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New 3-amino-2-thioxothiazolidin-4-one-based inhibitors of acetyl- and butyryl-cholinesterase: synthesis and activity

    Martin Krátký

    *Author for correspondence:

    E-mail Address: martin.kratky@faf.cuni.cz

    Department of Organic & Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 03, Hradec Králové, Czech Republic

    ,
    Karolína Nováčková

    Department of Organic & Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 03, Hradec Králové, Czech Republic

    ,
    Katarína Svrčková

    Department of Biological & Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10, Pardubice, Czech Republic

    ,
    Markéta Švarcová

    Department of Organic & Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 03, Hradec Králové, Czech Republic

    Department of Chemistry, Faculty of Science, J. E. Purkinje University, Pasteurova 3632/15, 400 96, Ústí nad Labem, Czech Republic

    &
    Šárka Štěpánková

    Department of Biological & Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10, Pardubice, Czech Republic

    Published Online:https://doi.org/10.4155/fmc-2023-0268

    Aim: 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. Materials & methods: 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). Results & conclusion: The derivatives were obtained with yields of 52–94%. They showed dual inhibition with IC50 values from 13.15 μM; 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.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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