Evaluation of Selected Natural Compounds as Dual Inhibitors of Catechol-O-Methyltransferase and Monoamine Oxidase

Cent Nerv Syst Agents Med Chem. 2019;19(2):133-145. doi: 10.2174/1871524919666190619090852.


Background: The most effective symptomatic treatment of Parkinson's disease remains the metabolic precursor of dopamine, L-dopa. To enhance the efficacy of L-dopa, it is often combined with inhibitors of the enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) B, key metabolic enzymes of L-dopa and dopamine.

Objective: This study attempted to discover compounds that exhibit dual inhibition of COMT and MAO-B among a library of 40 structurally diverse natural compounds. Such dual acting inhibitors may be effective as adjuncts to L-dopa and offer enhanced value in the management of Parkinson's disease.

Methods: Selected natural compounds were evaluated as in vitro inhibitors of rat liver COMT and recombinant human MAO. Reversibility of MAO inhibition was investigated by dialysis.

Results: Among the natural compounds morin (IC50 = 1.32 µM), chlorogenic acid (IC50 = 6.17 µM), (+)-catechin (IC50 = 0.86 µM), alizarin (IC50 = 0.88 µM), fisetin (IC50 = 5.78 µM) and rutin (IC50 = 25.3 µM) exhibited COMT inhibition. Among these active COMT inhibitors only morin (IC50 = 16.2 µM), alizarin (IC50 = 8.16 µM) and fisetin (IC50 = 7.33 µM) were noteworthy MAO inhibitors, with specificity for MAO-A.

Conclusion: None of the natural products investigated here are dual COMT/MAO-B inhibitors. However, good potency COMT inhibitors have been identified, which may serve as leads for future development of COMT inhibitors.

Keywords: Catechol-O-methyltransferase; Parkinson's disease; inhibition; monoamine oxidase; multi-target-directed; natural compounds..

MeSH terms

  • Animals
  • Anthraquinones / chemistry
  • Anthraquinones / pharmacology
  • Antioxidants / chemistry
  • Antioxidants / pharmacology
  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • Catechol O-Methyltransferase / chemistry
  • Catechol O-Methyltransferase / pharmacology*
  • Catechol O-Methyltransferase Inhibitors / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • Flavonoids / chemistry
  • Flavonoids / pharmacology
  • Flavonols
  • Humans
  • Liver / drug effects
  • Liver / enzymology
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Rats
  • Rats, Sprague-Dawley


  • Anthraquinones
  • Antioxidants
  • Biological Products
  • Catechol O-Methyltransferase Inhibitors
  • Flavonoids
  • Flavonols
  • Monoamine Oxidase Inhibitors
  • alizarin
  • morin
  • Monoamine Oxidase
  • Catechol O-Methyltransferase
  • fisetin