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.
Kaja Keček Plešec  1 ,  Dunja Urbančič  1 ,  Martina Gobec  1 ,  Aleksandra Pekošak  1 ,  Tihomir Tomašič  1 ,  Marko Anderluh  1 ,  Irena Mlinarič-Raščan  1 ,  Žiga Jakopin  2
Affiliations
  • 1. Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
  • 2. Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: [email protected].
PMID: 27601373 DOI: 10.1016/j.bmc.2016.08.044
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.
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