IntroductionThe combination of BRAF and tyrosine kinase (TK) inhibitors has been demonstrated to be highly effective in inhibiting tumor development and is an approach for overcoming resistance in clinical trials. Accordingly, a novel series of 1,2,4-oxadiazole/quinazoline-4-one hybrids was developed as antiproliferative multitargeted inhibitors.MethodsThe structures of the newly synthesized compounds 9a-o were validated using IR, NMR, MS, and elemental techniques. 9a–o were tested as antiproliferative agents.Results and DiscussionThe results showed that the majority of the tested compounds showed significant antiproliferative action with 9b, 9c, 9h, 9k, and 9l being the most potent. Compounds 9b, 9c, 9h, 9k, and 9l were tested as EGFR and BRAFV600E inhibitors. These in vitro tests revealed that compounds 9b, 9c, and 9h are strong antiproliferative agents that may act as dual EGFR/BRAFV600E inhibitors. 9b, 9c, and 9h were further investigated for their inhibitory effect on mutant EGFR (EGFRT790M), and the results showed that the tested compounds had considerable inhibitory action. Cell cycle study and apoptosis detection demonstrated that compound 9b exhibits cell cycle arrest at the G2/M transition. Molecular docking simulations reveal the binding mechanism of the most active antiproliferative agents.

中文翻译：

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具有抗增殖活性的新型 1,2,4-恶二唑/喹唑啉-4-一杂化物的设计和合成作为多靶点抑制剂


简介BRAF和酪氨酸激酶（TK）抑制剂的组合已被证明在抑制肿瘤发展方面非常有效，是临床试验中克服耐药性的一种方法。因此，开发了一系列新型1,2,4-恶二唑/喹唑啉-4-酮杂化物作为抗增殖多靶点抑制剂。方法使用IR、NMR、MS和元素技术验证了新合成的化合物9a-o的结构。 9a-o 被测试为抗增殖剂。结果与讨论结果表明，大多数测试化合物显示出显着的抗增殖作用，其中 9b、9c、9h、9k 和 9l 最为有效。测试化合物9b、9c、9h、9k和9l作为EGFR和BRAFV600E抑制剂。这些体外测试表明，化合物 9b、9c 和 9h 是强效抗增殖剂，可作为 EGFR/BRAFV600E 双重抑制剂。进一步考察9b、9c、9h对突变型EGFR（EGFRT790M）的抑制作用，结果表明受试化合物具有相当大的抑制作用。细胞周期研究和细胞凋亡检测表明，化合物 9b 在 G2/M 转变时表现出细胞周期停滞。分子对接模拟揭示了最活跃的抗增殖药物的结合机制。