title: Structure-activity relationship of 6-methylidene penems bearing 6,5 bicyclic heterocycles as broad-spectrum beta-lactamase inhibitors: evidence for 1,4-thiazepine intermediates with C7 R stereochemistry by computational methods.
abstract: The design and synthesis of a series of 6-methylidene penems containing [6,5]-fused bicycles (thiophene, imidazole, or pyrazle-fused system) as novel class A, B, and C beta-lactamase inhibitors is described. These penems proved to be potent inhibitors of the TEM-1 (class A) and AmpC (class C) beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. Their in vitro and in vivo activities in combination with piperacillin are discussed. On the basis of the crystallographic structures of a serine-bound reaction intermediate of 2 with SHV-1 (class A) and GC1 (class C) enzymes, compounds 14a-l were designed and synthesized. Penems are proposed to form a seven-membered 1,4 thiazepine ring in both class A and C beta-lactamases. The interaction energy calculation for the enzyme-bound intermediates favor the formation of the C7 R enantiomer over the S enantiomer of the 1,4-thiazepine in both beta-lactamases, which is consistent with those obtained from the crystal structure of 2 with SHV-1 and GC1.
authors.affiliation: Wyeth Research, Chemical and Screening Sciences, Department of Infectious Disease and Biological Technologies, 401 N. Middletown Road, Pearl River, New York 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: Itsuka
authors.initials: I
authors.lastname: Yamamura
authors.forename: Mihira
authors.initials: M
authors.lastname: Ado
authors.forename: Takasaki
authors.initials: T
authors.lastname: Tsuyoshi
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Dos Santos
authors.forename: Yansong
authors.initials: Y
authors.lastname: Gu
authors.forename: Fuk-Wah
authors.initials: FW
authors.lastname: Sum
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.forename: Gerry
authors.initials: G
authors.lastname: Francisco
authors.forename: Yang-I
authors.initials: YI
authors.lastname: Lin
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Petersen
authors.forename: Youjun
authors.initials: Y
authors.lastname: Yang
authors.forename: Toshio
authors.initials: T
authors.lastname: Kumagai
authors.forename: William J
authors.initials: WJ
authors.lastname: Weiss
authors.forename: David M
authors.initials: DM
authors.lastname: Shlaes
authors.forename: James R
authors.initials: JR
authors.lastname: Knox
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D021902:Enterobacter aerogenes; D004756:Enterobacteriaceae Infections / Q000188:drug therapy / Q000401:mortality; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000401:mortality; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000737:chemistry*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry
chemical_list: D000447:Aldehydes; D000900:Anti-Bacterial Agents; D006574:Heterocyclic Compounds, 2-Ring; D007093:Imidazoles; D011720:Pyrazoles; D013841:Thiazepines; D013876:Thiophenes; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases