Novel large ring bridged azetidinones : design, synthesis and biochemical evaluation against Penicillin Binding Proteins
(2011)
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- Authors
- Supervisors
- Marchand-Brynaert, Jacqueline
- Abstract
- (en) Since the discovery of Penicillin, bacteria counteract the action of antibiotics leading to a worrisome situation about antibiotics efficiency. We focused our research on the synthesis of non-traditional 1,3-bridged beta-lactam embedded into macrocycles as potential inhibitors of Penicillin Binding Proteins (PBPs). As the key-step of the macrocyclization, we have selected the Ring-Closing Metathesis (RCM) reaction. 12- to 22-Membered bicyclic beta-lactams were successfully synthesized by this strategy. We also unexpectedly observed bis-2-oxoazetidinyl macrocycles arising from a dimerization reaction under RCM conditions. Compounds from this last family revealed to be good inhibitors of the problematic methicillin-resistant Staphylococcus aureus (MRSA). In order to explain the biological results, the 3D structures of all the macrocycles were studied by quantum chemistry calculations, and docking experiments were also performed. Our results highlighted that the activity of the compounds is most probably related to their conformational adaptability. The activity of our 1,3-bridged macrocycles suggests a way to design novel beta-lactam antibiotics with a planar amide bond, and without a carboxylic group, a model quite different from the previous model of reactivity of "the magical drug".
- Affiliations
Citations
Sliwa, A. (2011). Novel large ring bridged azetidinones : design, synthesis and biochemical evaluation against Penicillin Binding Proteins. https://hdl.handle.net/2078.5/160532