Novel imidazole substituted 6-methylidene-penems as broad-spectrum β-lactamase inhibitors

Aranapakam M. Venkatesan, Atul Agarwal, Takao Abe, Hideki Ushirogochi, Itsuki Yamamura, Toshio Kumagai, Peter J. Petersen, William J. Weiss, Eileen Lenoy, Youjun Yang, David M. Shlaes, John L. Ryan, Tarek S. Mansour

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Abstract

A series of novel imidazole substituted 6-methylidene-penems has been synthesized (R = heterocycle) and was shown to be potent, broad-spectrum β-lactamase inhibitors against class-A and class-C enzymes. The present paper deals with the design, synthesis, and structure-activity relationships (SAR) of compounds 11-15. β-Lactamases are serine and metallo-dependent enzymes produced by the bacteria in defense against β-lactam antibiotics. Production of class-A, class-B, and class-C enzymes by the bacteria make the use of β-lactam antibiotics ineffective in certain cases. To overcome resistance to β-lactam antibiotics, several β-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam are widely used in the clinic in combination with β-lactam antibiotics. However, single point mutations within these enzymes have allowed bacteria to overcome the inhibitory effect of the commercially approved β-lactamase inhibitors. Although the commercially available β-lactamase inhibitor/β-lactam antibiotic combinations are effective against class-A producing bacteria and many extended spectrum β-lactamase (ESBL's) producing bacteria they are less effective against class-C enzymes expressing bacteria. To circumvent this problem, based on modeling studies several novel imidazole substituted 6-methylidene-penem derivatives were synthesized and tested against various β-lactamase producing isolates. The present paper deals with the synthesis and structure-activity relationships (SAR) of these compounds.

Original languageEnglish
Pages (from-to)5807-5817
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number22
DOIs
StatePublished - 15 Nov 2004

Keywords

  • β-lactamase inhibitors

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    Venkatesan, A. M., Agarwal, A., Abe, T., Ushirogochi, H., Yamamura, I., Kumagai, T., Petersen, P. J., Weiss, W. J., Lenoy, E., Yang, Y., Shlaes, D. M., Ryan, J. L., & Mansour, T. S. (2004). Novel imidazole substituted 6-methylidene-penems as broad-spectrum β-lactamase inhibitors. Bioorganic and Medicinal Chemistry, 12(22), 5807-5817. https://doi.org/10.1016/j.bmc.2004.08.039