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<p>In this study, molecular hybridization strategy was applied to design, synthesize a new series of quinazoline-4-one derivatives (<b>E1</b>–<b>E8</b>) as potential EGFR-targeting anticancer agents. The synthetic approach involved nucleophilic substitution reactions yielding high-purity compounds, characterized using FT-IR, <sup>1</sup>H-NMR, and <sup>13</sup>C-NMR spectroscopy. In vitro cytotoxicity assays against MCF-7 and SW480 cell lines revealed compound <b>E8</b> as the most active derivative, exhibiting moderate antiproliferative activity (IC<sub>50</sub> = 53.65 µM and 42.55 µM, respectively), highlighting the significance of 3-chlorobenzyl substitution on phenyl ring. Molecular docking studies confirmed strong interactions with key EGFR residues, including Lys721 and Phe699, while DFT calculations provided insights into electronic properties and stability profiles. Pharmacokinetic and toxicity analyses suggested favorable absorption and membrane permeability, albeit with some concerns regarding mutagenicity and HERG channel inhibition. Overall, these findings suggest that the newly synthesized quinazoline derivatives, particularly <b>E8</b>, represent promising scaffolds for further development as potentially EGFR-targeted anticancer agents, though additional studies on non-cancerous cells are needed to evaluate selectivity and safety.</p>

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Design, synthesis, and evaluation of novel quinazoline-4-one derivatives as potential EGFR-targeting anticancer agents: integrated computational and biological insights

  • 期刊论文

  • 发表日期：

    2026年2月13日

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  • Maryam Moghtader Mansouri,
  • Elaheh Ataollahi,
  • Soghra Khabnadideh,
  • Keyvan Heidarneghad,
  • Maryam Sedigh,
  • Alireza Poustforoosh,
  • Mina Emami,
  • Leila Emami,
  • Zahra Rezaei

摘要

In this study, molecular hybridization strategy was applied to design, synthesize a new series of quinazoline-4-one derivatives (E1–E8) as potential EGFR-targeting anticancer agents. The synthetic approach involved nucleophilic substitution reactions yielding high-purity compounds, characterized using FT-IR, 1H-NMR, and 13C-NMR spectroscopy. In vitro cytotoxicity assays against MCF-7 and SW480 cell lines revealed compound E8 as the most active derivative, exhibiting moderate antiproliferative activity (IC50 = 53.65 µM and 42.55 µM, respectively), highlighting the significance of 3-chlorobenzyl substitution on phenyl ring. Molecular docking studies confirmed strong interactions with key EGFR residues, including Lys721 and Phe699, while DFT calculations provided insights into electronic properties and stability profiles. Pharmacokinetic and toxicity analyses suggested favorable absorption and membrane permeability, albeit with some concerns regarding mutagenicity and HERG channel inhibition. Overall, these findings suggest that the newly synthesized quinazoline derivatives, particularly E8, represent promising scaffolds for further development as potentially EGFR-targeted anticancer agents, though additional studies on non-cancerous cells are needed to evaluate selectivity and safety.