Synthesis and Molecular Modeling Studies of N'-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

Molecules. 2017 Nov 9;22(11):1936. doi: 10.3390/molecules22111936.

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that is highly overexpressed in various cancer cells and antigen-presenting cells. It has emerged as an attractive therapeutic target for cancer immunotherapy, which has prompted high interest in the development of small-molecule inhibitors. To discover novel IDO1 inhibitors, we designed and synthesized a series of N'-hydroxyindazolecarboximidamides. Among the compounds synthesized, compound 8a inhibited both tryptophan depletion and kynurenine production through the IDO1 enzyme. Molecular docking studies revealed that 8a binds to IDO1 with the same binding mode as the analog, epacadostat (INCB24360). Here, we report the synthesis and biological evaluation of these hydroxyindazolecarboximidamides and present the molecular docking study of 8a with IDO1.

Keywords: N’-hydroxyindazolecarboximidamide; cancer immunotherapy; indoleamine 2,3-dioxygenase 1; kynurenine production; tryptophan depletion.

MeSH terms

  • Chemistry Techniques, Synthetic
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / chemistry*
  • Models, Molecular*
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Structure-Activity Relationship

Substances

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