title: 7-alkylidenecephalosporin esters as inhibitors of human leukocyte elastase.
abstract: A series of 7-alkylidenecephalosporins and 7-vinylidenecephalosporins, as their benzhydryl esters, have been tested as inhibitors of both porcine pancreatic elastase and human leukocyte elastase. Selected 7-alkylidenecephalosporin esters are found to be potent inhibitors of HLE. One category of new inhibitors is the 7-(haloalkylidene)cephalosporins. In contrast to previously reported cephalosporin-based elastase inhibitors, these haloalkylidene cephems show optimum inhibitory activity as sulfides, rather than as sulfones. They are efficient and irreversible inhibitors. A second class of active compounds is represented by the benzhydryl ester 7-(cyanomethylidene)cephalosporin sulfone. In contrast to the activity of these new inhibitors, the benzhydryl ester of the mechanism-based beta-lactamase inhibitor, 7-[(2'-pyridyl)methylidene]-cephalosporin sulfone showed little inhibitory activity as an elastase inhibitor. 7-Vinylidenecephalosporins were also relatively poor inhibitors, although the terminally unsubstituted allene sulfide showed activity as an inhibitor of PPE. A modeling analysis suggests the 7-alkylidene substituents can be readily accommodated in the S1 pocket. A potential mechanism of inhibition is proposed.
authors.affiliation: Department of Chemistry, Southern Methodist University, Dallas, Texas 75275, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Buynak
authors.forename: A S
authors.initials: AS
authors.lastname: Rao
authors.forename: G P
authors.initials: GP
authors.lastname: Ford
authors.forename: C
authors.initials: C
authors.lastname: Carver
authors.forename: G
authors.initials: G
authors.lastname: Adam
authors.forename: B
authors.initials: B
authors.lastname: Geng
authors.forename: B
authors.initials: B
authors.lastname: Bachmann
authors.forename: S
authors.initials: S
authors.lastname: Shobassy
authors.forename: S
authors.initials: S
authors.lastname: Lackey
mesh_terms: D000818:Animals; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013552:Swine
chemical_list: D002511:Cephalosporins; D004791:Enzyme Inhibitors; D004952:Esters; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase