Synthesis and SAR studies of novel benzodiazepinedione-based inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB)

Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3601-3605. doi: 10.1016/j.bmcl.2018.10.047. Epub 2018 Oct 29.

Abstract

Synthesis and structure-activity relationships (SAR) of a novel series of benzodiazepinedione-based inhibitors of Clostridium difficile toxin B (TcdB) are described. Compounds demonstrating low nanomolar affinity for TcdB, and which possess improved stability in mouse plasma vs. earlier compounds from this series, have been identified. Optimized compound 11d demonstrates a good pharmacokinetic (PK) profile in mouse and hamster and is efficacious in a hamster survival model of Clostridium difficile infection.

Keywords: Benzodiazepinedione; Clostridium difficile; Inhibitor; TcdB; Toxin.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / therapeutic use
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Bacterial Toxins / antagonists & inhibitors*
  • Bacterial Toxins / metabolism
  • Benzodiazepines / chemistry*
  • Benzodiazepines / pharmacokinetics
  • Benzodiazepines / therapeutic use
  • CHO Cells
  • Clostridioides difficile / metabolism
  • Clostridium Infections / drug therapy
  • Clostridium Infections / veterinary
  • Cricetinae
  • Cricetulus
  • Half-Life
  • Mice
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Bacterial Toxins
  • toxB protein, Clostridium difficile
  • Benzodiazepines