1. Academic Validation
  2. Structural features and functional activities of benzimidazoles as NOD2 antagonists

Structural features and functional activities of benzimidazoles as NOD2 antagonists

  • Eur J Med Chem. 2020 Mar 15;190:112089. doi: 10.1016/j.ejmech.2020.112089.
Samo Guzelj 1 Martina Gobec 1 Dunja Urbančič 1 Irena Mlinarič-Raščan 1 Emanuela Corsini 2 Žiga Jakopin 3
Affiliations

Affiliations

  • 1 Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
  • 2 Laboratory of Toxicology, Department of Environmental Science and Policy, University of Milan, Via Balzaretti 9, 20133, Milan, Italy.
  • 3 Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia. Electronic address: ziga.jakopin@ffa.uni-lj.si.
Abstract

NOD1 and NOD2 are Pattern Recognition Receptors that have important roles in innate immune responses. Although their overactivation has been linked to a number of diseases, NOD2 in particular remains a virtually unexploited target in this respect, with only one structural class of antagonist reported. To gain insight into the structure-activity relationships of NOD2 antagonists, a series of novel analogs was designed and synthesized, and then screened for antagonist activity versus NOD2, and counter-screened versus NOD1. Compounds 32 and 38 were identified as potent and moderately selective NOD2 antagonists, and 33 and 42 as dual NOD1/NOD2 antagonists, with balanced activities against both targets in the low micromolar range. These data enable in-depth exploration of their structure-activity relationships and provide deeper understanding of the structural features required for NOD2 antagonism.

Keywords

Immunomodulation; Interleukin-8; NF-κB activation; NOD1 antagonist; NOD2 antagonist; Tumor necrosis factor-α.

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