Synthesis of 2-Thio-Substituted 1,6-Diazabicyclo[3.2.1]octane Derivatives, Potent β-Lactamase Inhibitors

J Org Chem. 2020 Aug 7;85(15):9650-9660. doi: 10.1021/acs.joc.0c00980. Epub 2020 Jul 20.

Abstract

Approval of avibactam by the FDA has led to the recognition of 1,6-diazabicyclo[3.2.1]octane (DBO) derivatives as attractive compounds for β-lactamase inhibition. We achieved a concise and collective synthesis of 2-thio-substituted DBO derivatives. The synthesis involves diastereoselective photo-induced Barton decarboxylative thiolation, which can be applied to large-scale synthesis. The DBO analogues exhibited strong inhibitory activities against serine β-lactamases and acceptable solution stabilities for clinical development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents
  • Azabicyclo Compounds / pharmacology
  • Microbial Sensitivity Tests
  • Octanes* / pharmacology
  • beta-Lactamase Inhibitors* / pharmacology
  • beta-Lactamases

Substances

  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Octanes
  • beta-Lactamase Inhibitors
  • beta-Lactamases