Cholinestrase inhibitory effects of geranylated flavonoids from Paulownia tomentosa fruits

Bioorg Med Chem. 2012 Apr 15;20(8):2595-602. doi: 10.1016/j.bmc.2012.02.044. Epub 2012 Mar 8.

Abstract

Alzheimer's disease is rapidly becoming one of the most prevalent human diseases. Inhibition of human acetylcholinestrase (hAChE) and butyrylcholinestrase (BChE) has been linked to amelioration of Alzheimer's symptoms and research into inhibitors is of critical importance. Purification of the methanol extract of Paulownia tomentosa fruits yielded potent hAChE and BChE inhibitory flavonoids (1-9). A comparative activity screen indicated that a geranyl group at C6 is crucial for both hAChE and BChE. For example, diplacone (8) showed 250-fold higher efficacy than its parent eriodictyol (12). IC(50)s of diplacone (8) were 7.2 μM for hAChE and 1.4 μM for BChE. Similar trends were also observed for 4'-O-methyldiplacone (4) (vs its parent, hesperetin 10) and mimulone (7) (vs its parent, naringenin 11). Representative inhibitors (1-8) showed mixed inhibition kinetics as well as time-dependent, reversible inhibition toward hAChE. The binding affinities of these compounds to hAChE were investigated by monitoring quenching of inherent enzyme fluorescence. The affinity constants (K(SA)) increased in proportion to inhibitory potencies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cholinesterases / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / isolation & purification
  • Enzyme Inhibitors / pharmacology*
  • Flavonoids / chemistry
  • Flavonoids / isolation & purification
  • Flavonoids / pharmacology*
  • Fruit / chemistry*
  • Humans
  • Molecular Structure
  • Plant Extracts / chemistry
  • Plant Extracts / isolation & purification
  • Plant Extracts / pharmacology*
  • Scrophulariaceae / chemistry*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Flavonoids
  • Plant Extracts
  • Cholinesterases