Spirocyclopropyl beta-lactams as mechanism-based inhibitors of serine beta-lactamases. Synthesis by rhodium-catalyzed cyclopropanation of 6-diazopenicillanate sulfone

J Med Chem. 2003 Jun 19;46(13):2569-71. doi: 10.1021/jm034056q.

Abstract

Class A-class C mechanism-based beta-lactamase inhibitors were designed on the basis of the intermediacy of an oxycarbenium species capable of cross-linking with amino acids residues in the active site. Penams 24 and 27 were very potent against AmpC in vitro. The MIC values of 24 in combination with piperacillin against class A and class C producing organisms showed improvement over clinically used tazobactam.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins*
  • Catalysis
  • Crystallography, X-Ray
  • Cyclopropanes / chemical synthesis*
  • Cyclopropanes / chemistry
  • Cyclopropanes / pharmacology
  • Diazonium Compounds / chemistry*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / drug effects
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Pseudomonas aeruginosa / drug effects
  • Rhodium*
  • Serine / chemistry*
  • Serratia marcescens / drug effects
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Structure-Activity Relationship
  • Sulbactam / analogs & derivatives
  • Sulbactam / chemistry*
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / chemistry
  • beta-Lactams / chemical synthesis*
  • beta-Lactams / chemistry
  • beta-Lactams / pharmacology

Substances

  • 6-diazopenicillanate sulfone
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Cyclopropanes
  • Diazonium Compounds
  • Enzyme Inhibitors
  • Spiro Compounds
  • beta-Lactamase Inhibitors
  • beta-Lactams
  • Serine
  • Rhodium
  • AmpC beta-lactamases
  • beta-Lactamases
  • beta-lactamase TEM-1
  • Sulbactam