7-Alkylidenecephalosporin Esters as Inhibitors of Human Leukocyte Elastase
- 1 October 1997
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 40 (21) , 3423-3433
- https://doi.org/10.1021/jm970351x
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.Keywords
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