Large ring 1,3-bridged 2-azetidinones: experimental and theoretical studies.
The relationship between angular strain and (re)activity of bicyclic 2-azetidinones is still an open question of major concern in the field of penicillin antibiotics. Our study deals with original 13-membered-ring 1,3-bridged 2-azetidinones related to the carbapenem family, and featuring a "planar amide" instead of the "twisted amide" typical of penam derivatives. The bicycles 11 and 12 were obtained from acetoxy-azetidinone 7, via the key-intermediate 10, by using the RCM (ring closing metathesis) strategy. Theoretical predictions and experimental results of hydrolysis showed that the large bicycle 12, endowed with high conformational flexibility, is more reactive than the bicycle 11, including a CC bond of E configuration, and the monocyclic 2-azetidinone precursor 10. The processing of 2-azetidinones 10-12 in the active site of serine enzymes has been computed by ab initio methods, considering three models. Due to geometrical parameters of the enzymic cavity (nucleophilic attack from the alpha-face), precursor 10 was predicted more active than 11 and 12 in the acylation step by Ser-OH. Indeed, bicycles 11 and 12 are modest inhibitors of PBP(2a), while 10 is a good to excellent inhibitor of PBP(2a) and R39 bacterial enzymes.
Urbach
Allan
A
Université catholique de LouvainUnité de Chimie Organique et Médicinale, Bâtiment Lavoisier, Place Louis Pasteur n degrees 1, 1348 Louvain-la-Neuve, Belgium.
Dive
Georges
G
Tinant
Bernard
B
Duval
Valérie
V
Marchand-Brynaert
Jacqueline
J
D000900:Anti-Bacterial Agents; D001384:Azetidines / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D010406:Penicillins; D012697:Serine Endopeptidases / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship
C116379:2-azetidinone; D000900:Anti-Bacterial Agents; D001384:Azetidines; D010406:Penicillins; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases