Synthesis and evaluation of novel 7- and 8-aminophenoxazinones for the detection of β-alanine aminopeptidase activity and the rapid identification of Pseudomonas aeruginosa in clinical samples

Bedernjak, Alexandre, Zaytsev, A.V., Babolat, M., Cellier, M., James, A.L., Orenga, S., Perry, J.D., Groundwater, Paul and Anderson, Rosaleen (2016) Synthesis and evaluation of novel 7- and 8-aminophenoxazinones for the detection of β-alanine aminopeptidase activity and the rapid identification of Pseudomonas aeruginosa in clinical samples. Journal of Medicinal Chemistry. ISSN 0022-2623

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Abstract

A series of novel 8-aminophenoxazin-3-one and 7-aminophenoxazin-3-one chromogens and their corresponding β-alanine derivatives were synthesized and evaluated for their ability to detect β-alanyl aminopeptidase activity in bacteria known to hydrolyse β-alanine derivatized substrates. The results provided insight into the structural requirements for effective visualization of enzymatic activity and the mechanism of formation of phenoxazinon-3-ones. 8-Aminophenoxazin-3-one substrates 23c, 23d and 23e were prepared in good to high overall yield and were selective for β-alanyl aminopeptidase activity in bacteria, producing a lighter agar background coloration facilitating visualization of colored colonies, with variable localization to the colonies, but had lower sensitivities for the detection of Pseudomonas aeruginosa in comparison to the analogous 7-aminophenoxazin-3-one substrates. The synthetic methodology employed here allows the preparation of a range of substrates for evaluation and the establishment of structure-activity relationships. For example, the 2-pentyl substituted aminophenoxazin-3-one 22b performed with analogous sensitivity to the corresponding 1-pentyl-7-aminophenoxazin-3-one substrate 1 used commercially, highlighting that the position of the pentyl substituent can be varied while maintaining detection sensitivity.

Item Type: Article
Subjects: Sciences
Divisions: Faculty of Applied Sciences
Faculty of Applied Sciences > Department of Pharmacy Health and Wellbeing
Health Sciences and Wellbeing Beacon
Health Sciences and Wellbeing Beacon > Drug Discovery and Application Workstream
Depositing User: Paula Normington
Date Deposited: 10 May 2016 14:14
Last Modified: 19 Sep 2017 16:04
URI: http://sure.sunderland.ac.uk/id/eprint/6287

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