Two series of thieno[2,3‐d][1,2,3]triazine derivatives were designed, synthesized, and biologically evaluated as potential epidermal growth factor receptor (EGFR) inhibitors targeting the non‐small‐cell lung cancer cell line H1299. Most of the synthesized compounds displayed IC50 values ranging from 25 to 58 nM against H1299, which are superior to that of gefitinib (40 µM). 3‐(5,6,7,8‐Tetrahydro‐7H‐cyclohexa[4:5]thieno[2,3‐d]‐1,2,3‐triazin‐4‐ylamino)benzene‐1,3‐diamine (6b) achieved the highest cytotoxic activity against H1299 with an IC50 value of 25 nM; it had the ability to decrease the EGFR concentration in H1299 cells from 7.22 to 2.67 pg/ml. In vitro, the IC50 value of compound 6b was 0.33 nM against EGFR, which is superior to that of gefitinib at 1.9 nM and erlotinib at 4 nM. The three‐dimensional quantitative structure–activity relationships and molecular modeling studies revealed comparable binding modes of compound 6b, gefitinib, and erlotinib in the EGFR active site. The in silico ADME (absorption, distribution, metabolism, and excretion) prediction parameters of this compound revealed promising pharmacokinetic and physicochemical properties. Moreover, DFT (density functional theory) calculations showed the high reactivity of compound 6b toward the EGFR compared with other compounds. The designed compound 6b might serve as an encouraging lead compound for the discovery of promising anti‐lung cancer agents targeting EGFR.

中文翻译：

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靶向EGFR的新型噻吩并[2,3-d][1,2,3]三嗪的药效团建模、3D-QSAR、合成和抗肺癌评估

设计、合成了两个系列的噻吩并 [2,3-d][1,2,3] 三嗪衍生物，并对其作为潜在的表皮生长因子受体 (EGFR) 抑制剂进行了生物评估，以靶向非小细胞肺癌细胞系 H1299 . 大多数合成的化合物对 H1299 的 IC50 值范围为 25 至 58 nM，优于吉非替尼 (40 µM)。3-(5,6,7,8-Tetrahydro-7H-cyclohexa[4:5]thieno[2,3-d]-1,2,3-triazin-4-ylamino)benzo-1,3-diamine ( 6b) 对 H1299 达到最高的细胞毒活性，IC50 值为 25 nM；它能够将 H1299 细胞中的 EGFR 浓度从 7.22 pg/ml 降低到 2.67 pg/ml。在体外，化合物6b对EGFR的IC50值为0.33 nM，优于1.9 nM的吉非替尼和4 nM的厄洛替尼。三维定量构效关系和分子建模研究揭示了化合物 6b、吉非替尼和厄洛替尼在 EGFR 活性位点的类似结合模式。该化合物的计算机模拟 ADME（吸收、分布、代谢和排泄）预测参数显示出有希望的药代动力学和理化特性。此外，DFT（密度泛函理论）计算表明，与其他化合物相比，化合物 6b 对 EGFR 具有高反应性。设计的化合物 6b 可能作为一种令人鼓舞的先导化合物，用于发现有前景的靶向 EGFR 的抗肺癌药物。和排泄）该化合物的预测参数显示出有希望的药代动力学和理化特性。此外，DFT（密度泛函理论）计算表明，与其他化合物相比，化合物 6b 对 EGFR 具有高反应性。设计的化合物 6b 可能作为一种令人鼓舞的先导化合物，用于发现有前景的靶向 EGFR 的抗肺癌药物。和排泄）该化合物的预测参数显示出有希望的药代动力学和理化特性。此外，DFT（密度泛函理论）计算表明，与其他化合物相比，化合物 6b 对 EGFR 具有高反应性。设计的化合物 6b 可能作为一种令人鼓舞的先导化合物，用于发现有前景的靶向 EGFR 的抗肺癌药物。