article · Journal of Enzyme Inhibition and Medicinal Chemistry
Two new series of benzimidazole-triazole hybrid molecules were synthesised and evaluated as multi-target inhibitors directed against EGFR, VEGFR-2, and Topo II. Laboratory tests against four cancer cell lines, namely HepG-2, HCT-116, MCF-7, and HeLa, identified compounds 5a and 6g as the most potent candidates. In enzyme assays, compound 5a demonstrated strong EGFR inhibition comparable to the reference drug Gefitinib, moderate VEGFR-2 inhibition relative to Sorafenib, and Topo II inhibition superior to Doxorubicin. Compound 6g exhibited moderate EGFR and VEGFR-2 inhibition alongside weaker Topo II inhibition. Further evaluations involving DNA binding assays, cell cycle analysis, apoptotic induction, molecular docking, and physicochemical studies were conducted to examine the biological mechanisms of these active hybrid compounds.
Developing multi-target inhibitors offers a strategy to improve anticancer treatment by addressing multiple biological drivers at once. By acting against EGFR, VEGFR-2, and Topo II simultaneously, such hybrid compounds could provide stronger therapeutic responses across various cancer types, including liver, colorectal, breast, and cervical malignancies, providing useful chemical scaffolds for future therapeutic development.
This work represents early-stage drug discovery that could provide pharmaceutical developers and medicinal chemists with new candidate structures for multi-target cancer therapeutics. Because the findings are limited to in vitro cell cultures and in silico computational assessments, these compounds remain at a discovery stage, requiring extensive preclinical animal validation and toxicity profiling before any clinical or commercial pipeline can be pursued.
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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 <b>5a</b> and <b>6g</b> 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 <b>5a</b> was especially good inhibitor for EGFR (IC<sub>50</sub> = 0.086 µM) compared to Gefitinib (IC<sub>50</sub> = 0.052 µM), moderate VEGFR-2 inhibitor (IC<sub>50</sub> = 0.107 µM) compared to Sorafenib (IC<sub>50</sub> = 0.0482 µM), and stronger Topo II inhibitor (IC<sub>50</sub> = 2.52 µM) than Doxorubicin (IC<sub>50</sub> = 3.62 µM). Compound <b>6g</b> 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.
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DOI: 10.1080/14756366.2023.2166037
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