Cancer is a leading cause of death in humans. Molecular targeted therapy for cancer has become a research hotspot as it is associated with low toxicity and high efficiency. In this study, a total of 36 derivatives of 4-(4-aminophenoxy)pyridinamide were designed and synthesized, based on the analysis of the binding patterns of cabozantinib and BMS-777607 to MET protein. Most target compounds exhibited moderate to excellent antiproliferative activity against three different cell lines (A549, HeLa and MCF-7). A total of 7 compounds had stronger inhibitory activities than cabozantinib, and the IC₅₀ value of the most promising compound 46 was 0.26 μM against the A549 cells, which was 2.4 times more active than that of cabozantinib. The structure-activity relationship of the target compounds was analyzed and summarized, and the action mechanism was discussed. The acridine orange (AO) staining assay and cell cycle apoptosis revealed that compound 46 dose-dependently induced apoptosis of A549 cells, and blocked the cells mainly in G0/G1 phase. The IC₅₀ value of compound 46 on c-Met kinase was 46.5 nM. Further docking studies and molecular dynamics simulations signaled that compound 46 formed four key hydrogen bonds to c-Met kinase, and these key amino acids played a major role in binding free energy. In addition, compound 46 also showed good pharmacokinetic characteristics in rats. In conclusion, compound 46 is a promising antitumor agent.

癌症是人类死亡的主要原因。癌症分子靶向治疗因其低毒、高效而成为研究热点。本研究基于卡博替尼和BMS-777607与MET蛋白的结合模式分析，设计并合成了总共36种4-(4-氨基苯氧基)吡啶酰胺衍生物。大多数目标化合物对三种不同的细胞系（A549、HeLa 和 MCF-7）表现出中等至优异的抗增殖活性。共有7种化合物比卡博替尼具有更强的抑制活性，其中最有前途的化合物46的IC _50值对 A549 细胞的作用浓度为 0.26 μM，其活性是卡博替尼的 2.4 倍。对目标化合物的构效关系进行了分析和总结，并探讨了作用机制。吖啶橙(AO)染色实验和细胞周期凋亡分析表明，化合物46剂量依赖性地诱导A549细胞凋亡，并主要将细胞阻滞于G0/G1期。化合物46对c-Met激酶的IC ₅₀值为46.5 nM。进一步的对接研究和分子动力学模拟表明，化合物46与c-Met激酶形成了四个关键氢键，这些关键氨基酸在结合自由能方面发挥了主要作用。此外，化合物46在大鼠中也显示出良好的药代动力学特征。总之，化合物46是一种有前途的抗肿瘤药物。