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