Selective butyrylcholinesterase inhibition by isatin dimers and 3-indolyl-3-hydroxy-2-oxindole dimers

Polymethylene-linked isatin dimers 1a-g and 3-indolyl-3-hydroxy-2-oxindole dimers 2a-g were synthesized and are reported here as selective butyrylcholinesterase (BChE) inhibitors. The best compound from each series, 1f and 2d, showed IC50 values of 3.20 µM and 4.49 µM, respectively. Both compounds showed > 11-fold selectivity towards BChE, and mixed-type inhibition by Lineweaver-Burk analysis. These two inhibitors shared π-π stacking interactions with Trp82 and H-bonding to Gly116 and Ser198, the catalytic Ser of the enzyme triad, within the BChE active site as predicted by molecular docking. Compound 1d was also shown to be good inhibitor with an IC50 of 7.56 µM, and it shares the same pentamethylene linker as 2d. Inhibitors 1d, 1f, and 2d were predicted to have moderate, low, and moderate blood–brain barrier (BBB) permeability, respectively, making them, overall, promising lead compounds for further exploration of selective BChE inhibitors.

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Work Title Selective butyrylcholinesterase inhibition by isatin dimers and 3-indolyl-3-hydroxy-2-oxindole dimers
Access
Open Access
Creators
  1. Kristin M. Reiland
  2. Todd J. Eckroat
Keyword
  1. Butyrylcholinesterase
  2. Acetylcholinesterase
  3. Isatin
  4. Indole
  5. Alzheimer’s disease
License CC BY-NC-ND 4.0 (Attribution-NonCommercial-NoDerivatives)
Work Type Article
Publisher
  1. Bioorganic and Medicinal Chemistry Letters
Publication Date December 1, 2022
Publisher Identifier (DOI)
  1. https://doi.org/10.1016/j.bmcl.2022.129037
Deposited February 27, 2023

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Version 1
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  • Created
  • Added Eckroat_Manuscript_revised.docx
  • Added Eckroat_Supplementary_revised.docx
  • Added Creator Kristin M. Reiland
  • Added Creator Todd J. Eckroat
  • Published
  • Updated Keyword Show Changes
    Keyword
    • Butyrylcholinesterase, Acetylcholinesterase, Isatin, Indole, Alzheimer’s disease
  • Updated