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  3. A series of 4-thiomorpholinophenyl-thiosemicarbazones as cholinesterase inhibitors with anti-neuroblastoma effects

A series of 4-thiomorpholinophenyl-thiosemicarbazones as cholinesterase inhibitors with anti-neuroblastoma effects

  • Bioorg Chem. 2026 Jan:168:109364. doi: 10.1016/j.bioorg.2025.109364.
Hina Aftab 1,  Furkan Çakır 2,  Gurbet Çelik Turgut 3,  Nastaran Sadeghian 4,  Rima D Alharthy 5,  Parham Taslimi 4,  Alaattin Şen 6,  Magdi E A Zaki 7,  Sobhi M Gomha 8,  Javid Hussain 9,  Zahid Shafiq 1,  Halil Şenol 10
Affiliations

Affiliations

  • 1 Institute of Chemical Sciences, Bahauddin Zakariya University, 60800 Multan, Pakistan.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093 Fatih, İstanbul, Turkey.
  • 3 Department of Organic Agriculture Management, Pamukkale University, Denizli, Turkey.
  • 4 Department of Biotechnology, Faculty of Science, Bartin University, 74110 Bartin, Turkey.
  • 5 Department of Chemistry, Science & Arts College, Rabigh Branch, King Abdulaziz University, Rabigh 21911, Saudi Arabia.
  • 6 Department of Biology, Faculty of Science, Pamukkale University, 20070 Denizli, Turkey.
  • 7 Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia.
  • 8 Chemistry Department, Faculty of Science, Islamic University of Madinah, Madinah, 42351, Saudi Arabia. Electronic address: [email protected].
  • 9 Department of Biological Sciences and Chemistry, College of Arts and Sciences, University of Nizwa, Nizwa 616, Oman.
  • 10 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093 Fatih, İstanbul, Turkey. Electronic address: [email protected].
PMID: 41389605 DOI: 10.1016/j.bioorg.2025.109364
Abstract

A novel series of 4-thiomorpholinophenyl-thiosemicarbazones (3a-p) was synthesized and characterized by spectroscopic techniques. The compounds were evaluated for inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), key Enzymes associated with neurodegenerative disorders. All derivatives exhibited potent inhibition, with nanomolar IC50 values ranging from 11.36 to 34.17 nM (AChE) and 33.42 to 79.77 nM (BChE), comparable to standard drugs galantamine and tacrine. Compound 3l, bearing a benzyl group, showed the strongest dual inhibition (AChE IC50 = 11.36 nM) and compound 3n exhibited the highest BChE selectivity (Ki = 33.42 ± 2.38 nM). Anticancer activity was assessed against SH-SY5Y neuroblastoma and HEK-293 cell lines. Compound 3l demonstrated selective cytotoxicity against SH-SY5Y cells (IC50 = 21.11 ± 0.42 μM) with minimal toxicity toward HEK-293 cells (IC50 = 69.49 ± 4.27 μM, SI = 3.3), comparable to sorafenib. Molecular docking showed multiple π-π and hydrogen-bond interactions of 3l with AChE (Tyr-72, Tyr-337, Trp-286, His-447, Phe-295, Tyr-124) and 3n with BChE (Trp-231, Phe-329, Pro-285, Gln-119, Thr-120). MM-GBSA calculations indicated favorable binding energies (-70.74 and - 67.09 kcal/mol) driven by van der Waals and lipophilic forces. Molecular dynamics simulations confirmed stable complexes with RMSD ∼1.4 Å for ligands, ∼2.0 Å for proteins, persistent interactions, and reduced flexibility (RMSF ∼1.5 Å). ADME analysis suggested acceptable drug-like properties. These results highlight 3l and 3n as promising scaffolds for dual cholinesterase inhibition and selective Anticancer activity.

Keywords

Cholinesterase inhibitors; Cytotoxicity; Molecular docking; Neuroblastoma; Thiosemicarbazones.

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