Synthesis, antitumor activity and molecular docking study of some novel 3-benzyl-4(3H)quinazolinone analogues

Abstract

<div><p></p><p>A novel series of 3-benzyl-substituted-4(3<i>H</i>)-quinazolinones were designed, synthesized and evaluated for their <i>in vitro</i> antitumor activity. The results of this study demonstrated that 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-<i>N</i>-(3,4,5-trimethoxyphenyl)acetamide, 2-(3-benzyl-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-ylthio)-<i>N</i>-(3,4,5-trimethoxyphenyl)acetamide and 3-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-<i>N</i>-(3,4,5-trimethoxyphenyl)-propanamide have shown amazing broad spectrum antitumor activity with mean GI₅₀ (10.47, 7.24 and 14.12 µM. respectively), and are nearly 1.5–3.0-fold more potent compared with the positive control 5-FU with mean GI₅₀, 22.60 µM. On the other hand, compounds <b>6</b> and <b>10</b> yielded selective activities toward CNS, renal and breast cancer cell lines, whereas compound <b>9</b> showed selective activities towards leukemia cell lines. Molecular docking methodology was performed for compounds <b>7</b> and <b>8</b> into ATP binding site of EGFR-TK which showed similar binding mode to erlotinib, while compound <b>11</b> into ATP binding site of B-RAF kinase inhibited the growth of melanoma cell lines through inhibition of B-RAF kinase, similar to PLX4032.</p></div