Nanomolar β-glucosidase and β-galactosidase inhibition by enantiomeric α-1-C-alkyl-1,4-dideoxy-1,4-imino-arabinitol derivatives

Eur J Med Chem. 2023 Feb 5:247:115056. doi: 10.1016/j.ejmech.2022.115056. Epub 2022 Dec 28.

Abstract

A series of α-1-C-alkyl DAB (1,4-dideoxy-1,4-imino-d-arabinitol) and LAB (1,4-dideoxy-1,4-imino-l-arabinitol) derivatives with aryl substituents have been designed as analogues of broussonetine W (12), and assayed as glycosidase inhibitors. While the inhibition spectrum of α-1-C-alkyl DAB derivative 16 showed a good correlation to that of broussonetine W (12), introduction of substituents on the terminal aryl (17a-f) or hydroxyl groups at C-1' position of the alkyl chains (18a-e) decreased their α-glucosidase inhibitions but greatly improved their inhibitions of bovine liver β-glucosidase and β-galactosidase. Furthermore, epimerization of C-1' configurations of compounds 18a-e clearly lowered their inhibition potency of bovine liver β-glucosidase and β-galactosidase. Notably, some of the α-1-C-alkyl DAB derivatives were also found to have potent human lysosome β-glucosidase inhibitions. In contrast, enantiomers of compounds 18a-e and 1'-epi-18a-e generally showed increased α-glucosidase inhibitions, but sharply decreased bovine liver β-glucosidase and β-galactosidase inhibitions. Molecular docking calculations unveiled the novel two set of binding modes for each series of compounds; introduction of C-1' hydroxyl altered the conformations of the pyrrolidine rings and orientation of their long chains, resulting in improved accommodation in the hydrophobic grooves. The compounds reported herein are very potent β-glucosidase and β-galactosidase inhibitions with novel binding mode; and the structure-activity relationship provides guidance for design and development of more pyrrolidine pharmacological chaperones for lysosomal storage diseases.

Keywords: DAB/LAB derivatives; Iminosugars; Molecular docking; Structure activity relationship; β-glucosidase and β-galactosidase inhibitor.

MeSH terms

  • Animals
  • Cattle
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Molecular Docking Simulation
  • Pyrrolidines / pharmacology
  • Structure-Activity Relationship
  • alpha-Glucosidases* / metabolism
  • beta-Galactosidase
  • beta-Glucosidase*

Substances

  • alpha-Glucosidases
  • arabitol
  • beta-Galactosidase
  • beta-Glucosidase
  • broussonetine W
  • Enzyme Inhibitors
  • Pyrrolidines
  • 1,4-dideoxy-1,4-iminoarabinitol