5,5,6-Fused tricycles bearing imidazole and pyrazole 6-methylidene penems as broad-spectrum inhibitors of β-lactamases

Aranapakam M. Venkatesan, Atul Agarwal, Takao Abe, Hideki Ushirogochi, Mihira Ado, Takasaki Tsuyoshi, Osvaldo Dos Santos, Zhong Li, Gerry Francisco, Yang I. Lin, Peter J. Petersen, Youjun Yang, William J. Weiss, David M. Shlaes, Tarek S. Mansour

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

β-Lactamases are serine- and metal-dependent hydrolases, produced by the bacteria as defense against β-lactam antibiotics. Commercially available inhibitors such as clavulanic acid, sulbactam, and tazobactam, which are currently used in the hospital settings, have reduced activity against newly emerging β-lactamases. Bacterial production of diverse β-lactamases including class-A, class-C, and ESBLs has motivated several research groups to search for inhibitors with a broader spectrum of activity. Previously, several novel 6-methylidene penems bearing, [5, 5] [5, 6] and [5, 5, 5] heterocycles have been synthesized in our laboratory and were shown to be potent and broad-spectrum β-lactamase inhibitors. As a continuation of our previous work and in order to extend the structure-activity relationships, in this paper, we describe herein the synthesis and in vitro, in vivo activities of several novel 5,5,6-fused tricyclic heterocycles attached to the 6-methylidene penem core. The compounds presented in the current paper are potent and broad-spectrum inhibitors of the TEM-1 and AmpC β-lactamases. In combination with piperacillin, their in vitro activities showed enhanced susceptibility to class A- and C-resistant strains studied in various bacteria. Some of the newly synthesized compounds such as 12a-c were shown to have in vivo activity in the acute lethal infection model against TEM-1 producing organisms. The 5,5,6-fused heterocyclic ring cores such as 21, 25, and 35 reported here are hitherto unknown in the literature.

Original languageEnglish
Pages (from-to)1890-1902
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number4
DOIs
StatePublished - 15 Feb 2008

Keywords

  • Beta-Lactamase Inhibitors

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    Venkatesan, A. M., Agarwal, A., Abe, T., Ushirogochi, H., Ado, M., Tsuyoshi, T., Dos Santos, O., Li, Z., Francisco, G., Lin, Y. I., Petersen, P. J., Yang, Y., Weiss, W. J., Shlaes, D. M., & Mansour, T. S. (2008). 5,5,6-Fused tricycles bearing imidazole and pyrazole 6-methylidene penems as broad-spectrum inhibitors of β-lactamases. Bioorganic and Medicinal Chemistry, 16(4), 1890-1902. https://doi.org/10.1016/j.bmc.2007.11.006