Gérard, Stéphane
Galleni, Moreno
Dive, Georges
Marchand-Brynaert, Jacqueline
[UCL]
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).
Bibliographic reference |
Gérard, Stéphane ; Galleni, Moreno ; Dive, Georges ; Marchand-Brynaert, Jacqueline. Synthesis and evaluation of N1/C4-substituted beta-lactams as PPE and HLE inhibitors.. In: Bioorganic & medicinal chemistry, Vol. 12, no. 1, p. 129-38 (2004) |
Permanent URL |
http://hdl.handle.net/2078.1/9700 |