In this article, we designed and synthesized a series of novel thiophene-triazine derivatives bearing arylurea unit as potent dual PI3K/mTOR inhibitors. The cytotoxicity of all the target compounds were evaluated against nine cancer cell lines (breast cancer cell line MCF-7, lung cancer cell lines A549, NCI-H460, H2228 and H1975, cervical cancer cell lines Hela and Hela-MDR, ovarian cancer cell lines Ovcar-2 and glioma U87MG) and the kinase inhibitory activity against PI3K/mTOR kinases was also tested. The results demonstrated that most of the target compounds exhibited moderate to excellent activity and high selectivity against one or more cancer cell lines. Among them, seven compounds displayed better activity than lead compound GDC-0941. The inhibitory activity of the most promising compound on nine cancer cell lines was 302.5 times better than that of GDC-0941 with the IC₅₀ values as low as 0.008 ± 0.002 μM, and the inhibitory activity against PI3Kα and mTOR kinase was excellent, with the IC₅₀ values of 177.41 and 12.24 nM, respectively, indicating that it was a potential dual PI3Kα/mTOR inhibitor. The Structure-Activity Relationships (SARs) indicated that the introduction of the arylurea group significantly improved the cellular and kinase activities of the target compounds. Moreover, the results of toxicity and hemolysis experiments demonstrated that the most promising compound had low toxicity and good safety. The results of PCR assay and molecular docking modes showed that it was a potential PI3K/mTOR inhibitor, which was worthy of further study.

在这篇文章中，我们设计并合成了一系列带有芳基脲单元的新型噻吩-三嗪衍生物作为有效的双重 PI3K/mTOR 抑制剂。评估了所有目标化合物对九种癌细胞系（乳腺癌细胞系 MCF-7、肺癌细胞系 A549、NCI-H460、H2228 和 H1975、宫颈癌细胞系 Hela 和 Hela-MDR、卵巢癌细胞系）的细胞毒性线 Ovcar-2 和神经胶质瘤 U87MG）和对 PI3K/mTOR 激酶的激酶抑制活性也进行了测试。结果表明，大多数目标化合物对一种或多种癌细胞系表现出中等至优异的活性和高选择性。其中，有 7 种化合物表现出比先导化合物 GDC-0941 更好的活性。最有希望的化合物对九种癌细胞系的抑制活性为 302。₅₀值低至 0.008 ± 0.002 μM，对 PI3Kα 和 mTOR 激酶具有优异的抑制活性，IC ₅₀值分别为 177.41 和 12.24 nM，表明它是一种潜在的双重 PI3Kα/mTOR 抑制剂。结构-活性关系 (SARs) 表明芳基脲基团的引入显着提高了目标化合物的细胞和激酶活性。此外，毒性和溶血实验的结果表明，最有希望的化合物具有低毒性和良好的安全性。PCR检测和分子对接模式的结果表明它是一种潜在的PI3K/mTOR抑制剂，值得进一步研究。