Selective trihydroxylated azepane inhibitors of NagZ, a glycosidase involved in Pseudomonas aeruginosa resistance to β-lactam antibiotics

Organic & Biomolecular Chemistry
J BouquetJ Désiré

Abstract

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 NHCOCF3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human O-GlcNAcase and lysosomal hexosaminidases HexA and B.

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Citations

Nov 1, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Harold SpeddingFei Liu
Nov 21, 2019·Protein Science : a Publication of the Protein Society·Jed F Fisher, Shahriar Mobashery
May 31, 2018·Chemical Reviews·David A DikShahriar Mobashery

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