N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer's agents

Bioorg Med Chem. 2017 Jan 15;25(2):633-645. doi: 10.1016/j.bmc.2016.11.032. Epub 2016 Nov 19.

Abstract

In the brains of patients with Alzheimer's disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer's disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid β-peptide species.

Keywords: Alzheimer’s disease; Butyrylcholinesterase inhibitors; MAO-B inhibitors; Multitarget-directed ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / pharmacology
  • Butyrylcholinesterase / metabolism
  • Cell Death / drug effects
  • Cell Line
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Naphthalenes / chemical synthesis
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology*
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Monoamine Oxidase Inhibitors
  • Naphthalenes
  • Peptide Fragments
  • Piperidines
  • Sulfonamides
  • amyloid beta-protein (1-42)
  • naphthalene-2-carboxamide
  • naphthalenesulfonamide
  • Monoamine Oxidase
  • Butyrylcholinesterase