In this study, novel series of thioureido-benzenesulfonamide derivatives bearing an enaminone linker either meta or para oriented and having terminal linear or substituted aromatic or heteroaromatic ring system 5–16a,b were designed and synthesized based on the general pharmacophoric features of type II VEGFR2 inhibitors. Evaluation of the synthesized compounds against HEPG2 hepatocellular carcinoma cells in vitro identified compounds 5b, 6b and 10–13b as most active anticancer agents with IC₅₀ equal to 0.12, 0.29, 0.58, 0.44, 0.42 and 0.66 µM, respectively. These compounds were evaluated for their ability to in vitro inhibit VEGFR2 kinase enzyme. The results demonstrated highly potent dose-related VEGFR2 inhibition with IC₅₀ values in nanomolar range (33, 57, 210, 37, 37 and 220 nM, respectively). The radiosensitizing ability of the most promising compounds was studied which showed an increase in the cell killing effect of radiation after combination with the synthesized compounds which revealed lowered IC₅₀ by nearly 50%. Molecular docking for the most potent compounds was performed to predict their possible binding mode within VEGFR2 active site and they showed binding affinity in a similar way to sorafenib.

在本研究中，基于 II 型 VEGFR2 的一般药效特征，设计并合成了一系列新型硫脲基苯磺酰胺衍生物，其带有间位或对位烯胺连接基，并具有末端线性或取代的芳香或杂芳香环系统5 – 16a,b抑制剂。对合成化合物针对 HEPG2 肝细胞癌细胞的体外评价表明，化合物5b 、 6b和10-13b是最有效的抗癌药物， IC ₅₀分别等于 0.12、0.29、0.58、0.44、0.42 和 0.66 µM。评估了这些化合物体外抑制 VEGFR2 激酶的能力。结果表明，VEGFR2 具有高效的剂量相关抑制作用，IC ₅₀值在纳摩尔范围内（分别为 33、57、210、37、37 和 220 nM）。对最有前途的化合物的放射增敏能力进行了研究，结果表明，与合成的化合物组合后，放射线的细胞杀伤作用增强，IC ₅₀降低了近50%。对最有效的化合物进行分子对接，以预测它们在 VEGFR2 活性位点内可能的结合模式，并且它们以与索拉非尼类似的方式显示出结合亲和力。