In this paper, a series of novel 3-methyl-quinazolinone derivatives was designed, synthesised and evaluated for antitumor activity in vitro on wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and three human cancer cell lines including A549, PC-3, and SMMC-7721. The results displayed that some of the compounds had good activities, especially 2-{4-[(3-Fluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 g), 2-{4-[(3,4-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5k) and 2-{4-[(3,5-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 l) showed high antitumor activities against three cancer cell lines. Moreover, compound 5k could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G2/M phase at tested concentrations. Also, compound 5k could inhibit the EGFRwt-TK with IC50 value of 10 nM. Molecular docking data indicates that the compound 5k may exert inhibitory activity by forming stable hydrogen bonds with the R817, T830 amino acid residues and cation-Π interaction with the K72 residue of EGFRwt-TK.

中文翻译：

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喹唑啉酮衍生物作为EGFR抑制剂的抗肿瘤治疗设计，合成和体外生物学评价。

本文设计，合成了一系列新型3-甲基-喹唑啉酮衍生物，并评估了它们对野生型表皮生长因子受体酪氨酸激酶（EGFRwt-TK）和三种人类癌细胞系（包括A549，PC- 3，SMMC-7721。结果表明，某些化合物具有良好的活性，特别是2- {4-[（3-氟-苯基亚氨基）-甲基]-苯氧基甲基} -3-甲基-3H-喹唑啉-4-酮（5 g），2 -{4-[（3,4-二氟-苯基亚氨基）-甲基]-苯氧基甲基} -3-甲基-3H-喹唑啉-4-酮（5k）和2- {4-[（3,5-二氟-苯基亚氨基） ）-甲基]-苯氧基甲基} -3-甲基-3H-喹唑啉-4-酮（5μl）对三种癌细胞具有很高的抗肿瘤活性。此外，化合物5k可以在高浓度下诱导A549细胞的晚期凋亡，并在测试浓度下阻止G2 / M期的A549细胞的细胞周期。同样，化合物5k可以抑制EGFRwt-TK，IC50值为10 nM。分子对接数据表明，化合物5k可通过与R817，T830氨基酸残基形成稳定的氢键以及与EGFRwt-TK的K72残基形成阳离子-II相互作用而发挥抑制活性。