title: Synthesis and evaluation of N1/C4-substituted beta-lactams as PPE and HLE inhibitors.
abstract: 4-(Alkylamino)carbonyl-1-(alkoxy)carbonyl-2-azetidinones (9-11) have been prepared in five steps from 4-(benzyloxy)carbonyl-1-(t-butyldimethyl)silyl-2-azetidinone (1). The beta-lactam reactivity of 9 has been established by 1H NMR experiment. Compound 11 was a good reversible inhibitor of PPE and HLE. Based on theoretical design, series of 2-azetidinones (12-17) and 4-(alkoxy)carbonyl-2-azetidinones (18-21) bearing various carbonyl (ester, thiolester, amide) and thiocarbonyl (thioamide) functionalities at position N1 were similarly prepared. In the absence of C4-substituent, the compounds were inactive against elastases. On the other hand, 4-(benzyloxy)carbonyl-1-(ethylthioxy)carbonyl-2-azetidinone (19) and 4-(benzyloxy)carbonyl-1-(benzylamino)thiocarbonyl-2-azetidinone (21) were both good reversible inhibitors, but acting most probably via different mechanisms (enzymic processing of the exocyclic ester function or beta-lactam ring opening).
authors.affiliation: Unité de Chimie Organique et Médicinale, Université catholique de Louvain, Bâtiment Lavoisier, place Louis Pasteur 1, B-1348, Louvain-la-Neuve, Belgium.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gérard
authors.forename: Moreno
authors.initials: M
authors.lastname: Galleni
authors.forename: Georges
authors.initials: G
authors.lastname: Dive
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Marchand-Brynaert
mesh_terms: D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity; D013552:Swine; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C116379:2-azetidinone; D001384:Azetidines; D004791:Enzyme Inhibitors; D047090:beta-Lactams; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase