Design, synthesis and biological evaluation of small molecules as potent glucosidase inhibitors

Eur J Med Chem. 2015 Jul 15:100:188-96. doi: 10.1016/j.ejmech.2015.04.059. Epub 2015 Apr 30.

Abstract

Herein we have reported design, synthesis and in vitro biological evaluation of a library of bicyclic lactams that led to the discovery of compounds 6 and 7 as a novel class of α-glucosidase inhibitors. They inhibited α-glucosidase (yeast origin) in a mixed type of inhibition with an IC50 of ∼150 nM. Molecular docking studies further substantiated screening results. Interestingly phenotypic screening of this library against the human malaria parasite revealed 7 as a potent antiplasmodial agent.

Keywords: Alpha-glucosidase; Antiplasmodial; Dihydroxylation; Epoxidation; Virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glucosidases / antagonists & inhibitors*
  • Glucosidases / metabolism
  • Humans
  • Malaria, Falciparum / drug therapy
  • Malaria, Falciparum / parasitology
  • Models, Molecular
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Saccharomyces cerevisiae / enzymology
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Glucosidases