Synthesis and Evaluation of 7-substituted Coumarin Derivatives as Multimodal Monoamine oxidase-B and Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease

Eur J Med Chem. 2017 Jan 5;125:853-864. doi: 10.1016/j.ejmech.2016.09.041. Epub 2016 Sep 15.

Abstract

A series of 7-substituted coumarin derivatives were designed and synthesised to display ChE and MAO-B inhibitory activity. The compounds consisted out of a coumarin structure (MAO-B inhibitor) and benzyl-, piperidine-, N-benzylpiperidine- or p-bromo-N-benzylpiperizine moiety, resembling the N-benzylpiperidine function of donepezil (ChE inhibitor), connected via an alkyl ether linkage at the 7 position. The biological assay results indicated that all the compounds (1-25) displayed selective inhibition to hMAO-B over hMAO-A, with the benzyloxy series (1-8, 10-13) showing nano-molar hMAO-B inhibition (IC50: 0.5-73 nM). Limited ChE inhibitory activity was however observed for the benzyloxy series with the exception of 2 and especially 3 showing selective BuChE inhibition. From this series 3 showed the best multifunctional activity (eqBuChE IC50 = 0.96 μM, hMAO-A IC50 = 2.13 μM, hMAO-B IC50 = 0.0021 μM). Within the N-benzylpiperidine (16-19) and p-bromo-N-benzylpiperizine (21-24) series the compounds in general showed moderate ChE and MAO-B inhibitory activity. Of these compounds 19 was the most potent multifunctional agent showing good eeAChE and eqBuChE inhibition (IC50 = 9.10 μM and 5.90 μM, respectively), and relatively potent and selective hMAO-B inhibition (IC50 = 0.30 μM, SI = >33). Molecular modeling revealed that 19 was able to bind simultaneously to the CAS, mid-gorge and PAS sites of AChE and BuChE suggesting that it will be able to inhibit AChE induced Aβ aggregation. From this study, compounds that 3 and 19 can be considered as promising multifunctional lead compounds.

Keywords: Alzheimer's disease; Cholinesterase; Coumarin; Donepezil; MAO-B; Molecular modeling.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / drug effects
  • Animals
  • Benzyl Compounds / chemistry
  • Binding Sites
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / pharmacology
  • Coumarins / chemical synthesis
  • Coumarins / chemistry
  • Coumarins / pharmacology
  • Coumarins / therapeutic use*
  • Dose-Response Relationship, Drug
  • Humans
  • Monoamine Oxidase / drug effects
  • Monoamine Oxidase Inhibitors / chemical synthesis*
  • Monoamine Oxidase Inhibitors / pharmacology
  • Peptide Fragments / drug effects
  • Piperidines / chemistry
  • Protein Aggregation, Pathological / drug therapy
  • Protein Aggregation, Pathological / prevention & control
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Benzyl Compounds
  • Cholinesterase Inhibitors
  • Coumarins
  • Monoamine Oxidase Inhibitors
  • Peptide Fragments
  • Piperidines
  • amyloid beta-protein (1-40)
  • Monoamine Oxidase