Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations

J Enzyme Inhib Med Chem. 2021 Dec;36(1):188-197. doi: 10.1080/14756366.2020.1842390.

Abstract

Nine compounds (MO1-MO9) containing the morpholine moiety were assessed for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Most of the compounds potently inhibited MAO-B; MO1 most potently inhibited with an IC50 value of 0.030 µM, followed by MO7 (0.25 µM). MO5 most potently inhibited AChE (IC50 = 6.1 µM), followed by MO9 (IC50 = 12.01 µM) and MO7 most potently inhibited MAO-A (IC50 = 7.1 µM). MO1 was a reversible mixed-type inhibitor of MAO-B (Ki = 0.018 µM); MO5 reversibly competitively inhibited AChE (Ki = 2.52 µM); and MO9 reversibly noncompetitively inhibited AChE (Ki = 7.04 µM). MO1, MO5 and MO9 crossed the blood-brain barrier, and were non-toxic to normal VERO cells. These results show that MO1 is a selective inhibitor of MAO-B and that MO5 is a dual-acting inhibitor of AChE and MAO-B, and that both should be considered candidates for the treatment of Alzheimer's disease.

Keywords: Docking analysis; Morpholine-containing chalcone; acetylcholinesterase; dual-acting inhibitor; monoamine oxidase.

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Animals
  • Chalcones / chemical synthesis
  • Chalcones / chemistry
  • Chalcones / pharmacology*
  • Chlorocebus aethiops
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • HeLa Cells
  • Humans
  • Hydrogen Peroxide / antagonists & inhibitors
  • Hydrogen Peroxide / pharmacology
  • Molecular Docking Simulation
  • Molecular Structure
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Morpholines / chemistry
  • Morpholines / pharmacology*
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship
  • Vero Cells

Substances

  • Chalcones
  • Cholinesterase Inhibitors
  • Monoamine Oxidase Inhibitors
  • Morpholines
  • Reactive Oxygen Species
  • morpholine
  • Hydrogen Peroxide
  • Monoamine Oxidase
  • Acetylcholinesterase

Grants and funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Republic of Korea government (Grant No. NRF-2019R1A2C1088967 to H. Kim).