TY - JOUR
T1 - 5,5,6-Fused tricycles bearing imidazole and pyrazole 6-methylidene penems as broad-spectrum inhibitors of β-lactamases
AU - Venkatesan, Aranapakam M.
AU - Agarwal, Atul
AU - Abe, Takao
AU - Ushirogochi, Hideki
AU - Ado, Mihira
AU - Tsuyoshi, Takasaki
AU - Dos Santos, Osvaldo
AU - Li, Zhong
AU - Francisco, Gerry
AU - Lin, Yang I.
AU - Petersen, Peter J.
AU - Yang, Youjun
AU - Weiss, William J.
AU - Shlaes, David M.
AU - Mansour, Tarek S.
PY - 2008/2/15
Y1 - 2008/2/15
N2 - 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.
AB - 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.
KW - Beta-Lactamase Inhibitors
UR - http://www.scopus.com/inward/record.url?scp=38949102310&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2007.11.006
DO - 10.1016/j.bmc.2007.11.006
M3 - Article
C2 - 18061461
AN - SCOPUS:38949102310
SN - 0968-0896
VL - 16
SP - 1890
EP - 1902
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 4
ER -