Pyridazinones containing dithiocarbamoyl moieties as a new class of selective MAO-B inhibitors

Bioorg Chem. 2021 Oct:115:105203. doi: 10.1016/j.bioorg.2021.105203. Epub 2021 Jul 23.

Abstract

A novel class of potential MAO-B inhibitors was designed and synthesized in good yield by combining the pyridazinone moiety with the dithiocarbamate framework, two relevant pharmacophores for drug discovery. The biological results obtained for the different pyridazinone/dithiocarbamate hybrids (compounds 8-14) indicated that most of them reversibly and selectively inhibit the hMAO-B in vitro with IC50 values in the µM range and exhibit not significant cellular toxicity. The analogues 9a1, 11a1, 12a2, 12b1 and 12b2, which present the dithiocarbamate fragment derivatized with a piperidin-1-yl or pyrrolidin-1-yl group and placed at C3 or C4 of the diazine ring, were the most attractive compounds of these series. Molecular modeling studies were performed to analyze the binding mode to the enzyme and the structure activity relationships of the titled compounds, as well as to predict their drug-like properties.

Keywords: Dithiocarbamate; Pyridazinone; Selective MAO-B inhibitors; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*
  • Structure-Activity Relationship
  • Thiocarbamates / chemistry
  • Thiocarbamates / pharmacology*

Substances

  • Monoamine Oxidase Inhibitors
  • Pyridazines
  • Thiocarbamates
  • Monoamine Oxidase