title: Novel C-2 substituted carbapenem derivatives. Part II. Synthesis and structure-activity relationships of isoxazolin-2-yl, isoxazolidin-2-yl and 2-pyrazolin-2-yl carbapenems generated using 1,3-dipolar cycloaddition chemistry.
abstract: A series of carbapenems containing novel C-2 semisaturated heterocyclic substituents were synthesised by 1,3 dipolar cycloaddition reactions of nitrile oxides, nitrile imines and a nitrone to 2-vinylcarbapenem. The isoxazoline and isoxazolidine compounds showed potent antibacterial activity but moderate stability to human dehydropeptidase 1 (DHP-1). Stability to DHP-1 was improved by methyl substitution in the isoxazoline ring, but at the expense of antibacterial activity. The pyrazolines exhibited excellent stability to DHP-1, but reduced potency against Gram-negative organisms.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Brockham Park, Betchworth, Surrey, U.K.
authors.forename: G
authors.initials: G
authors.lastname: Burton
authors.forename: G J
authors.initials: GJ
authors.lastname: Clarke
authors.forename: J D
authors.initials: JD
authors.lastname: Douglas
authors.forename: A J
authors.initials: AJ
authors.lastname: Eglington
authors.forename: C H
authors.initials: CH
authors.lastname: Frydrych
authors.forename: J D
authors.initials: JD
authors.lastname: Hinks
authors.forename: N W
authors.initials: NW
authors.lastname: Hird
authors.forename: E
authors.initials: E
authors.lastname: Hunt
authors.forename: S F
authors.initials: SF
authors.lastname: Moss
authors.forename: A
authors.initials: A
authors.lastname: Naylor
authors.forename: N H
authors.initials: NH
authors.lastname: Nicholson
authors.forename: M J
authors.initials: MJ
authors.lastname: Pearson
mesh_terms: D015780:Carbapenems / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004150:Dipeptidases / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D015780:Carbapenems; D004150:Dipeptidases; C038937:dipeptidase