Background and purpose: In this study, some new cytotoxic hybrid structures were synthesized by combining pyrazolinone and imidazolinone rings with quinazoline pharmacophores. Experimental approach: The benzoxazinone, pyrazolo-quinazoline fused ring, and imidazolinone anchored quinazoline derivatives were synthesized by simple ring-opening, ring expansion, and ring closure strategies from oxazolones. The molecular docking studies of the final derivatives were accomplished on the epidermal growth factor receptor enzyme. The cytotoxic effect of the final compounds on the MCF-7 cell line was evaluated by MTT assay. Findings/Results: The docking results confirmed the optimized electrostatic, H-bonding, and hydrophobic interactions of structures with the key residues of the active site (ΔG bin < -9Kcal/mol). The derivatives have been obtained in good yield and purity, and their structures were confirmed by different methods (FT-IR, 1 H-NMR, 13 C-NMR, and CHNS analysis). The IC 50 s of all final derivatives against the MCF-7 cell line were lower than 10 μM, and between all, the IXa from pyrazolo-quinazolinone class (IC 50 : 6.43 μM) with chlorine substitute was the most potent. Furthermore, all derivatives showed negligible cytotoxicity on HUVEC normal cell line which would be a great achievement for a novel cytotoxic agent. Conclusion and implications: Based on the obtained results, pyrazolo[1,5-c] quinazolin-2-one series were more cytotoxic than imidazolinone methyl quinazoline-4(3H)-ones against MCF-7 cells. Chlorine substitute in the para position of the aromatic ring improved the cytotoxicity effect in both classes. It could be related to the polarizability of a chlorine atom and making better intermolecular interactions. Further pre-clinical evaluations are required for the promising synthesized cytotoxic compounds.

In this study, by combining azlactone–benzoxazinone chemistry, we synthesized new hybrid compounds and evaluated the in vitro cytotoxicity on the breast cancer cell line. The desired compounds were synthesized using green and straightforward chemical reactions on azlactone and benzoxazinone structures through simple ring closure and nucleophilic ring-opening reactions. Preliminary in vitro cytotoxic results on the MCF-7 breast cancer cell line showed that the synthesized compounds have excellent anticancer activity with interestingly low inhibitory concentrations (IC50s in the range of 8–20 mM). Fortunately, our structures simultaneously had low toxicity on the normal HUVEC cell line. Finally, molecular docking studies were performed on the EGFR enzyme as one of the active signaling pathways in cancer cells for the best cytotoxic candidates. In this regard, the alignment of the docking and cytotoxicity results was interesting. In conclusion, these potential cytotoxic compounds could be considered in further studies.