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Abstract <p><b>Objective:</b> This study aimed to design, synthesize, and evaluate novel quinoline–dihydropyridine hybrids as potential inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK), assessing their antiproliferative activity against the human lung cancer cell line A549. <b>Methods:</b> The compounds were designed <i>in silico</i> and synthesized. Molecular docking studies were performed to assess their binding affinities within the EGFR-TK active site. Molecular dynamics (MD) simulations were conducted to investigate the stability and conformational dynamics of the ligand–protein complexes. Additionally, density functional theory (DFT) calculations were used to optimize the molecular geometry of the hybrids and confirm their electronic properties. <b>Results and Discussion:</b> Among the synthesized compounds, two demonstrated notable EGFR-TK inhibitory activity: compound (<b>VIc</b>), bearing a methoxy substituent at the 4-position, exhibited an IC<sub>50</sub> of 1.455 ± 1.17 µg/mL, while compound (<b>VIh</b>), containing a hydroxy group at the same position, showed an IC<sub>50</sub> of 1.736 ± 1.24 µg/mL. For comparison, the reference drug erlotinib exhibited an IC<sub>50</sub> of 7.32 ± 0.52 µg/mL. Molecular modeling identified structural determinants responsible for the observed activity, including favorable hydrogen bonding and hydrophobic interactions within the EGFR-TK active site. <b>Conclusions:</b> This integrated experimental and computational study underscores the potential of quinoline–dihydropyridine hybrids as promising EGFR-TK inhibitors. The findings provide a structural basis for further optimization of these compounds as candidates for targeted lung cancer therapy.</p>

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Cytotoxic Potential of Newly Synthesized Quinoline–Bearing Dihydropyridine Hybrids on A549 Lung Cancer Cells

  • 期刊论文

  • 发表日期：

    2025年6月3日

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  • V. Kuthe,
  • S. G. Alegaon,
  • R. S. Kavalapure,
  • S. Gharge,
  • S. D. Ranade

摘要

Abstract

Objective: This study aimed to design, synthesize, and evaluate novel quinoline–dihydropyridine hybrids as potential inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK), assessing their antiproliferative activity against the human lung cancer cell line A549. Methods: The compounds were designed in silico and synthesized. Molecular docking studies were performed to assess their binding affinities within the EGFR-TK active site. Molecular dynamics (MD) simulations were conducted to investigate the stability and conformational dynamics of the ligand–protein complexes. Additionally, density functional theory (DFT) calculations were used to optimize the molecular geometry of the hybrids and confirm their electronic properties. Results and Discussion: Among the synthesized compounds, two demonstrated notable EGFR-TK inhibitory activity: compound (VIc), bearing a methoxy substituent at the 4-position, exhibited an IC50 of 1.455 ± 1.17 µg/mL, while compound (VIh), containing a hydroxy group at the same position, showed an IC50 of 1.736 ± 1.24 µg/mL. For comparison, the reference drug erlotinib exhibited an IC50 of 7.32 ± 0.52 µg/mL. Molecular modeling identified structural determinants responsible for the observed activity, including favorable hydrogen bonding and hydrophobic interactions within the EGFR-TK active site. Conclusions: This integrated experimental and computational study underscores the potential of quinoline–dihydropyridine hybrids as promising EGFR-TK inhibitors. The findings provide a structural basis for further optimization of these compounds as candidates for targeted lung cancer therapy.