Identification and initial optimization of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB)

Bioorg Med Chem Lett. 2018 Feb 15;28(4):756-761. doi: 10.1016/j.bmcl.2018.01.005. Epub 2018 Jan 5.

Abstract

The discovery, synthesis and preliminary structure-activity relationship (SAR) of a novel class of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB) is described. A high throughput screening (HTS) campaign resulted in the identification of moderately active screening hits 1-5 the most potent of which was compound 1 (IC50 = 0.77 µM). In silico docking of an early analog offered suggestions for structural modification which resulted in the design and synthesis of highly potent analogs 13j(IC50 = 1 nM) and 13 l(IC50 = 7 nM) which were chosen as leads for further optimization.

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

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology*
  • Apoptosis / drug effects
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Toxins / antagonists & inhibitors*
  • CHO Cells
  • Clostridioides difficile / drug effects*
  • Cricetulus
  • Drug Stability
  • Enterotoxins / antagonists & inhibitors
  • High-Throughput Screening Assays
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Microsomes, Liver / metabolism
  • Molecular Docking Simulation
  • Molecular Structure
  • Nucleotidases / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Bacterial Toxins
  • Enterotoxins
  • tcdA protein, Clostridium difficile
  • toxB protein, Clostridium difficile
  • Nucleotidases