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Chandrakala PS , Katz AK , Carrell HL , Sailaja PR , Podile AR , Nangia A , Desiraju GR
Synthesis, X-ray crystal structures and biological evaluation of some mono- and bi-cyclic 1,3-diazetidin-2-ones: non-natural beta-lactam analogues
Journal of the Chemical Society-Perkin Transactions 1. 1998 Aug 21 :2597-2608
PMID: ISI:000075664000023   
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Abstract
Mono- and bi-cyclic 1,3-diazetidin-2-ones (aza-beta-lactams) are synthesised and evaluated as non-natural analogues of beta- lactams, The aza-beta-lactams are designed on the principle that their reaction with active site serine hydroxy will form a carbamoyl-enzyme intermediate that is sluggish to hydrolysis, The synthesis of racemic mono- and bi-cyclic aza-beta-lactams is carried out starting from pyrimidinone 18 which is transformed to the densely functionalised substrate 20, The chemical reactivity of tricarbonyl 20 for selective functional group manipulation was first assessed and then it was transformed to amino alcohol 24, Cyclisation of 24 affords aza- carbapenams and its homologation followed by aldol cyclisation provides access to aza-carbacephams. The X-ray structures of aza-carbapenam 35 and aza-carbacepham 42 suggest that the structural requirements for biological activity in B-lactams are fulfilled. An unexpected ozonolysis product, phenol 52 resolves spontaneously during crystallisation and its crystal structure was also determined. The biological activity of the novel mono- and bi-cyclic aza-beta-lactams was evaluated with potent gram-positive bacterial strain, Bacillus subtilis and compared with beta-lactam antibiotics, ampicillan and penicillin G, Of the 19 aza-beta-lactams tested, eight compounds show inhibition better than the standards while another eight are of comparable activity. This study shows that aza-beta-lactams represent a novel and non-natural lead towards serine peptidase inhibitors.
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Times Cited: 6 English Article 115KT J CHEM SOC PERKIN TRANS 1