Rhodanine and 2,4-dioxothiazolidine-based amides: synthesis and evaluation as dual-action cholinesterase inhibitors and antioxidants.

This study presents the synthesis and biological evaluation of substituted 2-(2,4-dioxothiazolidin-3-yl)-N-phenylacetamides and their thioxo analogues as potential multitarget agents for neurodegenerative diseases. A diverse library of amides was designed to explore structure-activity relationships and synthesized using two complementary approaches: a carbodiimide-mediated coupling and a microwave-assisted procedure. The compounds were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition and antioxidant activity. Several derivatives displayed micromolar dual inhibition, with 2-(4-oxo-2-thioxothiazolidin-3-yl)-N-(3,4,5-trichlorophenyl)acetamide (compound 1h) emerging as the most effective BChE inhibitor (IC50 = 2.91 μM), which is also one of the most potent AChE inhibitors in this series. It acts as a specific, reversible, and competitive inhibitor of both BChE and AChE. Polyhalogenated analogues consistently outperformed their mono- and di-substituted counterparts, highlighting the critical role of lipophilic electron-withdrawing substituents. Within this series, rhodanines were generally preferred over thiazolidine-2,4-diones. Our results have demonstrated that rational modifications of the rhodanine and thiazolidine-2,4-dione cores support further investigation of selected derivatives as multitarget cholinesterase inhibitors with complementary antioxidant properties.