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Gluco-1 H-imidazole: A New Class of Azole-Type β-Glucosidase Inhibitor

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  • Sybrin P Schröder
  • Liang Wu
  • Marta Artola
  • Thomas Hansen
  • Wendy A Offen
  • Maria J. Ferraz
  • Kah-Yee Li
  • Johannes M F G Aerts
  • Gijsbert A. Van Der Marel
  • Jeroen D C Codée
  • Gideon J Davies
  • Herman S. Overkleeft


Publication details

JournalJournal of the American Chemical Society
DateE-pub ahead of print - 30 Mar 2018
DatePublished (current) - 2018
Number of pages4
Pages (from-to)1-4
Early online date30/03/18
Original languageEnglish


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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© 2018 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

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