate growth inhibitory effect towards the MDA-MB 231 cell line compared to the reference, doxorubicin. These compounds showed cytotoxicity activity with IC₅₀ values ranging from 43.7 to 138 µM in MDA-MB 231 cell line. The results of cytotoxic activity revealed that flavone derivatives with N-aryl acetamide substituted at the 3-position of flavone backbone have better cytotoxic activity. Moreover, the highest activity was observed with compound VIi that has oxy-N-pyriden-2-yl acetamide substituent at the 3-position of flavone backbone followed by compound VIh with IC₅₀ values of 43.7 and 50 μM, respectively. The biological activity results were elucidated by molecular docking studies using the homology model of the human adenosine A_2B receptor. As a result, the present study has highlighted that the bicyclic moiety of the compounds attached to hydrogen bond donor-acceptor capability and π-π stacking is an attractive scaffold for obtaining cytotoxic activity.