Penicillins

Jastrzebski, Johann T. B. H.; VanKoten, Gerard

doi:10.1016/b978-008096518-5.00020-4

“…It is widely accepted that the high reactivity of b-lactam antibiotics results from the lack of amide resonance in the 2-azetidinone ring [1][2][3]. In penams (1), penems (2, X ¼ S) and carbapenems (2, X ¼ CH 2 ), the p electrons of the N-C]O function cannot be delocalized over the three atoms owing to the structural constraints which prevent the amide substituents to lie in the same plane.…”

Section: Introductionmentioning

confidence: 99%

Large ring 1,3-bridged 2-azetidinones: Experimental and theoretical studies

Urbach

¹

,

Dive

²

,

Tinant

³

et al. 2009

European Journal of Medicinal Chemistry

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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.

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“…It is widely accepted that the high reactivity of b-lactam antibiotics results from the lack of amide resonance in the 2-azetidinone ring [1][2][3]. In penams (1), penems (2, X ¼ S) and carbapenems (2, X ¼ CH 2 ), the p electrons of the N-C]O function cannot be delocalized over the three atoms owing to the structural constraints which prevent the amide substituents to lie in the same plane.…”

Section: Introductionmentioning

confidence: 99%

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

Urbach

¹

,

Dive

²

,

Marchand‐Brynaert

³

2009

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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.

show abstract