5,5,6-Fused tricycles bearing imidazole and pyrazole 6-methylidene penems as broad-spectrum inhibitors of beta-lactamases.
Beta-lactamases are serine- and metal-dependent hydrolases, produced by the bacteria as defense against beta-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 beta-lactamases. Bacterial production of diverse beta-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 beta-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 beta-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.
Wyeth Research, Chemical and Screening Sciences, 401 N. Middletown Road, Pearl River, NY 10965, USA. venkata@wyeth.com
Aranapakam M
AM
Venkatesan
Atul
A
Agarwal
Takao
T
Abe
Hideki
H
Ushirogochi
Mihira
M
Ado
Takasaki
T
Tsuyoshi
Osvaldo
O
Dos Santos
Zhong
Z
Li
Gerry
G
Francisco
Yang I
YI
Lin
Peter J
PJ
Petersen
Youjun
Y
Yang
William J
WJ
Weiss
David M
DM
Shlaes
Tarek S
TS
Mansour
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D007769:Lactams; D011720:Pyrazoles; D065093:beta-Lactamase Inhibitors; C031280:pyrazole; C029899:imidazole; C048795:AmpC beta-lactamases; D001618:beta-Lactamases