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  3. Design, synthesis, and antiproliferative efficacy of an innovative series of triazino[5,6-b]indole derivatives targeting EGFR, CD1, Hsp90, PI3K, and ERK/AKT as key molecular targets in cancer therapy

Design, synthesis, and antiproliferative efficacy of an innovative series of triazino[5,6-b]indole derivatives targeting EGFR, CD1, Hsp90, PI3K, and ERK/AKT as key molecular targets in cancer therapy

  • Eur J Med Chem. 2025 Oct 16;302(Pt 1):118263. doi: 10.1016/j.ejmech.2025.118263.
Eman S Ezz-ElDien 1,  Waleed A Badawi 2,  Mohamed A El-Atawy 3,  Mohammed Elhag 4,  Ezzat A Hamed 5,  Hoda A Ahmed 6,  Mariusz Jaremko 7,  Abdul-Hamid Emwas 8,  Tarek M Okda 9,  Mahmoud Z El-Readi 10,  Alaa Z Omar 11
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, University of Damanhour, 22511, Egypt. Electronic address: [email protected].
  • 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy, University of Damanhour, 22511, Egypt.
  • 3 Chemistry Department, Faculty of Science, Alexandria University, P.O. 426 Ibrahemia, Alexandria 21321, Egypt; Department of Chemistry, College of Science at Yanbu, Taibah University, Madinah, Saudi Arabia.
  • 4 Chemistry Department, Faculty of Science, Damanhour University, 22511 Damanhour, Egypt.
  • 5 Chemistry Department, Faculty of Science, Alexandria University, P.O. 426 Ibrahemia, Alexandria 21321, Egypt.
  • 6 Department of Chemistry, College of Science at Yanbu, Taibah University, Madinah, Saudi Arabia; Chemistry Department, Faculty of Science, Cairo University, 12613-Giza, Egypt.
  • 7 Biological and Environmental Sciences & Engineering Division (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
  • 8 Core Labs., King Abdullah University of Science and Technology, Thuwal, 23955-6900, Saudi Arabia.
  • 9 Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour, 22511, Egypt.
  • 10 Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Al Adeyah, Makkah, 24381, Saudi Arabia.
  • 11 Chemistry Department, Faculty of Science, Alexandria University, P.O. 426 Ibrahemia, Alexandria 21321, Egypt. Electronic address: [email protected].
PMID: 41124878 DOI: 10.1016/j.ejmech.2025.118263
Abstract

The development of novel triazino[5,6-b]indole-hydrazone conjugates and triazino[5,6-b]indole-fused heterocyclic hybrids was achieved through structural optimization. The growth-inhibitory activity of the newly synthesized derivatives was evaluated against MCF-7 and MDA-MB-231 human breast Cancer cell lines, relative to the reference drug doxorubicin, by MTT assay. According to the results obtained, the tested compounds showed significant antiproliferative activity versus MCF-7 cell line with IC50 values ranging from 1.06 + 0.05 μM to 66.58 + 0.05 μM and MDA-MB-231 cell line IC50 values ranging from 0.78 + 0.04 μM to 51.99 + 3.85 μM in comparison to doxorubicin (IC50 = 7.45 ± 0.38 μM and 2.08 ± 0.074 μM respectively), with compounds 4, 6, 7, 9, 11, and 12 exhibited valuable biological effect towards MCF-7 cells and derivatives 4, 6, 11, and 12 effective towards MDA-MB-231 cells. Derivatives demonstrated outstanding activities in the MTT assay were subjected to additional testing using multiple assay methods for interpretation of their promising activity. A set of promising candidates was assessed for EGFR inhibition, and their activity levels were compared to the reference drug, lapatinib. Compounds 4 and 11 showed significant inhibitory activity against the EGFR enzyme. IC50 values 0.199 + 0.0321 μM and 0.538 + 0.054 μM, respectively in comparison to lapatinib (IC50 = 0.238 + 0.023 μM). The active compounds were further evaluated for their inhibitory activity against CDK, HSP90, PI3K, and ERK/Akt signaling pathways, as well as for their potential to enhance caspase-9 expression levels. Additionally, cell cycle analysis and apoptotic induction by flow cytometry were performed. Eventually, predictive binding affinities of our molecules employing molecular docking analysis were utilized to investigate the possible interaction modes affirming a rationale for the observed activities. Meanwhile, docking studies indicated that derivatives 4, 6, and 11 displayed favorable binding interactions with the predicted in silico protein-ligand complexes, suggesting their potential as effective molecular Binders to the target proteins.

Keywords

Cancer drug design; Caspase-9 activation; EGFR enzyme inhibition; ERK/AKT signaling; Hsp90 inhibition; In silico docking study; Multi-target inhibitors in cancer therapy; PI3K-AKT signaling; Triazino[5,6-b]indole-fused heterocyclic hybrids; Triazino[5,6-b]indole-hydrazones.

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