Research output: Contribution to journal › Article › peer-review
8.11 MB, PDF document
Journal | Journal of the American Chemical Society |
---|---|
Date | E-pub ahead of print - 30 Mar 2018 |
Date | Published (current) - 2018 |
Number of pages | 4 |
Pages (from-to) | 1-4 |
Early online date | 30/03/18 |
Original language | English |
Gluco-azoles competitively inhibit glucosidases by transition-state mimicry and their ability to interact with catalytic acid residues in glucosidase active sites. We noted that no azole-type inhibitors described, to date, possess a protic nitrogen characteristic for 1 H-imidazoles. Here, we present gluco-1 H-imidazole, a gluco-azole bearing a 1 H-imidazole fused to a glucopyranose-configured cyclitol core, and three close analogues as new glucosidase inhibitors. All compounds inhibit human retaining β-glucosidase, GBA1, with the most potent ones inhibiting this enzyme (deficient in Gaucher disease) on a par with glucoimidazole. None inhibit glucosylceramide synthase, cytosolic β-glucosidase GBA2 or α-glucosidase GAA. Structural, physical and computational studies provide first insights into the binding mode of this conceptually new class of retaining β-glucosidase inhibitors.
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Project: Research project (funded) › Research
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