The eradication of multifactorial diseases, such as cancer, requires the design of drug candidates that attack multiple targets that contribute to the progression and proliferation of such diseases. Here, 1,5-diarylpyrazole derivatives bearing vanillin or sulfanilamide are developed as potential dual inhibitors of epidermal growth factor receptor (EGFR)/c-Jun -terminal kinase 2 (JNK-2) for possible anticancer activity. These derivatives inhibited the growths of DLD-1, HeLa, K-562, SUIT-2 and HepG2 cancer cell lines, with minimum concentration required to inhibit half of the cellular growth (IC) values of 2.7–63 μM. The tests confirmed that and were potent JNK-2 inhibitors, with IC of 2.0 and 0.9 μM, respectively, whereas selectively inhibited EGFR protein kinase (EGFR-PK) (IC = 1.7 μM). Notably, inhibited both kinases, with IC values of 2.7 and 3.0 μM against EGFR-PK and JNK-2, respectively, offering a reference for designing mutual inhibitors of EGFR/JNK-2. The docking studies revealed the ability of the pyrazole ring to bind to the hinge region of the ATP binding site, thereby supporting the experimental inhibitory results. Furthermore, the developed compounds could induce apoptosis and induce cell cycle arrest at different cell phases.

中文翻译：

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1,5-二芳基吡唑作为 EGFR/JNK-2 双抑制剂的开发：设计、合成、分子对接和生物活性评估

根除癌症等多因素疾病需要设计能够攻击导致此类疾病进展和扩散的多个靶点的候选药物。在此，含有香草醛或磺胺的 1,5-二芳基吡唑衍生物被开发为表皮生长因子受体 (EGFR)/c-Jun 末端激酶 2 (JNK-2) 的潜在双重抑制剂，具有潜在的抗癌活性。这些衍生物抑制 DLD-1、HeLa、K-562、SUIT-2 和 HepG2 癌细胞系的生长，抑制一半细胞生长 (IC) 值所需的最低浓度为 2.7–63 μM。测试证实 和 是有效的 JNK-2 抑制剂，IC 值分别为 2.0 和 0.9 μM，同时选择性抑制 EGFR 蛋白激酶 (EGFR-PK) (IC = 1.7 μM)。值得注意的是，对两种激酶都有抑制作用，对 EGFR-PK 和 JNK-2 的 IC 值分别为 2.7 和 3.0 μM，为设计 EGFR/JNK-2 互抑制剂提供了参考。对接研究揭示了吡唑环与 ATP 结合位点铰链区结合的能力，从而支持了实验抑制结果。此外，所开发的化合物可以诱导细胞凋亡并诱导不同细胞阶段的细胞周期停滞。