RhII -Catalyzed De-symmetrization of Ethane-1,2-dithiol and Propane-1,3-dithiol Yields Metallo-β-lactamase Inhibitors

ChemMedChem. 2021 Nov 19;16(22):3410-3417. doi: 10.1002/cmdc.202100344. Epub 2021 Aug 3.

Abstract

Diversity-oriented synthesis (DOS) is a rich source for novel lead structures in Medicinal Chemistry. In this study, we present a DOS-compatible method for synthesis of compounds bearing a free thiol moiety. The procedure relies on Rh(II)-catalyzed coupling of dithiols to diazo building blocks. The synthetized library was probed against metallo-β-lactamases (MBLs) NDM-1 and VIM-1. Biochemical and biological evaluation led to identification of novel potent MBL inhibitors with antibiotic adjuvant activity.

Keywords: Rh(II) catalysis; diazo compounds; metallo β lactamases; multiresistant bacteria; thiol inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azo Compounds / chemical synthesis
  • Azo Compounds / chemistry
  • Azo Compounds / pharmacology*
  • Catalysis
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Rhodium / chemistry*
  • Structure-Activity Relationship
  • Toluene / analogs & derivatives*
  • Toluene / chemistry
  • Toluene / pharmacology
  • beta-Lactamase Inhibitors / chemical synthesis
  • beta-Lactamase Inhibitors / chemistry
  • beta-Lactamase Inhibitors / pharmacology*
  • beta-Lactamases / metabolism*

Substances

  • Azo Compounds
  • beta-Lactamase Inhibitors
  • Toluene
  • Rhodium
  • VIM-1 metallo-beta-lactamase
  • beta-Lactamases
  • beta-lactamase NDM-1
  • dithiol