Design, synthesis and biological evaluation of new coumarin-dithiocarbamate hybrids as multifunctional agents for the treatment of Alzheimer's disease

Eur J Med Chem. 2018 Feb 25:146:287-298. doi: 10.1016/j.ejmech.2018.01.055. Epub 2018 Feb 4.

Abstract

A series of new coumarin-dithiocarbamate hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's Disease (AD). The biological assays indicated that most of them showed potent inhibition and excellent selectivity towards acetylcholinesterase (AChE), and could inhibit self-induced β-amyloid (Aβ) aggregation. Especially, compound 4n presented the highest ability to inhibit AChE (IC50, 0.027 μM for hAChE) and good inhibition of Aβ aggregation (40.19% at 25 μM). Kinetic and molecular modeling studies revealed that 4n was a mixed-type inhibitor, which could interact simultaneously with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. In addition, it also possessed specific metal-chelating ability, good BBB permeability and low toxicity on SH-SY5Y neuroblastoma cells. Moreover, compound 4n did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and could reverse the cognitive dysfunction of scopolamine-induced AD mice. As far as we know, 4n was the first reported dithiocarbamate derivative with multifunctional activity. Its excellent profiles in vitro and effectivity in vivo highlight this structurally distinct compound as a potential lead compound in the research of innovative multifunctional drugs for AD.

Keywords: Alzheimer's disease; Cholinesterase; Coumarin; Dithiocarbamate; Multifunctional agents.

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Blood-Brain Barrier / drug effects
  • Cell Line, Tumor
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Coumarins / chemistry
  • Coumarins / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Kinetics
  • Male
  • Mice
  • Mice, Inbred Strains
  • Models, Molecular
  • Molecular Structure
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Protein Aggregates / drug effects
  • Range of Motion, Articular / drug effects
  • Structure-Activity Relationship
  • Thiocarbamates / chemistry
  • Thiocarbamates / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Coumarins
  • Peptide Fragments
  • Protein Aggregates
  • Thiocarbamates
  • amyloid beta-protein (1-42)
  • coumarin
  • Acetylcholinesterase