Recently, the diarylurea scaffold has been used widely to design potential anticancer agents. Pursuing our design strategy based on the modification of sorafenib as the lead compound using de novo design approaches, a new series of diaryl urea derivatives were synthesized through an efficient sequential one-pot reaction and evaluated for their in vitro antiproliferative activities against A549 and HT-29 cell lines. Notably, compound 11j exhibited antiproliferative activity against HT-29 with an IC₅₀ value of 17.87 µM. SAR analyses revealed that substitution of the core diaryl scaffold with chlorine and methyl groups, and linear elongation of the molecules by the introduction of a methylene spacer group could cooperatively improve antiproliferative activity. The most active compound 11j induced mild apoptosis in HT-29 cells assessed based on DAPI staining experiments. The results of molecular docking simulations showed that the novel compounds bind to VEGFR-2 in a similar fashion to that observed for sorafenib. Molecular docking calculations also revealed that the most active compound 11j can bind well to the active site of VEGFR-2 by forming various interactions similar to those known for sorafenib particularly the π–π interaction, which is almost unique to sorafenib and highly active derivatives.

最近，二芳基脲支架已被广泛用于设计潜在的抗癌剂。按照从头设计方法将索拉非尼修饰为先导化合物的设计策略，通过有效的一锅法反应合成了一系列新的二芳基尿素衍生物，并评估了其对A549和HT-的体外抗增殖活性29个细胞系。值得注意的是，化合物11j对HT-29具有抗增殖活性，IC ₅₀值为17.87 µM。SAR分析表明，核心二芳基支架被氯和甲基取代，并且通过引入亚甲基间隔基团线性延伸分子可以协同提高抗增殖活性。活性最高的化合物根据DAPI染色实验评估，11j诱导HT-29细胞轻度凋亡。分子对接模拟的结果表明，新化合物以与索拉非尼类似的方式与VEGFR-2结合。分子对接计算还显示，活性最高的化合物11j可通过形成类似于索拉非尼已知的各种相互作用（特别是π-π相互作用）与VEGFR-2的活性位点良好结合，这几乎是索拉非尼和高活性衍生物所特有的。