ChemInform Abstract: The mechanisms of Reactions of Cephalosporins and the Synthesis of Non‐β‐lactam Analogs

Agathocleous, D. C.; Buckwell, Stephen C.; Proctor, Philip; Page, Michael I.

doi:10.1002/chin.198725339

ChemInform

1987

DOI: 10.1002/chin.198725339

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ChemInform Abstract: The mechanisms of Reactions of Cephalosporins and the Synthesis of Non‐β‐lactam Analogs

D. C. Agathocleous

Stephen C. Buckwell

Philip Proctor

et al.

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2010

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“…Such strategies showed limited success, however, and only weak inhibition of R-TEM-2 β-lactamase, BcI β-lactamase, and R61 transpeptidase was reported. No antibiotic activity was detected in vivo for any of the cyclobutanones. , As a result, the cyclobutanone system was set aside in favor of other inhibitor templates including that of the penicillanic acid sulfones.…”

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Cyclobutanone Analogues of β-Lactams Revisited: Insights into Conformational Requirements for Inhibition of Serine- and Metallo-β-Lactamases

et al. 2010

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The most important mode of bacterial resistance to beta-lactam antibiotics is the expression of beta-lactamases. New cyclobutanone analogues of penams and penems have been prepared and evaluated for inhibition of class A, B, C, and D beta-lactamases. Inhibitors which favor conformations in which the C4 carboxylate is equatorial were found to be more potent than those in which the carboxylate is axial, and molecular modeling studies with enzyme-inhibitor complexes indicate that an equatorial orientation of the carboxylate is required for binding to beta-lactamases. An X-ray structure of OXA-10 complexed with a cyclobutanone confirms that a serine hemiketal is formed in the active site and that the inhibitor adopts the exo envelope. An unsaturated penem analogue was also found to enhance the potency of meropenem against carbapenem-resistant MBL-producing strains of Chryseobacterium meningosepticum and Stenotrophomonas maltophilia. These cyclobutanones represent the first type of reversible inhibitors to show moderate (low micromolar) inhibition of both serine- and metallo-beta-lactamases and should be considered for further development into practical inhibitors.

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Cyclobutanone Analogues of β-Lactams Revisited: Insights into Conformational Requirements for Inhibition of Serine- and Metallo-β-Lactamases

et al. 2010

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ChemInform Abstract: The mechanisms of Reactions of Cephalosporins and the Synthesis of Non‐β‐lactam Analogs

Cited by 1 publication

References 0 publications

Cyclobutanone Analogues of β-Lactams Revisited: Insights into Conformational Requirements for Inhibition of Serine- and Metallo-β-Lactamases

Cyclobutanone Analogues of β-Lactams Revisited: Insights into Conformational Requirements for Inhibition of Serine- and Metallo-β-Lactamases

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