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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
26
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pubmed:dateCreated |
2004-12-13
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pubmed:abstractText |
The design and synthesis of a series of seven tricyclic 6-methylidene penems as novel class A and C serine beta-lactamase inhibitors is described. These compounds proved to be very potent inhibitors of the TEM-1 and AmpC beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. In combination with piperacillin, their in vitro activities enhanced susceptibility of all class C resistant strains from various bacteria. Crystallographic structures of a serine-bound reaction intermediate of 17 with the class A SHV-1 and class C GC1 enzymes have been established to resolutions of 2.0 and 1.4 A, respectively, and refined to R-factors equal 0.163 and 0.145. In both beta-lactamases, a seven-membered 1,4-thiazepine ring has formed. The stereogenic C7 atom in the ring has the R configuration in the SHV-1 intermediate and has both R and S configurations in the GC1 intermediate. Hydrophobic stacking interactions between the tricyclic C7 substituent and a tyrosine side chain, rather than electrostatic or hydrogen bonding by the C3 carboxylic acid group, dominate in both complexes. The formation of the 1,4- thiazepine ring structures is proposed based on a 7-endo-trig cyclization.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AbeTakaoT,
pubmed-author:AgarwalAtulA,
pubmed-author:BonomoRobert ARA,
pubmed-author:Dos SantosOsvaldoO,
pubmed-author:GuYansongY,
pubmed-author:HujerAndrea MAM,
pubmed-author:KnoxJames RJR,
pubmed-author:MansourTarek STS,
pubmed-author:NukagaMichiyoshiM,
pubmed-author:PetersenPeter JPJ,
pubmed-author:VenkatesanAranapakam MAM,
pubmed-author:WeissWilliam JWJ,
pubmed-author:YangYoujunY
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pubmed:issnType |
Print
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pubmed:day |
16
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pubmed:volume |
47
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6556-68
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:15588091-Binding Sites,
pubmed-meshheading:15588091-Crystallography, X-Ray,
pubmed-meshheading:15588091-Enterobacter cloacae,
pubmed-meshheading:15588091-Escherichia coli,
pubmed-meshheading:15588091-Heterocyclic Compounds, 2-Ring,
pubmed-meshheading:15588091-Heterocyclic Compounds, 3-Ring,
pubmed-meshheading:15588091-Hydrolysis,
pubmed-meshheading:15588091-Klebsiella pneumoniae,
pubmed-meshheading:15588091-Microbial Sensitivity Tests,
pubmed-meshheading:15588091-Models, Molecular,
pubmed-meshheading:15588091-Protein Binding,
pubmed-meshheading:15588091-Pseudomonas aeruginosa,
pubmed-meshheading:15588091-Serratia marcescens,
pubmed-meshheading:15588091-Staphylococcus aureus,
pubmed-meshheading:15588091-Structure-Activity Relationship,
pubmed-meshheading:15588091-Thiazepines,
pubmed-meshheading:15588091-beta-Lactamases,
pubmed-meshheading:15588091-beta-Lactams
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pubmed:year |
2004
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pubmed:articleTitle |
Structure-activity relationship of 6-methylidene penems bearing tricyclic heterocycles as broad-spectrum beta-lactamase inhibitors: crystallographic structures show unexpected binding of 1,4-thiazepine intermediates.
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pubmed:affiliation |
Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.
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