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.

Keywords::

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

Acknowledgments

We would like to thank financial support of Iran National Science Foundation (INSF)-Grant nos. 88001578 and 88001894. Also the financial supports of research councils of Shiraz University and Shiraz University of Technology are gratefully acknowledged.

Declaration of interest

The authors declared no conflicts of interest.

Notes

ND, not determined; NI, no inhibition.