title: Thiophenyl oxime-derived phosphonates as nano-molar class C beta-lactamase inhibitors reducing MIC of imipenem against Pseudomonas aeruginosa and Acinetobacter baumannii.
abstract: The preparation and characterization of a series of thiophenyl oxime phosphonate beta-lactamase inhibitors is described. A number of these analogs were potent and selective inhibitors of class C beta-lactamases from Pseudomonas aeruginosa and Enterobacter cloacae. Compounds 3b and 7 reduced the MIC of imipenem against an AmpC expressing strain of imipenem-resistant P. aeruginosa. A number of the title compounds retained micromolar potency against the class D OXA-40 beta-lactamase from Acinetobacter baumannii and at high concentrations compound 3b was shown to reduce the MIC of imipenem against a highly imipenem-resistant strain of A. baumanii expressing the OXA-40 beta-lactamase. In mice compound 3b exhibited phamacokinetics similar to imipenem.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., Rahway, NJ 07065, USA. qiang_tan@merck.com
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tan
authors.forename: Aimie M
authors.initials: AM
authors.lastname: Ogawa
authors.forename: Susan L
authors.initials: SL
authors.lastname: Raghoobar
authors.forename: Douglas
authors.initials: D
authors.lastname: Wisniewski
authors.forename: Lawrence
authors.initials: L
authors.lastname: Colwell
authors.forename: Young-Whan
authors.initials: YW
authors.lastname: Park
authors.forename: Katherine
authors.initials: K
authors.lastname: Young
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hermes
authors.forename: Frank P
authors.initials: FP
authors.lastname: Dininno
authors.forename: Milton L
authors.initials: ML
authors.lastname: Hammond
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015378:Imipenem / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013876:Thiophenes / Q000737:chemistry; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D010091:Oximes; D013876:Thiophenes; D065093:beta-Lactamase Inhibitors; D015378:Imipenem; D001618:beta-Lactamases