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

A series of novel 5,5,6-fused tricyclic-6-methylidene penems have been synthesized and were shown to be potent, broad spectrum β-lactamase inhibitors against class-A, class-B, and class-C enzymes. The present paper deals with the synthesis and structure–activity relationships of these derivatives. β...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-02, Vol.16 (4), p.1890-1902
Main Authors: Venkatesan, Aranapakam M., Agarwal, Atul, Abe, Takao, Ushirogochi, Hideki, Ado, Mihira, Tsuyoshi, Takasaki, Dos Santos, Osvaldo, Li, Zhong, Francisco, Gerry, Lin, Yang I., Petersen, Peter J., Yang, Youjun, Weiss, William J., Shlaes, David M., Mansour, Tarek S.
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Bacterial Proteins - antagonists & inhibitors
Beta-Lactamase Inhibitors
beta-Lactamases
Biological and medical sciences
Heterocyclic Compounds, 3-Ring - chemistry
Heterocyclic Compounds, 3-Ring - pharmacology
Imidazoles - chemistry
Imidazoles - pharmacology
Lactams - chemistry
Lactams - pharmacology
Medical sciences
Microbial Sensitivity Tests
Pharmacology. Drug treatments
Pyrazoles - chemistry
Pyrazoles - pharmacology
Structure-Activity Relationship
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Summary:A series of novel 5,5,6-fused tricyclic-6-methylidene penems have been synthesized and were shown to be potent, broad spectrum β-lactamase inhibitors against class-A, class-B, and class-C enzymes. The present paper deals with the synthesis and structure–activity relationships of these derivatives. 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2007.11.006