Vascular endothelial growth factor (VEGF) is a crucial key factor in breast tumorigenesis. VEGF plays an important role in angiogenesis, tumor proliferation, and metastasis. Herein, we report the design and synthesis of twenty-one novel piperidine/oxindole derivatives as potential VEGFR-2 inhibitors. The designed compound library aimed to occupy the binding site of VEGFR-2 in a similar binding pattern to that of the reference VEGFR-2 inhibitor Sorafenib. The synthesized compounds were biologically evaluated for their cytotoxic effects against two breast cancer cell lines (MCF-7 and MDA-MB-468). Compounds 12e and 6n were the most potent cytotoxic derivatives against the former and the latter cell lines, showing IC50 values of 8.00 and 0.60 µM, respectively. Furthermore, all the synthesized compounds were evaluated for their inhibitory activities towards VEGFR-2, with compound 12e showing the most potent activity with an IC50 value of 45.9 nM, surpassing the reference standard Sorafenib (IC50 = 48.6 nM). Additionally, compound 6n emerged as the top performer when tested with the other most promising compounds for their cytotoxic effects on HUVEC (IC50 = 28.77 nM). The designed library of compounds was subjected to molecular docking and molecular dynamic simulations, which revealed key binding interactions within the VEGFR-2 active site, including hydrogen bonding with Cys919, Glu885, and Asp1046 residues. Moreover, in silico predictions of physicochemical and pharmacokinetic properties for the target compounds indicated favorable drug-like characteristics.

中文翻译：

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作为 VEGFR-2 抑制剂的新型 N'-(2-氧吲哚啉-3-亚基)哌啶-4-碳酰肼衍生物的设计、合成和计算机见解


血管内皮生长因子（VEGF）是乳腺肿瘤发生的关键因素。 VEGF在血管生成、肿瘤增殖和转移中发挥重要作用。在此，我们报告了 21 种新型哌啶/羟吲哚衍生物作为潜在 VEGFR-2 抑制剂的设计和合成。设计的化合物库旨在以与参考 VEGFR-2 抑制剂索拉非尼相似的结合模式占据 VEGFR-2 的结合位点。合成的化合物对两种乳腺癌细胞系（MCF-7 和 MDA-MB-468）的细胞毒性作用进行了生物学评估。化合物12e和6n是针对前者和后者细胞系最有效的细胞毒性衍生物，显示IC50值分别为8.00和0.60 µM。此外，评估了所有合成化合物对 VEGFR-2 的抑制活性，其中化合物 12e 显示出最强的活性，IC50 值为 45.9 nM，超过参考标准索拉非尼 (IC50 = 48.6 nM)。此外，当与其他最有前途的化合物一起测试其对 HUVEC 的细胞毒性作用时，化合物 6n 表现最佳（IC50 = 28.77 nM）。设计的化合物库经过分子对接和分子动力学模拟，揭示了 VEGFR-2 活性位点内的关键结合相互作用，包括与 Cys919​​、Glu885 和 Asp1046 残基的氢键结合。此外，目标化合物的理化和药代动力学特性的计算机预测表明了良好的药物样特征。