Selective trihydroxylated azepane inhibitors of NagZ, a glycosidase involved in Pseudomonas aeruginosa resistance to β-lactam antibioticsElectronic supplementary information (ESI) available: Copies of 1H, 19F and 13C spectra of all new compounds; glycosidase assays. See DOI: 10.1039/c7ob00838d

The synthesis of a series of d - gluco -like configured 4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinated acetamide moiety at C-3 is described. These synthetic derivatives have been tested for their ability to selectively inhibit the muropeptide recycling glucosaminidase Na...

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Main Authors: Bouquet, J, King, D. T, Vadlamani, G, Benzie, G. R, Iorga, B, Ide, D, Adachi, I, Kato, A, Vocadlo, D. J, Mark, B. L, Blériot, Y, Désiré, J
Format: Article
Language:English
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Summary:The synthesis of a series of d - gluco -like configured 4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinated acetamide moiety at C-3 is described. These synthetic derivatives have been tested for their ability to selectively inhibit the muropeptide recycling glucosaminidase NagZ and to thereby increase sensitivity of Pseudomonas aeruginosa to β-lactams, a pathway with substantial therapeutic potential. While introduction of triazole and sulfamide groups failed to lead to glucosaminidase inhibitors, the NHCOCF 3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human O -GlcNAcase and lysosomal hexosaminidases HexA and B. Fluorination of the NHCOCH 3 moiety of a trihydroxylated azepane-based broad hexosaminidase inhibitor significantly improves its selectivity toward bacterial NagZ.
ISSN:1477-0520
1477-0539
DOI:10.1039/c7ob00838d