Design, synthesis and biological evaluation of benzimidazole derivatives as novel human Pin1 inhibitors

Bioorg Med Chem Lett. 2019 Jul 15;29(14):1859-1863. doi: 10.1016/j.bmcl.2018.11.045. Epub 2018 Nov 23.

Abstract

In this work, a series of novel benzimidazole derivatives were designed and synthesized as Pin1 inhibitors. Protease-coupled assay was used to investigate the Pin1 inhibitory potency of all synthesized compounds. Thirteen of them showed preferable Pin1 inhibitory effects with IC50 values lower than 5 μM, and 12a, 15b, 15d and 16c exhibited the most promising Pin1 inhibitory activity at low micromolar level (0.33-1.00 μM) than the positive control compound Juglone. Flow cytometry results showed that treating PC-3 cells with 16c caused slight cycle arrest in a concentration-dependent manner. The structure-activity relationships of R1, R2, R3 and linker of the benzimidazole derivatives were analyzed in detail, which would help further exploration of new Pin1 inhibitors.

Keywords: 4-(1H-benzoimidazol-2-yl)-benzsulfamides; PC-3; PPIase; Pin1 inhibitors; Prostate cancer.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • NIMA-Interacting Peptidylprolyl Isomerase / antagonists & inhibitors*
  • NIMA-Interacting Peptidylprolyl Isomerase / metabolism
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzimidazoles
  • Enzyme Inhibitors
  • NIMA-Interacting Peptidylprolyl Isomerase
  • PIN1 protein, human