Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies

Int J Mol Sci. 2021 Aug 2;22(15):8308. doi: 10.3390/ijms22158308.

Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1-20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC50 values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC50 value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.

Keywords: Alzheimer’s disease; amaryllidaceae alkaloid; butyrylcholinesterase; docking studies; norbelladine-type.

Publication types

  • Evaluation Study

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Amaryllidaceae Alkaloids / chemistry*
  • Butyrylcholinesterase / chemistry*
  • Cell Proliferation
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Computer Simulation
  • Humans
  • Molecular Docking Simulation*
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / pathology
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Tyramine / analogs & derivatives*
  • Tyramine / chemistry

Substances

  • Amaryllidaceae Alkaloids
  • Cholinesterase Inhibitors
  • norbelladine
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Tyramine