title: Design, synthesis, and evaluation of 2 beta-alkenyl penam sulfone acids as inhibitors of beta-lactamases.
abstract: A general method for synthesis of 2 beta-alkenyl penam sulfones has been developed. The new compounds inhibited most of the common types of beta-lactamase. The level of activity depended very strongly on the nature of the substituent in the 2 beta-alkenyl group. The inhibited species formed with the beta-lactamase from Citrobacter freundii 1205 was sufficiently stable for X-ray crystallographic studies. These, together with UV absorption spectroscopy and studies of chemical degradation, suggested a novel reaction mechanism for the new inhibitors that might account for their broad spectrum of action. The (Z)-2 beta-acrylonitrile penam sulfone Ro 48-1220 was the most active inhibitor from this class of compound. The inhibitor enhanced the action of, for example, ceftriaxone against a broad selection of organisms producing beta-lactamases. The organisms included strains of Enterobacteriaceae that produce cephalosporinases, which is an exceptional activity for penam sulfones.
authors.affiliation: Preclinical Research, F. Hoffmann-LaRoche Ltd, Basel, Switzerland.
authors.forename: H G
authors.initials: HG
authors.lastname: Richter
authors.forename: P
authors.initials: P
authors.lastname: Angehrn
authors.forename: C
authors.initials: C
authors.lastname: Hubschwerlen
authors.forename: M
authors.initials: M
authors.lastname: Kania
authors.forename: M G
authors.initials: MG
authors.lastname: Page
authors.forename: J L
authors.initials: JL
authors.lastname: Specklin
authors.forename: F K
authors.initials: FK
authors.lastname: Winkler
mesh_terms: D002443:Ceftriaxone / Q000494:pharmacology; D016971:Citrobacter freundii / Q000201:enzymology; D019818:Clavulanic Acid; D002969:Clavulanic Acids / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D004357:Drug Synergism; D004754:Enterobacter / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007769:Lactams; D008958:Models, Molecular; D015394:Molecular Structure; D011549:Pseudomonas / Q000187:drug effects / Q000201:enzymology; D013056:Spectrophotometry, Ultraviolet; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C101609:3-(2-cyanoethenyl)-3-methyl-4,4,7-trioxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid; D002969:Clavulanic Acids; D004791:Enzyme Inhibitors; D007769:Lactams; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D019818:Clavulanic Acid; D002443:Ceftriaxone