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<p>1,2,4-Triazole-3-thiones bearing 2-amino-5-chloropyridine or 2-amino-3,5-dibromopyridine moieties were <i>S</i>-alkylated with substituted bromoacetamides to obtain target 1,2,4-triazole-3-thiols. Anticancer effects of the synthesized compounds were evaluated in vitro using cell monolayer (MTT and ‘wound healing’ assays) and 3D spheroid models against human lung adenocarcinoma (A549), triple-negative breast cancer (MDA-MB-231), and melanoma (IGR39) cell lines. In the initial screening, compounds incorporating the 3,5-dibromopyridyl fragment were generally the most cytotoxic and compound <b>34</b> (5-chloropyridinyl derivative) was the most potent, with EC<sub>50</sub> values below 5 µM for all tested cancer cell lines. Although cytotoxic, they did not markedly inhibit cancer cell migration. In 3D spheroid cultures, <b>34</b> significantly inhibited the growth of MDA-MB-231 and IGR39 spheroids, while compounds <b>24</b> (phenyl) and <b>26</b> (<i>p</i>-tolyl) decreased spheroid viability without altering their size. Compound <b>26</b> also demonstrated notable antimicrobial properties, exhibiting stronger antifungal activity against <i>C. tenuis</i> (7.8&#xa0;µg/mL) than nystatin (15.6&#xa0;µg/mL) and matching the antibacterial potency of vancomycin against <i>M. luteum</i> (7.8&#xa0;µg/mL). Molecular docking suggested possible MEK/BRAF-related interactions within the mitogen-activated protein kinase pathway. Compound <b>34</b> showed the most favourable predicted binding profile for MEK (-11.134&#xa0;kcal/mol) and BRAF (–10.336&#xa0;kcal/mol). However, these in silico findings require to be confirmed experimentally.</p>

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New hybrid pyridine–1,2,4-triazole scaffolds: synthesis, in vitro evaluation of anticancer and antimicrobial activity, and in silico insights

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月22日

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  • Aida Šermukšnytė,
  • Dainius Lukauskas,
  • Maryna Stasevych,
  • Viktor Zvarych,
  • Olena Komarovska-Porokhnyavets,
  • Kristina Kantminienė,
  • Ingrida Tumosienė,
  • Vilma Petrikaitė

摘要

1,2,4-Triazole-3-thiones bearing 2-amino-5-chloropyridine or 2-amino-3,5-dibromopyridine moieties were S-alkylated with substituted bromoacetamides to obtain target 1,2,4-triazole-3-thiols. Anticancer effects of the synthesized compounds were evaluated in vitro using cell monolayer (MTT and ‘wound healing’ assays) and 3D spheroid models against human lung adenocarcinoma (A549), triple-negative breast cancer (MDA-MB-231), and melanoma (IGR39) cell lines. In the initial screening, compounds incorporating the 3,5-dibromopyridyl fragment were generally the most cytotoxic and compound 34 (5-chloropyridinyl derivative) was the most potent, with EC50 values below 5 µM for all tested cancer cell lines. Although cytotoxic, they did not markedly inhibit cancer cell migration. In 3D spheroid cultures, 34 significantly inhibited the growth of MDA-MB-231 and IGR39 spheroids, while compounds 24 (phenyl) and 26 (p-tolyl) decreased spheroid viability without altering their size. Compound 26 also demonstrated notable antimicrobial properties, exhibiting stronger antifungal activity against C. tenuis (7.8 µg/mL) than nystatin (15.6 µg/mL) and matching the antibacterial potency of vancomycin against M. luteum (7.8 µg/mL). Molecular docking suggested possible MEK/BRAF-related interactions within the mitogen-activated protein kinase pathway. Compound 34 showed the most favourable predicted binding profile for MEK (-11.134 kcal/mol) and BRAF (–10.336 kcal/mol). However, these in silico findings require to be confirmed experimentally.