Synthesis and evaluation of N1/C4-substituted beta-lactams as PPE and HLE inhibitors.
(2004) Bioorganic & Medicinal Chemistry : the tetrahedron journal for research at the interface of chemistry and biology — Vol. 12, n° 1, p. 129-138 (2004)
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- 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).
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Gérard, S., Galleni, M., Dive, G., & Marchand-Brynaert, J. (2004). Synthesis and evaluation of N1/C4-substituted beta-lactams as PPE and HLE inhibitors. Bioorganic & Medicinal Chemistry : the tetrahedron journal for research at the interface of chemistry and biology, 12(1), 129-138. https://doi.org/10.1016/j.bmc.2003.10.009 (Original work published 2004)