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<p>This study focuses on the synthesis, characterization, and evaluation of 13 novel hydroxypiperidine-substituted thiosemicarbazone derivatives <b>(5a-m)</b> for their anticancer activity and enzyme inhibition properties. The compounds were tested for cytotoxicity against A549 lung cancer and BEAS2B non-cancerous cells, with compound <b>5f</b> (<i>R</i> = 2,3-dichlorophenyl) demonstrating the lowest IC<sub>50</sub> value of 0.58 µM and high selectivity (SI = 28.9) for A549 cells. Enzyme inhibition assays revealed that <b>5f</b> exhibited potent inhibition against human carbonic anhydrase isoforms hCA I and hCA II, with the lowest IC<sub>50</sub> and <i>K</i><sub>i</sub> values. Molecular docking studies showed that <b>5f</b> had the best binding affinity across multiple targets, including hCA isoforms, VEGFR-2, and BRAF, further supported by favorable MM-GBSA binding free energy calculations. Additionally, molecular dynamics simulations confirmed the stability and key interactions in the <b>5f</b>-protein complexes. ADMET predictions indicated that <b>5f</b> has favorable drug-likeness and low organ toxicity risk, showing good permeability and oral absorption potential. These findings suggest that <b>5f</b> is a promising lead compound for further development as a multi-target therapeutic agent for lung cancer.</p>

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Synthesis, antiproliferative activity targeting lung cancer and in silico studies of hydroxypiperidine substituted thiosemicarbazones

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Hina Aftab,
  • Muhammad Islam,
  • Halil Şenol,
  • Zahra Batool,
  • Şeyma Ateşoğlu,
  • Furkan Çakır,
  • Fahri Akbaş,
  • Parham Taslimi,
  • Abdullah K. Alanazi,
  • Faiqa Noreen,
  • Zahid Shafiq

摘要

This study focuses on the synthesis, characterization, and evaluation of 13 novel hydroxypiperidine-substituted thiosemicarbazone derivatives (5a-m) for their anticancer activity and enzyme inhibition properties. The compounds were tested for cytotoxicity against A549 lung cancer and BEAS2B non-cancerous cells, with compound 5f (R = 2,3-dichlorophenyl) demonstrating the lowest IC50 value of 0.58 µM and high selectivity (SI = 28.9) for A549 cells. Enzyme inhibition assays revealed that 5f exhibited potent inhibition against human carbonic anhydrase isoforms hCA I and hCA II, with the lowest IC50 and Ki values. Molecular docking studies showed that 5f had the best binding affinity across multiple targets, including hCA isoforms, VEGFR-2, and BRAF, further supported by favorable MM-GBSA binding free energy calculations. Additionally, molecular dynamics simulations confirmed the stability and key interactions in the 5f-protein complexes. ADMET predictions indicated that 5f has favorable drug-likeness and low organ toxicity risk, showing good permeability and oral absorption potential. These findings suggest that 5f is a promising lead compound for further development as a multi-target therapeutic agent for lung cancer.