Design, Synthesis, Cytotoxic Evaluation and Molecular Docking of New Fluoroquinazolinones as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects.

A series of new fluoroquinazolinone <bold>6</bold>–<bold>8</bold> and <bold>10a</bold>–<bold>g</bold> derivatives was designed, prepared and screened for their in vitro cytotoxic activity against human cancer cell lines MCF-7 and MDA-MBA-231. Compounds <bold>6</bold> (IC50 = 0.35 ± 0.01 µM), <bold>10f</bold> (IC50 = 0.71 ± 0.01 µM), <bold>10d</bold> (IC50 = 0.89 ± 0.02 µM) and <bold>10a</bold> (IC50 = 0.95 ± 0.01 µM) displayed broad spectrum anticancer activity better than the reference drug gefitinib (IC50 = 0.97 ± 0.02 µM) against MCF-7. Compounds <bold>10e</bold> (IC50 = 0.28 ± 0.02 µM), <bold>10d</bold> (IC50 = 0.38 ± 0.01 µM), <bold>7</bold> (IC50 = 0.94 ± 0.07 µM) and <bold>10c</bold> (IC50 = 1.09 ± 0.01 µM) showed better activity than the reference gefitinib (IC50 = 1.30 ± 0.04 µM) against MDA-MBA-231. Moreover, EGFR and tubulin inhibition assays were performed for the highest active derivatives and showed remarkable results comparing to the reference drugs. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. [ABSTRACT FROM AUTHOR]