Design, synthesis and biological evaluation of tricyclic pyrazolo[1,5-c][1,3]benzoxazin-5(5H)-one scaffolds as selective BuChE inhibitors

J Enzyme Inhib Med Chem. 2018 Dec;33(1):1506-1515. doi: 10.1080/14756366.2018.1488696.

Abstract

Based on the structural analysis of tricyclic scaffolds as butyrylcholinesterase (BuChE) inhibitors, a series of pyrazolo[1,5-c][1,3]benzoxazin-5(5H)-one derivatives were designed, synthesized and evaluated for their acetylcholinesterase (AChE) and BuChE inhibitory activity. Compounds with 5-carbonyl and 7- or/and 9-halogen substitutions showed potential BuChE inhibitory activity, among which compounds 6a, 6c and 6g showed the best BuChE inhibition (IC50 = 1.06, 1.63 and 1.63 µM, respectively). The structure-activity relationship showed that the 5-carbonyl and halogen substituents significantly influenced BuChE activity. Compounds 6a and 6g were found nontoxic, lipophilic and exhibited remarkable neuroprotective activity and mixed-type inhibition against BuChE (Ki = 7.46 and 3.09 µM, respectively). Docking studies revealed that compound 6a can be accommodated into BuChE via five hydrogen bonds, one Pi-Sigma interaction and three Pi-Alkyl interactions.

Keywords: Alzheimer’s disease; acetylcholinesterase; butyrylcholinesterase; pyrazolo[1,5-c][1,3]benzoxazin-5(5H)-one; tricyclic scaffold.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Animals
  • Benzoxazines / chemical synthesis
  • Benzoxazines / chemistry
  • Benzoxazines / pharmacology*
  • Butyrylcholinesterase / metabolism*
  • Cell Survival / drug effects
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / isolation & purification
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Hydrogen Peroxide
  • Molecular Docking Simulation
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • PC12 Cells
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Benzoxazines
  • Cholinesterase Inhibitors
  • Neuroprotective Agents
  • Pyrazoles
  • pyrazolo(1,5-c)(1,3)benzoxazin-5(5H)-one
  • Hydrogen Peroxide
  • Acetylcholinesterase
  • Butyrylcholinesterase

Grants and funding

This study was financial supported by Anhui University Natural Science Research Project [KJ2016A339, 12925KJ2018B12].