2. Academic Validation
  3. Expanding the chemical and therapeutic landscape of 5H-Indeno[1,2-b]pyridin-5-one derivatives: Novel anticancer activity, EGFR inhibition, and modulation of HIF-VEGF and PI3K/AKT/mTOR pathways supported by computational insights

Expanding the chemical and therapeutic landscape of 5H-Indeno[1,2-b]pyridin-5-one derivatives: Novel anticancer activity, EGFR inhibition, and modulation of HIF-VEGF and PI3K/AKT/mTOR pathways supported by computational insights

  • Bioorg Chem. 2026 Mar:170:109476. doi: 10.1016/j.bioorg.2026.109476.
Hagar S El-Hema 1,  Hadeer A El-Shazly 2,  Mohamed A Hawata 2,  Nabil M Yousif 3,  Modather F Hussein 4,  Mohamed A Said 5,  Esraa A Aidy 6,  Haitham E Shehata 2,  Adel A-H Abdel-Rahman 7
Affiliations

Affiliations

  • 1 Basic Science Department (Chemistry), Thebes Higher Institute for Engineering, Thebes Academy, Maadi 11434, Egypt. Electronic address: [email protected].
  • 2 Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Egypt.
  • 3 Photochemistry Department, Chemical Industries Research Institute, National Research Centre, Cairo, Egypt.
  • 4 Chemistry Department, College of Science, Jouf University, P.O. Box 2014, Sakaka, Aljouf 72341, Saudi Arabia.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo 11829, Egypt; Department of pharmaceutical chemistry, college of Pharmacy, University of Kut, Wasit 52001, Iraq.
  • 6 Medical Biochemistry and Molecular Biology unit, Cancer biology Department, National Cancer Institute, Cairo University, Egypt.
  • 7 Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Egypt. Electronic address: [email protected].
PMID: 41518939 DOI: 10.1016/j.bioorg.2026.109476
Abstract

A novel series of eleven 5H-indeno[1,2-b]pyridin-5-one derivatives (1-11) was rationally designed and synthesized to explore their Anticancer potential. The compounds were screened for cytotoxicity against PC-3, HePG-2, and MCF-7 Cancer cell lines, and the normal WI-38 line using the MTT assay. Among them, compounds 5 and 7 exhibited the strongest cytotoxicity, with compound 7 showing remarkable potency toward MCF-7 cells (IC₅₀ = 5.53 μM). Target prediction and enrichment analyses identified EGFR as the most relevant molecular target associated with the observed activity. Compound 7 significantly inhibited EGFR (IC₅₀ = 0.12 ± 0.004 μg mL-1), comparable to erlotinib, confirming its mechanism-based action. Flow cytometry analysis revealed G₂/M cell-cycle arrest and a marked increase in apoptotic cell populations, indicating apoptosis-mediated cytotoxicity. Furthermore, gene expression analysis of MCF-7 cells treated with compound 7 demonstrated a significant down-regulation of HIF-1α and VEGF genes, accompanied by modulation of PI3K, Akt, mTOR, and PTEN expression levels, suggesting suppression of the HIF-VEGF signaling crosstalk that governs tumor angiogenesis and proliferation. Molecular docking against EGFR (PDB ID: 4I23) showed a strong binding affinity (-7.85 kcal/mol) through hydrogen bonding with Met793 and hydrophobic interactions with Lys745 and Gly796, consistent with the biological findings. DFT analysis (ΔE = 0.069 eV; η = 0.0347) supported the molecule's high reactivity and optimal donor acceptor features. Molecular dynamics confirmed stable complex formation with favorable flexibility, while ADMET profiling indicated acceptable drug-likeness but limited oral absorption and potential metabolic liabilities. Overall, compound 7 emerged as the most promising EGFR-targeted lead with strong selectivity toward MCF-7 cells, induction of Apoptosis, inhibition of HIF-VEGF signaling, and favorable electronic behavior, highlighting its ability to modulate the EGFR-PI3K/AKT-HIF-VEGF axis as a potential multi-pathway strategy for breast Cancer therapy.

Keywords

5H-indeno[1,2-b]pyridin-5-one; Anticancer; Apoptosis; Cell cycle; Computational studies; EGFR; HIF–VEGF; PI3K/AKT/mTOR.

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