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
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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, 59 (10). pp. 4476-4487. 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 Health Sciences and Wellbeing Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences |
| Depositing User: | Paula Normington |
| Date Deposited: | 10 May 2016 14:14 |
| Last Modified: | 01 Apr 2020 14:18 |
| URI: | http://sure.sunderland.ac.uk/id/eprint/6287 |
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