A new family of diphenylpyrimidine derivatives bearing an amino acid substituent were identified as potent BTK inhibitors. Among them, compound 7b, which features an l-proline substituent, was identified as the strongest BTK inhibitor, with an IC₅₀ of 8.7 nM. Compound 7b also displayed similar activity against B-cell lymphoma cell lines as ibrutinib. Moreover, 7b exhibited low cytotoxic activity against normal PBMC cells. In addition, the acridine orange/ethidium bromide (AO/EB) staining assay, Western blot analysis and flow cytometry analysis also showed its effectiveness in interfering with B-cell lymphoma cell growth. The molecular simulation performance showed that 7b forms additional strong hydrogen bonds with the BTK protein. All these findings provided new clues about the pyrimidine scaffold as an effective BTK inhibitor for the treatment of B-cell lymphoma.

带有氨基酸取代基的新的二苯基嘧啶衍生物家族被确定为有效的BTK抑制剂。其中，具有1-脯氨酸取代基的化合物7b被确定为最强的BTK抑制剂，IC ₅₀为8.7 nM。化合物7b还显示出与依鲁替尼相似的针对B细胞淋巴瘤细胞系的活性。此外，7b表现出对正常PBMC细胞低的细胞毒活性。此外，cr啶橙/溴化乙锭（AO / EB）染色测定，Western印迹分析和流式细胞仪分析也显示出其在干扰B细胞淋巴瘤细胞生长中的有效性。分子模拟性能表明7b与BTK蛋白形成额外的强氢键。所有这些发现为嘧啶支架作为治疗B细胞淋巴瘤的有效BTK抑制剂提供了新的线索。