title: Novel imidazole substituted 6-methylidene-penems as broad-spectrum beta-lactamase inhibitors.
abstract: 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.
authors.affiliation: Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. venkata@wyeth.com
authors.forename: Aranapakam M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: Atul
authors.initials: A
authors.lastname: Agarwal
authors.forename: Takao
authors.initials: T
authors.lastname: Abe
authors.forename: Hideki
authors.initials: H
authors.lastname: Ushirogochi
authors.forename: Itsuki
authors.initials: I
authors.lastname: Yamamura
authors.forename: Toshio
authors.initials: T
authors.lastname: Kumagai
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Petersen
authors.forename: William J
authors.initials: WJ
authors.lastname: Weiss
authors.forename: Eileen
authors.initials: E
authors.lastname: Lenoy
authors.forename: Youjun
authors.initials: Y
authors.lastname: Yang
authors.forename: David M
authors.initials: DM
authors.lastname: Shlaes
authors.forename: John L
authors.initials: JL
authors.lastname: Ryan
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
mesh_terms: 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
chemical_list: D007093:Imidazoles; D011480:Protease Inhibitors; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases