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.
Venkatesan
Aranapakam M
AM
Wyeth Research, Chemical and Screening Sciences, 401 N. Middletown Road, Pearl River, NY 10965, USA. venkata@wyeth.com
Agarwal
Atul
A
Abe
Takao
T
Ushirogochi
Hideki
H
Ado
Mihira
M
Tsuyoshi
Takasaki
T
Dos Santos
Osvaldo
O
Li
Zhong
Z
Francisco
Gerry
G
Lin
Yang I
YI
Petersen
Peter J
PJ
Yang
Youjun
Y
Weiss
William J
WJ
Shlaes
David M
DM
Mansour
Tarek S
TS
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