BRAF^V600E mutation has been detected in various malignant tumours. Developing of potent BRAF^V600E inhibitors is considered a leading step in the way to cure different cancer types. In the current work, a series of 38 4-(1H-imidazol-5-yl)pyridin-2-amine derivatives was designed and synthesized using Dabrafenib as a lead compound for structural-guided optimization. The target compounds were evaluated as potential anticancer agents against NCI 60 human cancer cell lines. In 5-dose testing mode, two compounds 14h and 16e were tested to determine their IC₅₀ values over each of the 60 cell lines. The selected candidates exhibited promising activity with mean IC₅₀ values of 2.4 µM and 3.6 µM, respectively. Melanoma cancer cell lines exhibited the highest sensitivity after the treatment with the tested compounds 14 h and 16e. The mean IC₅₀ values of compounds 14 h and 16e against Melanoma cancer cell lines are 1.8 µM and 1.88 µM, respectively. In addition, BRAF^V600E kinase inhibitory activity was determined for each derivative. Compounds 15i, 15j, 16a, and 16d were the most potent inhibitors against BRAF^V600E with IC₅₀ 76 nM, 32 nM, 35 nM, and 68 nM. The newly developed compounds represent a therapeutically promising approach for the treating various cancer types.

已在多种恶性肿瘤中检测到BRAF ^V600E突变。开发有效的 BRAF ^V600E抑制剂被认为是治愈不同癌症类型的领先一步。在目前的工作中，使用 Dabrafenib 作为结构引导优化的先导化合物，设计并合成了一系列 38 4-(1H-imidazol-5-yl)pyridin-2-amine 衍生物。目标化合物被评估为针对 NCI 60 人类癌细胞系的潜在抗癌剂。在 5 剂量测试模式中，测试了两种化合物 14h 和 16e，以确定它们对 60 个细胞系中每一个的IC ₅₀值。选定的候选者表现出有希望的活性，平均 IC ₅₀值分别为 2.4 µM 和 3.6 µM。黑色素瘤癌细胞系在用测试化合物 14 小时和 16e 处理后表现出最高的敏感性。化合物 14 h 和 16e 对黑色素瘤癌细胞系的平均 IC ₅₀值分别为 1.8 µM 和 1.88 µM。此外，还测定了每种衍生物的BRAF ^V600E激酶抑制活性。化合物 15i、15j、16a 和 16d 是最有效的 BRAF ^V600E抑制剂，IC _{50 为}76 nM、32 nM、35 nM 和 68 nM。新开发的化合物代表了治疗各种癌症类型的有希望的治疗方法。