Novel Large‐Ring 1,3‐Bridged 2‐Azetidinones as Potential Inhibitors of Penicillin‐Binding Proteins

Abstract

a b s t r a c tThe 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 C]C 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 a-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.

Crystal structure of (10R,11S,13R)-10-(methyl)-8,12-dioxo-13-(propyl)-9-oxa-1-aza-bicyclo[9.1.1]-tridecane, C15H25NO3

“…The co-existence of conformers remained to be proved by experimental methods. Conformers were detected by 1 H-NMR, only in the case of one monocyclic 2-azetidinone precursor of RCM cyclization [4]. Here, the occurrence of conformers is demonstrated in the case of one bicyclic 2-azetidinone by X-ray diffraction analysis.…”

“…The title compound was prepared in five steps from (3S,4R)-3-[1(R)-t-butyldimethylsilyloxy)-ethyl]-4-(propyl)-2-azetidinone as described in [1]. Crystallization from aceton/ether mixture (v/v,1:2) gave white crystals suitable for X-ray diffraction analysis (m.p.…”

“…This hypothesis has been validated theoretically, by ab initio quantum chemistry calculations, and experimentally for afew compounds, by the recruitement of modest inhibitors of PBPs (Penicillin Binding Proteins) [1,4]. The co-existence of conformers remained to be proved by experimental methods.…”

“…der nucleophilic attack (basic hydrolysis or processing by a serine-enzyme), an important conformational reorganization of all the molecular skeleton has to occur, and our idea was to decrease the activation barrier of the N-C(O) bond cleavage thanks to the high conformational adaptability of the bridging macrocycle [1]. This hypothesis has been validated theoretically, by ab initio quantum chemistry calculations, and experimentally for afew compounds, by the recruitement of modest inhibitors of PBPs (Penicillin Binding Proteins) [1,4].…”

The Synthesis of Macrocycles for Drug Discovery

“…159 A series of bicyclic 1,3-bridged-2-azetidinones (66 as a representative structure), which have been demonstrated to be inhibitors of penicillin-binding proteins, represents another novel macrocyclic structural class accessed by RCM methodology. [160][161][162] Interestingly, both monomer and dimer-derived structures obtained from these latter efforts have been found to have utility. The steric and conformational constraints imposed by the bicyclic structures made RCM difficult in a number of cases.…”