1-Hydroxy-2(1 H)-pyridinone-Based Chelators with Potential Catechol O-Methyl Transferase Inhibition and Neurorescue Dual Action against Parkinson's Disease

Molecules. 2022 Apr 28;27(9):2816. doi: 10.3390/molecules27092816.

Abstract

Two analogues of tolcapone where the nitrocatechol group has been replaced by a 1-hydroxy-2(1H)-pyridinone have been designed and synthesised. These compounds are expected to have a dual mode of action both beneficial against Parkinson's disease: they are designed to be inhibitors of catechol O-methyl transferase, which contribute to the reduction of dopamine in the brain, and to protect neurons against oxidative damage. To assess whether these compounds are worthy of biological assessment to demonstrate these effects, measurement of their pKa and stability constants for Fe(III), in silico modelling of their potential to inhibit COMT and blood-brain barrier scoring were performed. These results demonstrate that the compounds may indeed have the desired properties, indicating they are indeed promising candidates for further evaluation.

Keywords: 1-hydroxy-2(1H)-pyridinone; Parkinson’s disease; catechol O-methyl transferase.

MeSH terms

  • Benzophenones
  • Catechol O-Methyltransferase
  • Catechol O-Methyltransferase Inhibitors* / pharmacology
  • Catechols / pharmacology
  • Chelating Agents
  • Enzyme Inhibitors / pharmacology
  • Ferric Compounds
  • Humans
  • Nitrophenols
  • Parkinson Disease* / drug therapy
  • Pyridones

Substances

  • Benzophenones
  • Catechol O-Methyltransferase Inhibitors
  • Catechols
  • Chelating Agents
  • Enzyme Inhibitors
  • Ferric Compounds
  • Nitrophenols
  • Pyridones
  • Catechol O-Methyltransferase
  • 1-hydroxy-2(1H)-pyridinone

Grants and funding

The synthesis was supported by internal funding at Northumbria University. VV, AD and RHS acknowledge support by the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale and the University of Strasbourg. We acknowledge particularly the support of the Strasbourg University High Performance Computing Center). This work was granted access to the HPC resources of TGCC under the allocation 2021-A0070705109 made by GENCI. J.B, C.-A.A. and V.H.-B. acknowledge support by the Centre National de la Recherche Scientifique and the University of Strasbourg.