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Synthesis and Evaluation of Novel 7-and 8-Aminophenoxazinones for the Detection of beta-Alanine Aminopeptidase Activity and the Reliable Identification of Pseudomonas aeruginosa in Clinical Samples

Lookup NU author(s): Dr Victorovich Zaytsev, Dr John Perry, Dr Jerome Anderson

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

A series of novel 8-aminophenoxazin-3-one and 7-aminophenoxazin-3-one chromogens and their corresponding beta-alanine derivatives were synthesized and evaluated for their ability to detect beta-alanyl aminopeptidase activity in bacteria known to hydrolyze beta-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 beta-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.

Publication metadata

Author(s): Bedernjak AF, Zaytsev AV, Babolat M, Cellier M, James AL, Orenga S, Perry JD, Groundwater PW, Anderson RJ

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2016

Volume: 59

Issue: 10

Pages: 4476-4487

Print publication date: 26/05/2016

Online publication date: 20/04/2016

Acceptance date: 02/04/2016

Date deposited: 17/03/2017

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society

URL: http://dx.doi.org/10.1021/acs.jmedchem.5b01591

DOI: 10.1021/acs.jmedchem.5b01591

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