title: Pyrimidine-fused heterocycle derivatives as a novel class of inhibitors for α-glucosidase.
abstract: The needs for diverse inhibitors of α-glucosidase (α-Gls) encouraged us to synthesize five different poly-hydroxy functionalized pyrimidine-fused heterocyclic (PHPFH) molecules, having either aliphatic or aromatic side chains (C1-C5) and their inhibitory activities were examined spectroscopically against yeast and mouse intestinal α-Gls. The results revealed that aromatic substitution of the synthetic compounds has significant impact on their inhibitory properties. Moreover C3 with the substituted moiety as 4-(4-aminophenylsulfonyl) phenyl (4-APSP) revealed strong inhibitory activity with non-competitive and competitive inhibition modes against yeast and mouse α-Gls, respectively. Furthermore, in the presence of increasing concentration of C3, both Trp and 1-anilinonaphthalene-8-sulfonic acid (ANS) fluorescence intensities of yeast α-Gls were gradually decreased, suggesting that C3 binding induced significant structural alteration which was accompanied with the reduction of hydrophobic surfaces. Also, the interaction between yeast α-Gls and C3 was proved to be spontaneous and driven mainly by hydrophobic forces. Overall, this study suggests that aromatic substitution on pyrimidine-fused heterocyclic (PFH) scaffold may represent a novel class of promising inhibitors of α-Gls.
authors.affiliation: Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University , Shiraz , Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Yousefi
authors.forename: Mohammad-Mehdi
authors.initials: MM
authors.lastname: Alavian-Mehr
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Mokhtari
authors.forename: Farhad
authors.initials: F
authors.lastname: Panahi
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Mehraban
authors.forename: Ali
authors.initials: A
authors.lastname: Khalafi-Nezhad
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D000520:alpha-Glucosidases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D006571:Heterocyclic Compounds; D008024:Ligands; D011743:Pyrimidines; D000520:alpha-Glucosidases