Synthesis and evaluation of N1/C4-substituted beta-lactams as PPE and HLE inhibitors

[en] 4-(Alkylamino)carbonyl-1-(alkoxy)carbonyl-2-azetidinones (9-11) have been prepared in five steps from 4-(benzyloxy)carbonyl-1-(t-butyidimethyl)silyl-2-azetidinone (1). The P-lactam reactivity of 9 has been established by H-1 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). (C) 2003 Elsevier Ltd. All rights reserved.

Disciplines :

Pharmacy, pharmacology & toxicology
Chemistry
Biochemistry, biophysics & molecular biology

Author, co-author :

Gérard, Stéphane

Galleni, Moreno

Dive, Georges ; Université de Liège - ULiège > Centre d'ingénierie des protéines

Marchand-Brynaert, Jacqueline

Language :

English

Title :

Synthesis and evaluation of N1/C4-substituted beta-lactams as PPE and HLE inhibitors

Publication date :

02 January 2004

Journal title :

Bioorganic and Medicinal Chemistry

ISSN :

0968-0896

eISSN :

1464-3391

Publisher :

Pergamon-Elsevier Science Ltd, Oxford, United Kingdom

Volume :

Issue :

Pages :

129-138

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 28 November 2009

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