Identification of 2-thioxoimidazolidin-4-one derivatives as novel noncovalent proteasome and immunoproteasome inhibitors

Bioorg Med Chem Lett. 2018 Feb 1;28(3):278-283. doi: 10.1016/j.bmcl.2017.12.053. Epub 2017 Dec 26.

Abstract

This paper describes the design, synthesis, and biological evaluation of 2-thioxoimidazolidin-4-one derivatives as inhibitors of proteasome and immunoproteasome, potential targets for the treatment of hematological malignancies. In particular, we focused our efforts on the design of noncovalent inhibitors, which might be a promising therapeutic option potentially devoid of drawbacks and side-effects related to irreversible inhibition. Among all the synthesized compounds, we identified a panel of active inhibitors with Ki values towards one or two chymotrypsin-like activities of proteasome (β5c) and immunoproteasome (β5i and β1i subunits) in the low micromolar range. Docking studies suggested a unique binding mode of the molecules in the catalytic site of immunoproteasome proteolytic subunits.

Keywords: 5-Arylidene-2-thioxoimidazolidin-4-ones; Docking studies; Immunoproteasome; Non-covalent inhibitors; Proteasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Imidazolidines / chemical synthesis
  • Imidazolidines / chemistry
  • Imidazolidines / pharmacology*
  • Molecular Docking Simulation
  • Molecular Structure
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / chemical synthesis
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • 2-thioxo-imidazolidine-4-one
  • Imidazolidines
  • Proteasome Inhibitors
  • Proteasome Endopeptidase Complex