Title | Monosaccharide inhibitors targeting carbohydrate esterase family 4 de-N-acetylases. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | DiFrancesco, BR, Morrison, ZA, Nitz, M |
Journal | Bioorg Med Chem |
Volume | 26 |
Issue | 21 |
Pagination | 5631-5643 |
Date Published | 2018 11 15 |
ISSN | 1464-3391 |
Abstract | The Carbohydrate Esterase family 4 contains virulence factors which modify peptidoglycan and biofilm-related exopolysaccharides. Despite the importance of this family of enzymes, a potent mechanism-based inhibition strategy has yet to emerge. Based on the postulated tridentate binding mode of the tetrahedral de-N-acetylation intermediate, GlcNAc derivatives bearing metal chelating groups at the 2 and 3 positions were synthesized. These scaffolds include 2-C phosphonate, 2-C sulfonamide, 2-thionoacetamide warheads as well as derivatives bearing thiol, amine and azide substitutions at the 3-position. The inhibitors were assayed against a representative peptidoglycan deacetylase, Pgda from Streptococcus pneumonia, and a representative biofilm-related exopolysaccharide deacetylase, PgaB from Escherichia coli. Of the inhibitors evaluated, the 3-thio derivatives showed weak to moderate inhibition of Pgda. The strongest inhibitor was benzyl 2,3-dideoxy-2-thionoacetamide-3-thio-β-d-glucoside, whose inhibitory potency showed an unexpected dependence on metal concentration and was found to have a partial mixed inhibition mode (K = 2.9 ± 0.6 μM). |
DOI | 10.1016/j.bmc.2018.10.008 |
Alternate Journal | Bioorg. Med. Chem. |
PubMed ID | 30344002 |
Grant List | / / CIHR / Canada |