Optimization of a novel potent and selective bacterial DNA helicase inhibitor scaffold from a high throughput screening hit

Bioorg Med Chem Lett. 2013 Jun 15;23(12):3481-6. doi: 10.1016/j.bmcl.2013.04.055. Epub 2013 Apr 30.

Abstract

Benzobisthiazole derivatives were identified as novel helicase inhibitors through high throughput screening against purified Staphylococcus aureus (Sa) and Bacillus anthracis (Ba) replicative helicases. Chemical optimization has produced compound 59 with nanomolar potency against the DNA duplex strand unwinding activities of both B. anthracis and S. aureus helicases. Selectivity index (SI=CC50/IC50) values for 59 were greater than 500. Kinetic studies demonstrated that the benzobisthiazole-based bacterial helicase inhibitors act competitively with the DNA substrate. Therefore, benzobisthiazole helicase inhibitors represent a promising new scaffold for evaluation as antibacterial agents.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Bacillus anthracis / enzymology
  • Bacterial Proteins / genetics*
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacology*
  • DNA Helicases / antagonists & inhibitors*
  • DNA Helicases / metabolism
  • DNA, Bacterial / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays / methods*
  • Microbial Sensitivity Tests / methods
  • Staphylococcus aureus / enzymology
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Benzothiazoles
  • DNA, Bacterial
  • Enzyme Inhibitors
  • DNA Helicases