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

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.