Benzimidazole-2-one: a novel anchoring principle for antagonizing p53-Mdm2

Bioorg Med Chem. 2013 Jul 15;21(14):3982-95. doi: 10.1016/j.bmc.2012.06.020. Epub 2012 Jun 20.


Herein we propose the benzimidazole-2-one substructure as a suitable tryptophan mimic and thus a reasonable starting point for the design of p53 Mdm2 antagonists. We devise a short multicomponent reaction route to hitherto unknown 2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamides by reacting mono N-carbamate protected phenylenediamine in a Ugi-3CR followed by base induced cyclisation. Our preliminary synthesis and screening results are presented here. The finding of the benzimidazolone moiety as a tryptophan replacement in mdm2 is significant as it offers access to novel scaffolds with potentially higher selectivity and potency and improved biological activities. Observing low μM affinities to mdm2 by NMR and fluorescence polarization we conclude that the 2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide scaffold might be a good starting point to further optimize the affinities to Mdm2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzimidazoles / chemistry*
  • Drug Design
  • Models, Molecular
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*


  • Benzimidazoles
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2