Discovery and structure-activity relationships of phenyl benzenesulfonylhydrazides as novel indoleamine 2,3-dioxygenase inhibitors

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3403-6. doi: 10.1016/j.bmcl.2014.05.084. Epub 2014 Jun 4.

Abstract

A novel class of phenyl benzenesulfonylhydrazides has been identified as potent inhibitors of indoleamine 2,3-dioxygenase (IDO), and their structure-activity relationship was explored. Coupling reactions between various benzenesulfonyl chlorides and phenylhydrazides were utilized to synthesize the sulfonylhydrazides bearing various substituents. Compound 3i exhibited 61 nM of IC50 in enzymatic assay and 172 nM of EC50 in the HeLa cell. The computational study of 3i suggested that the major interactions between 3i and IDO protein are the coordination of sulfone and heme iron, the hydrogen bonding and hydrophobic interactions between 3i and IDO. This novel class of IDO inhibitor provides a new direction to discover effective anti-cancer agents.

Keywords: Indoleamine 2,3-dioxygenase; Molecular docking; Structure–activity relationship; Sulfonylhydrazide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Models, Molecular
  • Molecular Structure
  • Phenylhydrazines / chemical synthesis
  • Phenylhydrazines / chemistry
  • Phenylhydrazines / pharmacology*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • 4-((2-(4-bromophenyl)hydrazinyl)sulfonyl)benzoic acid
  • Enzyme Inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Phenylhydrazines
  • Sulfonamides