Pyrimidine-fused heterocycle derivatives as a novel class of inhibitors for alpha-glucosidase

作者：Yousefi Reza^*; Alavian Mehr Mohammad Mehdi; Mokhtari Fatemeh; Panahi Farhad; Mehraban Mohammad H; Khalafi Nezhad Ali

来源：Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, 28(6): 1228-1235.

DOI：10.3109/14756366.2012.727812

• Alpha-glucosidase (alpha-Gls)
• pyrimidine-fused heterocycles (PFH)
• inhibition
• structural alteration

The needs for diverse inhibitors of alpha-glucosidase (alpha-Gls) encouraged us to synthesize five different poly-hydroxy functionalized pyrimidine-fused heterocyclic (PHPFH) molecules, having either aliphatic or aromatic side chains (C-1-C-5) and their inhibitory activities were examined spectroscopically against yeast and mouse intestinal alpha-Gls. The results revealed that aromatic substitution of the synthetic compounds has significant impact on their inhibitory properties. Moreover C-3 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 alpha-Gls, respectively. Furthermore, in the presence of increasing concentration of C-3, both Trp and 1-anilinonaphthalene-8-sulfonic acid (ANS) fluorescence intensities of yeast alpha-Gls were gradually decreased, suggesting that C-3 binding induced significant structural alteration which was accompanied with the reduction of hydrophobic surfaces. Also, the interaction between yeast alpha-Gls and C-3 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 alpha-Gls.

• 出版日期2013-12