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<p>A series of novel biphenyl- and naphthyl-based amidrazone derivatives was synthesized and evaluated for anticancer activity against breast (MDA-MB-231) and colon (HL-60) cancer cell lines. Seven piperazine-containing derivatives exhibited significant anticancer effects with IC<sub>50</sub> values ranging from 7 to 30 μM while showing low toxicity toward fibroblasts (IC<sub>50</sub> &gt; 300 μM). Molecular docking studies revealed that the most active compounds, <b>10a</b> and <b>10e</b>, bind strongly within the ATP-binding site of c-Abl kinase (PDB: 1IEP, resolution: 2.10 Å), achieving LibDock scores of 64.26 and 87.68, respectively, and enzyme inhibition IC<sub>50</sub> values of 18.29 μM and 10.28 μM. Compounds <b>12b, 12c, 12e</b>, and <b>15b</b> significantly inhibited PKN2 activity, while <b>12d</b> and <b>16d</b> showed enhanced potency against IKKβ despite lower c-Abl inhibition. These findings indicate that the anticancer effects of the synthesized derivatives are likely mediated by multitarget kinase inhibition, underscoring their promise as candidates for developing multi-kinase-targeting anticancer agents.</p><p></p>

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New amidrazone analogs as multi-kinase inhibitors: in-silico and biological investigation as an anticancer agent

  • 期刊论文

  • 发表日期：

    2025年3月26日

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  • Almeqdad Y. Habashneh,
  • Mahmoud A. Al-Sha’er,
  • Sanaa K. Bardaweel

摘要

A series of novel biphenyl- and naphthyl-based amidrazone derivatives was synthesized and evaluated for anticancer activity against breast (MDA-MB-231) and colon (HL-60) cancer cell lines. Seven piperazine-containing derivatives exhibited significant anticancer effects with IC50 values ranging from 7 to 30 μM while showing low toxicity toward fibroblasts (IC50 > 300 μM). Molecular docking studies revealed that the most active compounds, 10a and 10e, bind strongly within the ATP-binding site of c-Abl kinase (PDB: 1IEP, resolution: 2.10 Å), achieving LibDock scores of 64.26 and 87.68, respectively, and enzyme inhibition IC50 values of 18.29 μM and 10.28 μM. Compounds 12b, 12c, 12e, and 15b significantly inhibited PKN2 activity, while 12d and 16d showed enhanced potency against IKKβ despite lower c-Abl inhibition. These findings indicate that the anticancer effects of the synthesized derivatives are likely mediated by multitarget kinase inhibition, underscoring their promise as candidates for developing multi-kinase-targeting anticancer agents.