Identification of indole scaffold-based dual inhibitors of NOD1 and NOD2

Bioorg Med Chem. 2016 Nov 1;24(21):5221-5234. doi: 10.1016/j.bmc.2016.08.044. Epub 2016 Aug 24.

Abstract

NOD1 and NOD2 are important members of the pattern recognition receptor family and play a crucial role within the context of innate immunity. However, overactivation of NODs, especially of NOD1, has also been implicated in a number of diseases. Surprisingly, NOD1 remains a virtually unexploited target in this respect. To gain additional insight into the structure-activity relationships of NOD1 inhibitors, a series of novel analogs has been designed and synthesized and then screened for their NOD1-inhibitory activity. Selected compounds were also investigated for their NOD2-inhibitory activity. Two compounds 4 and 15, were identified as potent mixed inhibitors of NOD1 and NOD2, displaying a balanced inhibitory activity on both targets in the low micromolar range. The results obtained have enabled a deeper understanding of the structural requirements for NOD1 and NOD2 inhibition.

Keywords: Bioisosteric replacement; Immunomodulation; NF-κB activation; NOD1 inhibitor; NOD2 inhibitor; Scaffold hopping.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Nod1 Signaling Adaptor Protein / antagonists & inhibitors*
  • Nod1 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / antagonists & inhibitors*
  • Nod2 Signaling Adaptor Protein / genetics
  • Structure-Activity Relationship

Substances

  • Indoles
  • NF-kappa B
  • NOD1 protein, human
  • NOD2 protein, human
  • Nod1 Signaling Adaptor Protein
  • Nod2 Signaling Adaptor Protein