As part of our ongoing efforts to produce promising cytotoxic agents, the novel compounds, 5-(4-(diethylamino)-2-((1-substitutedphenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1,3,4-thiadiazol-2-yl)pyrrolidine-2,5-dione derivatives (9a-l) were developed, synthesized, and characterized using several analytical techniques, including ¹H NMR, ¹³C NMR, and LC-MS. New series of 1,2,3-triazole and thiadiazole molecular hybrids synthesized were evaluated for their anti-cancer activity against human esophageal carcinoma cell line KYSE-450 and human pancreatic carcinoma cell line MIA PaCa-2 cells. According to cytotoxic evaluation data, compounds 9b, 9i, 9j, and 9l exhibited potential cytotoxic activity against KYSE-450 and MIAPaCa-2 cells. Compound 9j had more significant anti-cancer potential than the standard employed across all compounds evaluated. The remaining compounds exhibited moderate to weak anti-proliferative potential. In-vitro kinase inhibition of compound 9j was significantly more effective against ARK-A and ERK2 enzymes, indicating its dual inhibition potential. Docking analysis showed that 9k, 9j, and 9i have substantial docking scores with the ARK-A receptor, indicating the presence of strong binding affinities. Significant binding interactions between molecules 9j and 9h and the ERK2 receptor suggest an inhibitory effect. Hence the compounds are promising dual inhibitors of ARK-A/ERK2.

Graphical Abstract

中文翻译：

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新型 1,2,3-三唑-噻二唑杂化衍生物的合成、基于计算机的虚拟筛选、作为极光激酶 A (ARK-A) 和细胞外调节激酶 2 (ERK2) 双重抑制剂的抗癌潜力

作为我们不断生产有前途的细胞毒性药物的努力的一部分，新型化合物 5-(4-(二乙氨基)-2-((1-取代苯基-1 H -1,2,3-三唑-4-基)甲氧基)使用多种分析技术（包括1 H ^NMR、¹³ C NMR 和LC-MS。合成的新系列1,2,3-三唑和噻二唑分子杂合体对人食管癌细胞系KYSE-450和人胰腺癌细胞系MIA PaCa-2细胞的抗癌活性进行了评估。根据细胞毒性评价数据，化合物9b、9i、9j和9l对 KYSE-450 和 MIAPaCa-2 细胞表现出潜在的细胞毒活性。化合物9j比所有评估的化合物所采用的标准具有更显着的抗癌潜力。其余化合物表现出中度至弱的抗增殖潜力。化合物9j的体外激酶抑制对 ARK-A 和 ERK2 酶明显更有效，表明其双重抑制潜力。对接分析表明，9k、9j和9i与 ARK-A 受体具有显着的对接分数，表明存在强结合亲和力。分子9j和9h之间存在显着的结合相互作用ERK2 受体表明有抑制作用。因此，这些化合物是有前途的 ARK-A/ERK2 双重抑制剂。

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