作为我们持续努力发现作为抗肿瘤药剂的新型c-Met抑制剂的一部分，我们设计、合成和评估了四系列的噻唑/噻二唑羧酰胺衍生物类似物的体外活性对c-Met和四种人类癌细胞系。在结构活性关系的五次优化周期后，发现化合物51am在生化和细胞实验中都表现出最有前景的抑制剂活性。此外，51am还对几种c-Met突变体具有高度抑制能力。在机制上，51am不仅能够诱导MKN-45细胞的细胞周期阻滞和凋亡，还能够在细胞和无细胞系统中抑制c-Met磷酸化。它还在BALB/c小鼠中显示出良好的药物动力学特性。此外，51am与c-Met和VEGFR-2的结合模式为发现选择性c-Met抑制剂提供了新颖的见解。总之，这些结果表明51am可能是一个有进一步发展价值的抗肿瘤候选化合物。

As part of our continuous efforts to discover novel c-Met inhibitors as antitumor agents, four series of thiazole/thiadiazole carboxamide-derived analogues were designed, synthesised, and evaluated for the in vitro activity against c-Met and four human cancer cell lines. After five cycles of optimisation on structure-activity relationship, compound 51am was found to be the most promising inhibitor in both biochemical and cellular assays. Moreover, 51am exhibited potency against several c-Met mutants. Mechanistically, 51am not only induced cell cycle arrest and apoptosis in MKN-45 cells but also inhibited c-Met phosphorylation in the cell and cell-free systems. It also exhibited a good pharmacokinetic profile in BALB/c mice. Furthermore, the binding mode of 51am with both c-Met and VEGFR-2 provided novel insights for the discovery of selective c-Met inhibitors. Taken together, these results indicate that 51am could be an antitumor candidate meriting further development.