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

J Am Chem Soc. 2018 Apr 18;140(15):5045-5048. doi: 10.1021/jacs.8b02399. Epub 2018 Apr 4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azoles / chemical synthesis
  • Azoles / chemistry
  • Azoles / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • beta-Glucosidase / antagonists & inhibitors*
  • beta-Glucosidase / metabolism

Substances

  • Azoles
  • Enzyme Inhibitors
  • beta-Glucosidase