Discovery of 5-(pyridin-3-yl)-1H-indole-4,7-diones as indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126901. doi: 10.1016/j.bmcl.2019.126901. Epub 2019 Dec 17.

Abstract

Early studies demonstrated that over expression of indoleamine 2,3-dioxygenase (IDO1) in tumor microenvironment results in tumor immune escape. Herein, in order to simplify the structure of two kinds of IDO1 inhibitors from marine alkaloid, Exiguamine A and Tsitsikammamines, we designed, synthesized a series of 1H-indole-4,7-dione derivatives and evaluated their inhibitory activity in IDO1 enzyme and in IFN-γ stimulated Hela cells in vitro. The structure-activity relationship demonstrated that 5-(pyridin-3-yl)-1H-indole-4,7-dione is a promising scaffold for IDO1 inhibitors and most compounds with this core showed moderate inhibition potency at micromole level. Our further enzyme kinetics experiments reveal that these new developed compounds might act as reversible competitive inhibitors of IDO1.

Keywords: 1H-indole-4,7-diones; Cancer immunotherapy; Indoleamine 2,3-dioxygenase 1; Marine alkaloid; Reversible competitive inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • HeLa Cells
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Indoles / chemistry*
  • Indoles / metabolism
  • Inhibitory Concentration 50
  • Kinetics
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Indoles