7-ALKYLIDENECEPHALOSPORIN ESTERS AS INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE

A series of 7-alkylidenecephalosporins and 7-vinylidenecephalosporins, as their benzhydryl esters, have been tested as inhibitors of both po rcine pancreatic elastase and human leukocyte elastase. Selected 7-alk ylidenecephalosporin 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 inhi bitors, these haloalkylidene cephems show optimum inhibitory activity as sulfides, rather than as sulfones. They are efficient and irreversi ble inhibitors. A second class of active compounds is represented by t he benzhydryl ester 7-(cyanomethylidene)cephalosporin sulfone. In cont rast to the activity of these new inhibitors, the benzhydryl ester of the mechanism-based beta-lactamase inhibitor, 7-(2'-pyridyl)methyliden e]cephalosporin sulfone showed little inhibitory activity as an elasta se inhibitor. 7-Vinylidenecephalosporins were also relatively poor inh ibitors, although the terminally unsubstituted allene sulfide showed a ctivity as an inhibitor of PPE. A modeling analysis suggests the 7-alk ylidene substituents can be readily accommodated in the S1 pocket. A p otential mechanism of inhibition is proposed.