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  3. Synthesis, characterization, In vitro and In silico investigations of novel 1,2,3-triazole substituted salicylic acid phenolic hydrazones hybrids targeting TGF-β2 expression in colorectal carcinoma

Synthesis, characterization, In vitro and In silico investigations of novel 1,2,3-triazole substituted salicylic acid phenolic hydrazones hybrids targeting TGF-β2 expression in colorectal carcinoma

  • Eur J Med Chem. 2025 Oct 15:296:117915. doi: 10.1016/j.ejmech.2025.117915.
Ebru Nur Ay 1,  Furkan Çakır 2,  Sarehan Akyüz 3,  Namık Kılınç 4,  Feyzi Sinan Tokalı 5,  Halil Şenol 6
Affiliations

Affiliations

  • 1 Istinye University, Faculty of Engineering and Natural Sciences, Department of Molecular Biology and Genetics, Sarıyer, 34396, Istanbul, Türkiye.
  • 2 Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Fatih, 34093, Istanbul, Türkiye. Electronic address: furkan.cakir@bezmialem.edu.tr.
  • 3 Yildiz Technical University, Faculty of Arts and Sciences, Department of Molecular Biology and Genetics, Esenler, 34220, Istanbul, Türkiye.
  • 4 Igdir University, Vocational School of Health Services, Department of Medical Services and Techniques, 76100, Igdir, Türkiye.
  • 5 Kafkas University, Kars Vocational School, Department of Material and Material Processing Technologies, 36100, Kars, Türkiye. Electronic address: feyzitokali@gmail.com.
  • 6 Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Fatih, 34093, Istanbul, Türkiye. Electronic address: hsenol@bezmialem.edu.tr.
PMID: 40582189 DOI: 10.1016/j.ejmech.2025.117915
Abstract

In this study, sixteen novel 1,2,3-triazole-substituted salicylic acid phenolic-hydrazone hybrids were synthesized and characterized using NMR, IR, HRMS, and HPLC techniques. The compounds were evaluated for their Anticancer potential against HCT-116, Caco-2 and HT-29 colorectal carcinoma cells and normal BEAS-2B epithelial cells. Among them, compound 10k exhibited potent antiproliferative effects on HCT-116, Caco-2 and HT-29 with IC50 values of 6.84, 10.21, and 9.47 μM, respectively, which were significantly lower than the reference drug sorafenib (IC50 = 18.25, 13.80 and 7.89 μM) for HTC-116 and Caco-2. Biological assays demonstrated that 10k effectively downregulated TGF-β2 receptor and cytokine expression in a dose-dependent manner, indicating its role in modulating the TGF-β signaling pathway. Apoptosis analysis suggested that cytotoxicity was mediated via non-apoptotic mechanisms. Molecular docking studies revealed a strong binding affinity for compound 10k with a docking score of -11.28 kcal/mol. Furthermore, 250 ns molecular dynamics simulations confirmed the stability of the ligand-receptor complex with an RMSD value stabilized around 1.15 Å. Key interactions included hydrogen bonds with Asn-332, π-π stacking, and halogen bonding. ADMET predictions confirmed favorable drug-like properties with good permeability and safety profiles. These findings position compound 10k as a promising lead candidate for colorectal Cancer therapy, targeting TGF-β2 mediated pathways with high efficacy and selectivity.

Keywords

1,2,3-Triazoles; Colorectal cancer; Hydrazone; Molecular docking; TGF-β2.

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