Synthesis, inhibitory activity towards human leukocyte elastase and molecular modelling studies of 1-carbamoyl-4-methyleneaminoxyazetidinones

• Published in: European journal of medicinal chemistry 2000, Vol.35 (1), p.53-67
• Main Authors: Macchia, Bruno, Gentili, Daniela, Macchia, Marco, Mamone, Francesca, Martinelli, Adriano, Orlandini, Elisabetta, Rossello, Armando, Cercignani, Giovanni, Pierotti, Rita, Allegretti, Marcello, Asti, Cinzia, Caselli, Gianfranco
• Format: Article
• Language: English
• Subjects: 1-carbamoyl-4-methyleneaminoxyazetidinone derivative; Animals; Azetidines - chemistry; Biological and medical sciences; elastase inhibitor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Hemorrhage - chemically induced; Hemorrhage - drug therapy; Humans; Lactams - chemical synthesis; Lactams - pharmacology; Leukocyte Elastase - antagonists & inhibitors; Lung Diseases - chemically induced; Lung Diseases - drug therapy; Medical sciences; Mice; Models, Molecular; oxime derivative; Pharmacology. Drug treatments; Phenylacetates - pharmacology; Respiratory system; β-lactam monocyclic inhibitor
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/S0223-5234(00)00111-2

Some monocyclic β-lactam derivatives of type 3 (MAOAs) in which the leaving group (LG) on the C(4) is a methyleneaminoxy moiety, were synthesised and tested in vitro and in vivo for their inhibitory activity towards human leukocyte elastase (HLE). Some compounds showed an appreciable in vitro inhibitory activity against this enzyme. Effects on the anti-HLE activity due to the nature of the substituents R and R 1 present on their LG were observed and rationalised by means of molecular modelling techniques. The results of in vivo pharmacological tests indicated that MAOAs, while showing an inhibitory activity on the haemorrhage induced by HLE, did not exhibit any effects due to the R and R 1 substituents.