Novel imidazole substituted 6-methylidene-penems as broad-spectrum beta-lactamase inhibitors.
Beta-lactamases are serine and metallo-dependent enzymes produced by the bacteria in defense against beta-lactam antibiotics. Production of class-A, class-B, and class-C enzymes by the bacteria make the use of beta-lactam antibiotics ineffective in certain cases. To overcome resistance to beta-lactam antibiotics, several beta-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam are widely used in the clinic in combination with beta-lactam antibiotics. However, single point mutations within these enzymes have allowed bacteria to overcome the inhibitory effect of the commercially approved beta-lactamase inhibitors. Although the commercially available beta-lactamase inhibitor/beta-lactam antibiotic combinations are effective against class-A producing bacteria and many extended spectrum beta-lactamase (ESBL's) producing bacteria they are less effective against class-C enzymes expressing bacteria. To circumvent this problem, based on modeling studies several novel imidazole substituted 6-methylidene-penem derivatives were synthesized and tested against various beta-lactamase producing isolates. The present paper deals with the synthesis and structure-activity relationships (SAR) of these compounds.
Venkatesan
Aranapakam M
AM
Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. venkata@wyeth.com
Agarwal
Atul
A
Abe
Takao
T
Ushirogochi
Hideki
H
Yamamura
Itsuki
I
Kumagai
Toshio
T
Petersen
Peter J
PJ
Weiss
William J
WJ
Lenoy
Eileen
E
Yang
Youjun
Y
Shlaes
David M
DM
Ryan
John L
JL
Mansour
Tarek S
TS
D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests / Q000706:statistics & numerical data; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
D007093:Imidazoles; D011480:Protease Inhibitors; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases