Synthesis of new pyrimidine-fused derivatives as potent and selective antidiabetic α-glucosidase inhibitors

Carbohydr Res. 2013 Oct 18:380:81-91. doi: 10.1016/j.carres.2013.07.008. Epub 2013 Aug 6.

Abstract

The synthesis of a set of pyrimidine-fused derivatives (L1-L8), resulting from the incorporation of different fragments on the pyrimidine-fused heterocycle (PFH) of the earlier reported α-glucosidase (α-Gls) inhibitor (C1-C5), allowed the discovery of new ligands with modest and selective inhibitory activity. The PFH core (substructure 2) was proved to play a significant role in their inhibitory properties. Additionally, the substituent on substructures 1 and 3 of the heterocyclic ring was demonstrated to be important in the enzyme inhibitory action of the pyrimidine-fused derivatives. Moreover, these ligands show selective inhibitory properties for α-Gls over porcine pancreatic α-amylase (α-Amy) which is important in terms of their reduced susceptibility for the possible development of intestinal disturbance side effects. Therefore, low to moderate α-Amy inhibition with effective α-Gls inhibitory action may offer a better therapeutic strategy. Overall, these compounds can potentially offer a new opportunity to develop novel antidiabetic drugs with selective inhibitory action against α-Gls.

Keywords: Antidiabetic; Inhibitors; Pyrimidine-fused heterocycles; α-Glucosidase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemistry Techniques, Synthetic
  • Glycoside Hydrolase Inhibitors*
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Ligands
  • Mice
  • Models, Molecular
  • Protein Structure, Secondary
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Saccharomyces cerevisiae / enzymology
  • Swine
  • alpha-Amylases / antagonists & inhibitors
  • alpha-Glucosidases / chemistry

Substances

  • Glycoside Hydrolase Inhibitors
  • Hypoglycemic Agents
  • Ligands
  • Pyrimidines
  • alpha-Amylases
  • alpha-Glucosidases
  • pyrimidine