Novel halogenated phenoxychalcones 2a–f and their corresponding N -acetylpyrazolines 3a–f were synthesised and evaluated for their anticancer activities against breast cancer cell line (MCF-7) and normal breast cell line (MCF-10a), compared with staurosporine. All compounds showed moderate to good cytotoxic activity when compared to control. Compound 2c was the most active, with IC 50 = 1.52 µM and selectivity index = 15.24. Also, chalcone 2f showed significant cytotoxic activity with IC 50 = 1.87 µM and selectivity index = 11.03. Compound 2c decreased both total mitogen activated protein kinase (p38α MAPK) and phosphorylated enzyme in MCF-7 cells, suggesting its ability to decrease cell proliferation and survival. It also showed the ability to induce ROS in MCF-7 treated cells. Compound 2c exhibited apoptotic behaviour in MCF-7 cells due to cell accumulation in G2/M phase and elevation in late apoptosis 57.78-fold more than control. Docking studies showed that compounds 2c and 2f interact with p38alpha MAPK active sites.

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The reaction of anthranilic acid with ethoxycarbonylisothiocyanate gave the ethyl 4-oxo-2-thioxo-1,2-dihydroquinazoline-3(4H)-carboxylate (4). The reaction of compound 4 with hydrazine hydrate and α-halocarbonyl derivatives was found to give either hydrazono or S-alkylated products. Heterocyclization reactions of some of the S-alkylated derivatives 8 and 12 were carried out to afford thiazole, pyran and pyridine derivatives. The cytotoxicity of the newly synthesized compounds towards the six cancer cell lines NUGC, DLD-1, HA22T, HEPG-2, HONE-1 and MCF-7 showed that compounds 6, 8, 13, 19c-f, 21b-f, 24a and 24c with the highest cytotoxicity. The c-Met kinase inhibition for some of the selected compounds showed that compounds 8, 13, 19d, 21e, 21f and 24a were the most active compounds. Screening toward tyrosine kinases revealed that compounds 13, 21e and 24a exhibit the highest inhibitions and therefore their molecular modeling was described. In addition, compounds 13 and 24a showed the highest activities towards Pim-1 kinase.

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