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

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

  • Sci Rep. 2025 Sep 29;15(1):33402. doi: 10.1038/s41598-025-18735-y.
Hina Aftab 1,  Muhammad Islam 2 3,  Halil Şenol 4,  Zahra Batool 1,  Şeyma Ateşoğlu 5 6,  Furkan Çakır 4,  Fahri Akbaş 6,  Parham Taslimi 7,  Abdullah K Alanazi 8,  Faiqa Noreen 1,  Zahid Shafiq 9
Affiliations

Affiliations

  • 1 Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan.
  • 2 Department of Basic Sciences and Humanities (Chemistry), Muhammad Nawaz Sharif University of Engineering and Technology (MNSUET), Multan, 60000, Pakistan.
  • 3 School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Tianjin, 300072, China.
  • 4 Department of Pharmaceutical Chemistry, Bezmialem Vakif University, Faculty of Pharmacy, Fatih, 34093, Istanbul, Turkey.
  • 5 Institute of Health Sciences, Department of Biotechnology, Bezmialem Vakif University, Fatih, 34093, Istanbul, Turkey.
  • 6 Department of Medical Biology, Bezmialem Vakif University, Faculty of Medicine, Fatih, 34093, Istanbul, Turkey.
  • 7 Department of Biotechnology, Faculty of Science, Bartin University, Bartin, 74110, Turkey. parham_taslimi_un@yahoo.com.
  • 8 Department of Chemistry, College of Science, Taif University, Taif, Saudi Arabia.
  • 9 Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan. zahidshafiq@bzu.edu.pk.
PMID: 41023226 DOI: 10.1038/s41598-025-18735-y
Abstract

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.

Keywords

Carbonic anhydrase; Lung cancer; Molecular docking; Molecular dynamics; Thiosemicarbazone.

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