Synthesis, <i>in vitro</i> antitumour activity, and molecular docking study of novel 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinone analogues

<p>A novel series of 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinones <b>1</b>–<b>20</b> was synthesised and evaluated for <i>in vitro</i> antitumour activity. <i>N</i>-(4-Chlorophenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio)acetamide <b>(7)</b> and <i>N</i>-(3,4,5 trimethoxybenzyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide <b>(19)</b> exhibited excellent antitumour properties, with mean growth inhibitory concentration (GI<sub>50</sub>) of 17.90 and 6.33 µΜ, respectively, compared with those of 5-fluorouracil 5-FU, gefitinib, and erlotinib (mean GI<sub>50</sub>: 18.60, 3.24, and 7.29 µΜ, respectively). Comparison of the GI<sub>50</sub> (µM) values of compounds <b>7</b> and <b>19</b> versus those of 5-FU, gefitinib, and erlotinib against an <i>in vitro</i> subpanel of tumour cells lines showed that compounds <b>7</b> and <b>19</b> have activities almost equal to or higher than that of those standard drugs, especially against lung, CNS, and breast cancer cells. However, compounds <b>5</b>, <b>10</b>, <b>14</b>, <b>15</b>, <b>16</b>, <b>17,</b> and <b>20</b> exhibited effective antitumour activity against the different cell lines tested, with growth inhibition percentage (MGI%) of 19, 24, 19, 17, 16, 15, and 16, respectively. A modelling study was performed for compounds <b>7</b> and <b>19</b> by docking them into the EGFR kinase enzyme to study their mode of binding with the putative binding site.</p>