New 3-amino-2-thioxothiazolidin-4-one-based inhibitors of acetyl- and butyryl-cholinesterase: synthesis and activity.
Martin Kr��tk��, Karol��na Nov����kov��, Katar��na Svr��kov��, Mark��ta ��varcov��, ����rka ��t��p��nkov��
Author Information
Martin Kr��tk��: Department of Organic & Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kr��lov��, Charles University, Akademika Heyrovsk��ho 1203, 500 03, Hradec Kr��lov��, Czech Republic. ORCID
Karol��na Nov����kov��: Department of Organic & Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kr��lov��, Charles University, Akademika Heyrovsk��ho 1203, 500 03, Hradec Kr��lov��, Czech Republic.
Katar��na Svr��kov��: Department of Biological & Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentsk�� 573, 532 10, Pardubice, Czech Republic.
Mark��ta ��varcov��: Department of Organic & Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kr��lov��, Charles University, Akademika Heyrovsk��ho 1203, 500 03, Hradec Kr��lov��, Czech Republic.
����rka ��t��p��nkov��: Department of Biological & Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentsk�� 573, 532 10, Pardubice, Czech Republic. ORCID
2-Thioxothiazolidin-4-one represents a versatile scaffold in drug development. The authors used it to prepare new potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors that can be utilized, e.g., to treat Alzheimer's disease. 3-Amino-2-thioxothiazolidin-4-one was modified at the amino group or active methylene, using substituted benzaldehydes. The derivatives were evaluated for inhibition of AChE and BChE (Ellman's method). The derivatives were obtained with yields of 52-94%. They showed dual inhibition with IC values from 13.15 ��M; many compounds were superior to rivastigmine. The structure-activity relationship favors nitrobenzylidene and 3,5-dihalogenosalicylidene scaffolds. AChE was inhibited noncompetitively, whereas BChE was inhibited with a mixed type of inhibition. Molecular docking provided insights into molecular interactions. Each enzyme is inhibited by a different binding mode.
