The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All compounds were evaluated for their inhibitory activities against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCR-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds showed promising results, with IC₅₀ values between 1.0 and 7.3 μM, and were subjected to molecular docking studies. The results suggest that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One compound showed the greatest interaction affinity for BCR-Abl-1 in the docking studies.

中文翻译：

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(苯氨基)嘧啶-1,2,3-三唑衍生物作为伊马替尼的类似物：寻找抗慢性粒细胞白血病的新化合物


酪氨酸激酶BCR-Abl-1是治疗慢性粒细胞白血病的主要分子靶点，可被伊马替尼等酪氨酸激酶抑制剂竞争性抑制。使用（苯氨基）嘧啶-吡啶（PAPP）基团作为药效基团片段合成了新的潜在竞争性抑制剂，并对这些化合物进行了生物学评估。分三步合成了12个新化合物，并在微波辐射辅助下进行1,3-偶极环加成反应，得到三唑核C-4碳上取代的1,2,3-三唑衍生物。评估了所有化合物对表达酪氨酸激酶 BCR-Abl-1 的慢性粒细胞白血病细胞系 (K562) 和健康细胞 (WSS-1) 的抑制活性，以观察其选择性。三种化合物显示出有希望的结果，IC ₅₀值在 1.0 至 7.3 μM 之间，并进行了分子对接研究。结果表明，此类化合物可以在与伊马替尼相同的结合位点相互作用，可能具有竞争性抑制机制。在对接研究中，一种化合物显示出与 BCR-Abl-1 最大的相互作用亲和力。