title: Synthesis of new pyrimidine-fused derivatives as potent and selective antidiabetic α-glucosidase inhibitors.
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.
authors: Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran; Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran.
authors: Farhad
authors: F
authors: Panahi
authors: Reza
authors: R
authors: Yousefi
authors: Mohammad Hossein
authors: MH
authors: Mehraban
authors: Ali
authors: A
authors: Khalafi-Nezhad
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013552:Swine; D000516:alpha-Amylases / Q000037:antagonists & inhibitors; D000520:alpha-Glucosidases / Q000737:chemistry
chemical_list: D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D008024:Ligands; D011743:Pyrimidines; D000516:alpha-Amylases; D000520:alpha-Glucosidases; C030986:pyrimidine
keywords: Antidiabetic; Inhibitors; Pyrimidine-fused heterocycles; α-Glucosidase