Discovery of novel dual-active 3-(4-(dimethylamino)phenyl)-7-aminoalcoxy-coumarin as potent and selective acetylcholinesterase inhibitor and antioxidant

J Enzyme Inhib Med Chem. 2019 Dec;34(1):631-637. doi: 10.1080/14756366.2019.1571270.

Abstract

A series of 3-substituted-7-aminoalcoxy-coumarin was designed and evaluated as cholinesterase inhibitors and antioxidants. All compounds were effective in inhibiting AChE with potencies in the nanomolar range. The 3-(4-(dimethylamino)phenyl)-7-aminoethoxy-coumarin (6a) was considered a hit, showing good AChE inhibition potency (IC50 = 20 nM) and selectivity (IC50 BuChE/AChE = 354), quite similar to the reference drug donepezil (IC50 = 6 nM; IC50 BuChE/AChE = 365), also presenting antioxidant properties, low citotoxicity and good-predicted ADMET properties. The mode of action (mixed-type) and SAR analysis for this series of compounds were described by means of kinetic and molecular modeling evaluations.

Keywords: Coumarins; antioxidant; bioisosterism; cholinesterase.

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Animals
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Butyrylcholinesterase / metabolism*
  • Cell Survival / drug effects
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Coumarins / chemical synthesis
  • Coumarins / chemistry
  • Coumarins / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Electrophorus
  • Horses
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antioxidants
  • Cholinesterase Inhibitors
  • Coumarins
  • Acetylcholinesterase
  • Butyrylcholinesterase

Grants and funding

Fellowship and financial support for this study was provided by the CNPq (BR), FAPERJ (BR) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.