Synthesis, antitumour and antioxidant activities of novel α,β-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study

<p>New α,β-unsaturated ketones <b>4a</b>,<b>b</b>; <b>5a–c</b>; and <b>6a</b>,<b>b</b>; as well as 4-<i>H</i> pyran <b>7</b>; pyrazoline <b>8a</b>,<b>b</b>; isoxazoline <b>9</b>; pyridine <b>10–11</b>; and quinoline-4-carboxylic acid <b>12a</b>,<b>b</b> derivatives were synthesized and evaluated for <i>in vitro</i> antitumour activity against HepG2, MCF-7, HeLa, and PC-3 cancer cell lines. Antioxidant activity was investigated by the ability of these compounds to scavenge the 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS<sup>•+</sup>). Compounds <b>6a</b>, <b>6b</b>, <b>7</b>, and <b>8b</b> exhibited potent antitumour activities against all tested cell lines with [IC<sub>50</sub>] ≅5.5–18.1 µΜ), in addition to significantly high ABTS<sup>•+</sup> scavenging activities. <i>In vitro</i> EGFR kinase assay for <b>6a</b>, <b>6b</b>, <b>7</b>, and <b>8b</b> as the most potent antitumour compounds showed that; compounds <b>6b</b>, and <b>7</b> exhibited worthy EGFR inhibition activity with IC<sub>50</sub> values of 0.56 and 1.6 µM, respectively, while compounds <b>6a</b> and <b>8b</b> showed good inhibition activity with IC<sub>50</sub> values of 4.66 and 2.16 µM, respectively, compared with sorafenib reference drug (IC<sub>50</sub> = 1.28 µM). Molecular modelling studies for compounds <b>6b</b>, <b>7</b>, and <b>8b</b> were conducted to exhibit the binding mode towards EGFR kinase, which showed similar interaction with erlotinib.</p>