Design, synthesis and α-glucosidase inhibition study of novel embelin derivatives

Xiaole Chen; Min Gao; Rongchao Jian; Weiqian David Hong; Xiaowen Tang; Yuling Li; Denggao Zhao; Kun Zhang; Wenhua Chen; Xi Zheng; Zhaojun Sheng; Panpan Wu

doi:10.1080/14756366.2020.1715386

Design, synthesis and α-glucosidase inhibition study of novel embelin derivatives

J Enzyme Inhib Med Chem. 2020 Dec;35(1):565-573. doi: 10.1080/14756366.2020.1715386.

Authors

Xiaole Chen¹, Min Gao¹, Rongchao Jian¹, Weiqian David Hong^{1

2

3}, Xiaowen Tang¹, Yuling Li¹, Denggao Zhao^{1

2}, Kun Zhang^{1

2

4}, Wenhua Chen^{1

2}, Xi Zheng^{1

2}, Zhaojun Sheng^{1

2}, Panpan Wu^{1

2

4}

Affiliations

¹ School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, P.R. China.
² International Healthcare Innovation Institute (Jiangmen), Jiangmen, P.R. China.
³ Department of Chemistry, University of Liverpool, Liverpool, UK.
⁴ School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, P.R. China.

Abstract

Embelin is a naturally occurring para-benzoquinone isolated from Embelia ribes (Burm. f.) of the Myrsinaceae family. It was first discovered to have potent inhibitory activity (IC₅₀ = 4.2 μM) against α-glucosidase in this study. Then, four series of novel embelin derivatives were designed, prepared and evaluated in α-glucosidase inhibition assays. The results show that most of the embelin derivatives synthesised are effective α-glucosidase inhibitors, with IC₅₀ values at the micromolar level, especially 10d, 12d, and 15d, the IC₅₀ values of which are 1.8, 3.3, and 3.6 μM, respectively. Structure-activity relationship (SAR) studies suggest that hydroxyl groups in the 2/5-position of para-benzoquinone are very important, and long-chain substituents in the 3-position are highly preferred. Moreover, the inhibition mechanism and kinetics studies reveal that all of 10d, 12d, 15d, and embelin are reversible and mixed-type inhibitors. Furthermore, docking experiments were carried out to study the interactions between 10d and 15d with α-glucosidase.

Keywords: Embelin; anti-diabetes; benzoquinone; hypoglycaemic agent; α-glucosidase inhibitor.

MeSH terms

Benzoquinones / chemical synthesis
Benzoquinones / chemistry
Benzoquinones / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Embelia / chemistry
Glycoside Hydrolase Inhibitors / chemical synthesis
Glycoside Hydrolase Inhibitors / chemistry
Glycoside Hydrolase Inhibitors / pharmacology*
Humans
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
alpha-Glucosidases / metabolism*

Substances

Benzoquinones
Glycoside Hydrolase Inhibitors
alpha-Glucosidases
embelin

Grants and funding

This work was supported by the Natural Science Foundation of Guangdong Province [No. 2016A030310441], National Natural Science Foundation of China [No. 81803390], the Special Fund Project of Science and Technology Innovation Strategy in Guangdong Province [No. Jiangke(2018)352], Jiangmen Science and Technology Project of Basic and Theoretical Science Research [No. 2019030102100008866], Science Foundation for Young Teachers of Wuyi University [No. 2016td01], the Foundation of Department of Education of Guangdong Province [Nos. 2017KQNCX200 and 2017KSYS010] and Innovation and Entrepreneurship Training Program for Undergraduates of Guangdong Province.