Chandrakala, P. S. ; Katz, Amy K. ; Sailaja, P. R. ; Podile, A. R. ; Nangia, Ashwini ; Desiraju, Gautam R. (1998) Synthesis, x-ray crystal structures and biological evaluation of some mono- and bi-cyclic 1,3-diazetidin-2-ones: non-natural β -lactam analogues Journal of the Chemical Society, Perkin Transactions 1 (16). pp. 2597-2608. ISSN 0300-922X
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Official URL: http://pubs.rsc.org/en/Content/ArticleLanding/1998...
Related URL: http://dx.doi.org/10.1039/A802438C
Abstract
Mono- and bi-cyclic 1,3-diazetidin-2-ones (aza-β -lactams) are synthesised and evaluated as non-natural analogues of β -lactams. The aza-β -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-β -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 β -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-β -lactams was evaluated with potent gram-positive bacterial strain, Bacillus subtilis and compared with β -lactam antibiotics, ampicillin and penicillin G. Of the 19 aza-β -lactams tested, eight compounds show inhibition better than the standards while another eight are of comparable activity. This study shows that aza-β -lactams represent a novel and non-natural lead towards serine peptidase inhibitors.
Item Type: | Article |
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Source: | Copyright of this article belongs to Royal Society of Chemistry. |
ID Code: | 11424 |
Deposited On: | 09 Nov 2010 06:08 |
Last Modified: | 16 May 2016 20:53 |
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