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.
From: Wyeth Research, Chemical and Screening Sciences, Department of Infectious Disease and Biological Technologies, 401 N. Middletown Road, Pearl River, New York 10965, USA. venkata@wyeth.com
Journal of medicinal chemistry
- Publish Date: Jul 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 15
- Pages: 4623-37
- Medium: Print
- Language: English
- Citation (JAMA): Venkatesan Aranapakam M, Agarwal Atul, Abe Takao, et al. 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. Jul 2006;49:4623-37
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 Headings (Keywords): Aldehydes, Animals, Anti-Bacterial Agents, Enterobacter aerogenes, Enterobacteriaceae Infections, Escherichia coli Infections, Gram-Negative Bacteria, Heterocyclic Compounds, 2-Ring, Imidazoles, Mice, Microbial Sensitivity Tests, Models, Molecular, Pyrazoles, Stereoisomerism, Structure-Activity Relationship, Thiazepines, Thiophenes, beta-Lactam Resistance, beta-Lactamases
Check for Full Text / PubMed Unique Identifier (PMID): 16854068
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