Scouting around 1,2,3,4-Tetrahydrochromeno[3,2-c]pyridin-10-ones for Single- and Multitarget Ligands Directed towards Relevant Alzheimer's Targets

ChemMedChem. 2020 Oct 19;15(20):1947-1955. doi: 10.1002/cmdc.202000468. Epub 2020 Sep 4.

Abstract

A number of 1,2,3,4-tetrahydrochromeno[3,2-c]pyridin-10-one derivatives have been synthesized and screened against different targets involved in the onset and progression of Alzheimer's disease (AD), such as acetyl- and butyrylcholinesterase (AChE and BChE), monoamine oxidases A and B (MAO A and B), aggregation of β-amyloid (Aβ) and reactive oxygen species (ROS) production. Derivatives 1 c, 3 b, 4 and 5 a showed multifaceted profiles of promising anti-AD features and returned well-balanced multitargeting inhibitory activities. Moreover, compound 1 f, a potent and selective human MAO B inhibitor (IC50 =0.89 μM), proved to be a safe neuroprotectant in a human neuroblastoma cell line (SH-SY5Y) by improving viability impaired by Aβ1-42 and pro-oxidant insult. Furthermore, structure-activity relationships (SARs) and docking models were derived in order to assist further hit-to-lead optimization stage.

Keywords: Alzheimer's disease; inhibitors; medicinal chemistry; multitarget-directed ligands; tetrahydrochromenopyridinone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / enzymology*
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Butyrylcholinesterase / metabolism
  • Cell Line, Tumor
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology*
  • Chromones / chemical synthesis
  • Chromones / metabolism
  • Chromones / pharmacology*
  • Horses
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Molecular Structure
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / metabolism
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology*
  • Peptide Fragments / pharmacology
  • Protein Binding
  • Pyridines / chemical synthesis
  • Pyridines / metabolism
  • Pyridines / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Chromones
  • Ligands
  • Monoamine Oxidase Inhibitors
  • Neuroprotective Agents
  • Peptide Fragments
  • Pyridines
  • Reactive Oxygen Species
  • amyloid beta-protein (1-42)
  • Monoamine Oxidase
  • Acetylcholinesterase
  • Butyrylcholinesterase