Thiol activated prodrugs of sulfur dioxide (SO2) as MRSA inhibitors

Bioorg Med Chem Lett. 2015 Jul 1;25(13):2694-7. doi: 10.1016/j.bmcl.2015.04.046. Epub 2015 Apr 23.

Abstract

Drug resistant infections are becoming common worldwide and new strategies for drug development are necessary. Here, we report the synthesis and evaluation of 2,4-dinitrophenylsulfonamides, which are donors of sulfur dioxide (SO2), a reactive sulfur species, as methicillin-resistant Staphylococcus aureus (MRSA) inhibitors. N-(3-Methoxyphenyl)-2,4-dinitro-N-(prop-2-yn-1-yl)benzenesulfonamide (5e) was found to have excellent in vitro MRSA inhibitory potency. This compound is cell permeable and treatment of MRSA cells with 5e depleted intracellular thiols and enhanced oxidative species both results consistent with a mechanism involving thiol activation to produce SO2.

Keywords: Drug resistance; MRSA; Reactive oxygen species; Sulfur dioxide; Thiol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Drug Design
  • Humans
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Microbial Sensitivity Tests
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Staphylococcal Infections / drug therapy
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology
  • Sulfur Dioxide / chemistry
  • Sulfur Dioxide / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Prodrugs
  • Sulfhydryl Compounds
  • Sulfur Dioxide