Discovery of 2-(1-(3-(4-Chloroxyphenyl)-3-oxo- propyl)pyrrolidine-3-yl)-1 H-benzo[d]imidazole-4-carboxamide: A Potent Poly(ADP-ribose) Polymerase (PARP) Inhibitor for Treatment of Cancer

Molecules. 2019 May 17;24(10):1901. doi: 10.3390/molecules24101901.

Abstract

A series of benzimidazole carboxamide derivatives have been synthesized and characterized by 1H-NMR, 13C-NMR and HRMS. PARP inhibition assays and cellular proliferation assays have also been carried out. Compounds 5cj and 5cp exhibited potential anticancer activities with IC50 values of about 4 nM against both PARP-1 and PARP-2, similar to the reference drug veliparib. The two compounds also displayed slightly better in vitro cytotoxicities against MDA-MB-436 and CAPAN-1 cell lines than veliparib and olaparib, with values of 17.4 µM and 11.4 µM, 19.8 µM and 15.5 µM, respectively. The structure-activity relationship based on molecular docking was discussed as well.

Keywords: PARP enzyme inhibition; benzimidazole carboxamide; poly(ADP-ribose) polymerase.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Models, Molecular
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
  • Poly (ADP-Ribose) Polymerase-1 / chemistry
  • Poly(ADP-ribose) Polymerase Inhibitors / chemical synthesis*
  • Poly(ADP-ribose) Polymerase Inhibitors / chemistry
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Poly(ADP-ribose) Polymerases / chemistry
  • Poly(ADP-ribose) Polymerases / metabolism
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Poly(ADP-ribose) Polymerase Inhibitors
  • PARP1 protein, human
  • PARP2 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases