Novel thiazolidinedione hybrids as cholinesterase inhibitors and targeting neuroblastoma: design, synthesis, in vitro and in silico biological evaluations

Turgut G. Ç., ÇAKIR F., ŞEN A., Tokalı F. S., ŞENOL H.

Bioorganic Chemistry, vol.164, 2025 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 164
  • Publication Date: 2025
  • Doi Number: 10.1016/j.bioorg.2025.108869
  • Journal Name: Bioorganic Chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, Veterinary Science Database
  • Keywords: AChE, BChE, Cholinesterase inhibition, Neurodegenerative disorders, SH-SY5Y
  • Abdullah Gül University Affiliated: Yes

Abstract

In this study, a novel series of eleven 3,5-disubstituted thiazolidine-2,4-dione (TZD) derivatives were rationally designed and synthesized, incorporating tertiary amine moieties to enhance cholinesterase binding. The acetamide-linked TZD scaffold was selected for its potential dual functionality: cholinesterase inhibition and cytotoxicity against neuronal cells. All compounds were evaluated for their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), alongside cytotoxicity assays on SH-SY5Y cancerous neuroblastoma and HEK-293 healthy cells. Compound 7 showed the strongest AChE inhibition (IC50 = 17.87 μM and Ki = 19.48 μM), while compound 8 exhibited the most potent BChE inhibition (IC50 = 34.98 μM and Ki = 26.15 μM), showing better activity than reference inhibitors (IC50Tacrine = 53.81 μM and IC50Galantamine = 43.21 μM). Several compounds, particularly 3, showed the greatest selectivity toward SH-SY5Y cells (SI = 4.9), followed by 8 (SI = 4.4) and 2 (SI = 3.4). All three compounds matched or exceeded Sorafenib's selectivity (SI = 3.8), despite Sorafenib exhibiting stronger cytotoxicity. Molecular docking and dynamics simulations supported the observed in vitro results, revealing strong and stable binding interactions of compound 7 with AChE and compound 8 with BChE. The correlation between BChE inhibition and cytotoxicity suggests potential multifunctionality. The findings highlight compounds 7 and 8 as promising lead candidates for neurodegenerative disorders and support their eligibility for further in-depth pharmacological investigations.