Rhodanine and 2,4-dioxothiazolidine-based amides: synthesis and evaluation as dual-action cholinesterase inhibitors and antioxidants.
- 1Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University Akademika Heyrovského 1203 500 03 Hradec Králové Czech Republic [email protected].
- 2Institute of Environmental and Chemical Engineering, Faculty of Chemical Technology, University of Pardubice Studentská 573 532 10 Pardubice Czech Republic.
- 3Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice Studentská 573 532 10 Pardubice Czech Republic [email protected].
Abstract
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.
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BibTeX
@article{sikorova2026rhodanine,
title = {{Rhodanine and 2,4-dioxothiazolidine-based amides: synthesis and evaluation as dual-action cholinesterase inhibitors and antioxidants.}},
author = {Enikő Šikorová and Adéla Kyslíková and Markéta Švarcová and Jiří Palarčík and Šárka Štěpánková and Martin Krátký},
journal = {RSC medicinal chemistry},
year = {2026},
month = aug,
doi = {10.1039/d6md00502k},
url = {https://europepmc.org/article/MED/42835501},
note = {CC BY},
}
RIS
TY - JOUR
TI - Rhodanine and 2,4-dioxothiazolidine-based amides: synthesis and evaluation as dual-action cholinesterase inhibitors and antioxidants.
AU - Enikő Šikorová
AU - Adéla Kyslíková
AU - Markéta Švarcová
AU - Jiří Palarčík
AU - Šárka Štěpánková
AU - Martin Krátký
PY - 2026
DA - 2026/08/18
JO - RSC medicinal chemistry
DO - 10.1039/d6md00502k
UR - https://europepmc.org/article/MED/42835501
AB - 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.
SN - 2632-8682
ER -