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

Mikhail Krasavin, Daniil Zhukovsky, Igor Solovyev, Darina Barkhatova, Dmitry Dar'in, Denia Frank, Giada Martinelli, Lilia Weizel, Anna Proschak, Marco Rotter, Jan S. Kramer, Steffen Brunst, Thomas A. Wichelhaus, Ewgenij Proschak

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalChemMedChem
DOIs
StateE-pub ahead of print - 29 Jun 2021

Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Keywords

  • diazo compounds
  • metallo β lactamases
  • multiresistant bacteria
  • Rh(II) catalysis
  • thiol inhibitors

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