Structure-activity relationship of 6-methylidene penems bearing 6,5 bicyclic heterocycles as broad-spectrum beta-lactamase inhibitors: evidence for 1,4-thiazepine intermediates with C7 R stereochemistry by computational methods

J Med Chem. 2006 Jul 27;49(15):4623-37. doi: 10.1021/jm060021p.

Abstract

The design and synthesis of a series of 6-methylidene penems containing [6,5]-fused bicycles (thiophene, imidazole, or pyrazle-fused system) as novel class A, B, and C beta-lactamase inhibitors is described. These penems proved to be potent inhibitors of the TEM-1 (class A) and AmpC (class C) beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. Their in vitro and in vivo activities in combination with piperacillin are discussed. On the basis of the crystallographic structures of a serine-bound reaction intermediate of 2 with SHV-1 (class A) and GC1 (class C) enzymes, compounds 14a-l were designed and synthesized. Penems are proposed to form a seven-membered 1,4 thiazepine ring in both class A and C beta-lactamases. The interaction energy calculation for the enzyme-bound intermediates favor the formation of the C7 R enantiomer over the S enantiomer of the 1,4-thiazepine in both beta-lactamases, which is consistent with those obtained from the crystal structure of 2 with SHV-1 and GC1.

MeSH terms

  • Aldehydes / chemistry
  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Enterobacter aerogenes
  • Enterobacteriaceae Infections / drug therapy
  • Enterobacteriaceae Infections / mortality
  • Escherichia coli Infections / drug therapy
  • Escherichia coli Infections / mortality
  • Gram-Negative Bacteria / drug effects
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / chemistry*
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Mice
  • Microbial Sensitivity Tests
  • Models, Molecular*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiazepines / chemistry*
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology
  • beta-Lactam Resistance
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / chemistry

Substances

  • Aldehydes
  • Anti-Bacterial Agents
  • Heterocyclic Compounds, 2-Ring
  • Imidazoles
  • Pyrazoles
  • Thiazepines
  • Thiophenes
  • beta-Lactamase Inhibitors
  • beta-Lactamases