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  3. Design, synthesis, and bioactivity assessment of highly potent isatin-based small-molecules bearing 3-hydrazineyl-6-aryl-1,2,4-triazine moieties as potential c-MET targeting anticancer agents

Design, synthesis, and bioactivity assessment of highly potent isatin-based small-molecules bearing 3-hydrazineyl-6-aryl-1,2,4-triazine moieties as potential c-MET targeting anticancer agents

  • Bioorg Chem. 2026 Sep 5:179:109990. doi: 10.1016/j.bioorg.2026.109990.
Zahra Zakeri Khatir 1,  Alireza Alipour 2,  Motahareh Mortazavi 2,  Marjan Tavakkoli 2,  Hamid Irannejad 3,  Alireza Foroumadi 4,  Omidreza Firuzi 5,  Mehdi Valipour 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
  • 2 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 3 Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran; Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
  • 4 Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 5 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: [email protected].
  • 6 Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran; Microbial Biotechnology Research Center, Iran University of Medical Sciences, Tehran, Iran. Electronic address: [email protected].
PMID: 42202586 DOI: 10.1016/j.bioorg.2026.109990
Abstract

The present study reports the design, synthesis, and biological evaluation of 25 novel isatin-based small molecules bearing 3-hydrazineyl-6-aryl-1,2,4-triazine motifs, generated through anticancer-scaffold hybridization and structure-guided modification of a c-MET inhibitor hit compound 3a. The antiproliferative properties of the target compounds (E1-25) were assessed against three Cancer cell lines comprising EBC-1 (c-MET-amplified NSCLC), SUIT-2 (pancreatic ductal adenocarcinoma), MDA-MB-231 (triple-negative breast adenocarcinoma) as well as non-malignant fibroblast cells NIH-3T3. Several derivatives exhibited pronounced antiproliferative activity, with IC50 values ranging from the sub-micromolar level to as low as 11 nM, while showing reduced effects on non-cancerous cells. Further analysis of the effects of highly active compounds E20, E21, E23 and E24 on cell cycle and Cancer cell growth in 3-dimensional spheroid cultures showed that these derivatives induce Apoptosis and significantly inhibit the growth of Cancer cells in the 3D environment. Molecular docking simulations revealed that the evaluated compounds adopt a linear binding mode within the c-MET active site, in contrast to the U-shaped binding pattern characteristic of class Ib c-MET inhibitors. Overall, the newly developed isatin-1,2,4-triazine hybrids exhibited potent Anticancer activity, highlighting their potential as promising lead structures for future Anticancer drug development.

Keywords

3D spheroid culture; Anticancer activity; Apoptosis induction; Isatin–triazine hybrids; c-MET inhibition.

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