Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2166037. doi: 10.1080/14756366.2023.2166037.
Multi-target inhibitors represent useful anticancer agents with superior therapeutic attributes. Here in, two novel series of benzimidazole-triazole hybrids were designed, synthesised as multi-target EGFR, VEGFR-2 and Topo II inhibitors, and evaluated for anticancer activity. Compounds and were the most potent analogues against four cancer cell lines, HepG-2, HCT-116, MCF-7 and HeLa, and were further evaluated for EGFR, VEGFR-2, and Topo II inhibition. Compound was especially good inhibitor for EGFR (IC = 0.086 µM) compared to Gefitinib (IC = 0.052 µM), moderate VEGFR-2 inhibitor (IC = 0.107 µM) compared to Sorafenib (IC = 0.0482 µM), and stronger Topo II inhibitor (IC = 2.52 µM) than Doxorubicin (IC = 3.62 µM). Compound exhibited moderate EGFR and VEGFR-2 inhibition and weaker Topo II inhibition. DNA binding assay, cell cycle analysis, apoptotic induction, molecular docking, and physicochemical studies were additionally implemented to explore the plausible mechanism of the active compounds.
多靶点抑制剂是一类具有优越治疗属性的抗癌药物。在这里，我们设计并合成了两个新的苯并咪唑-三唑杂合体系列，作为多靶点 EGFR、VEGFR-2 和拓扑异构酶 II 抑制剂进行评估，并研究其抗癌活性。化合物 和 对 HepG-2、HCT-116、MCF-7 和 HeLa 四种癌细胞系的抑制活性最强，进一步对 EGFR、VEGFR-2 和拓扑异构酶 II 的抑制作用进行了评价。与吉非替尼（IC = 0.052 µM）相比，化合物 对 EGFR 的抑制作用更强（IC = 0.086 µM），与索拉非尼（IC = 0.0482 µM）相比，对 VEGFR-2 的抑制作用中等（IC = 0.107 µM），对拓扑异构酶 II 的抑制作用更强（IC = 2.52 µM），而阿霉素（IC = 3.62 µM）。化合物 对 EGFR 和 VEGFR-2 有中等抑制作用，对拓扑异构酶 II 的抑制作用较弱。此外，还进行了 DNA 结合实验、细胞周期分析、凋亡诱导、分子对接和物理化学研究，以探讨活性化合物的可能作用机制。
