Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy

Xin Zhang; Huan Chen; Yanqi Lei; Xiaonan Zhang; Long Xu; Wenchao Liu; Zhenya Fan; Zequn Ma; Zhechang Yin; Lingyun Li; Changjin Zhu; Bing Ma

doi:10.1016/j.ejmech.2021.113269

Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy

Eur J Med Chem. 2021 Apr 5:215:113269. doi: 10.1016/j.ejmech.2021.113269. Epub 2021 Feb 7.

Authors

Xin Zhang¹, Huan Chen², Yanqi Lei³, Xiaonan Zhang⁴, Long Xu⁵, Wenchao Liu⁶, Zhenya Fan⁷, Zequn Ma⁸, Zhechang Yin⁹, Lingyun Li¹⁰, Changjin Zhu¹¹, Bing Ma¹²

Affiliations

¹ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081, Beijing, China. Electronic address: 1175852337@qq.com.
² School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081, Beijing, China. Electronic address: chenhuaninbuct@163.com.
³ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081, Beijing, China. Electronic address: 15313252939@163.com.
⁴ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081, Beijing, China. Electronic address: zhangxiaonan965@163.com.
⁵ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081, Beijing, China. Electronic address: 1938270368@qq.com.
⁶ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081, Beijing, China. Electronic address: Liuwhhh@163.com.
⁷ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081, Beijing, China. Electronic address: 729266587@qq.com.
⁸ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081, Beijing, China. Electronic address: 834238277@qq.com.
⁹ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081, Beijing, China. Electronic address: 2261820165@qq.com.
¹⁰ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081, Beijing, China. Electronic address: 3220191170@bit.edu.cn.
¹¹ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081, Beijing, China. Electronic address: zcj@bit.edu.cn.
¹² School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081, Beijing, China. Electronic address: mabing@bit.edu.cn.

PMID: 33588177
DOI: 10.1016/j.ejmech.2021.113269

Abstract

Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.

Keywords: Antioxidants; Diabetic nephropathy; Drug design; Hypoglycemic; Inhibitors.

MeSH terms

Aldehyde Reductase / antagonists & inhibitors
Aldehyde Reductase / metabolism
Animals
Antioxidants / chemical synthesis
Antioxidants / metabolism
Antioxidants / therapeutic use*
Benzoxazoles / chemical synthesis
Benzoxazoles / metabolism
Benzoxazoles / therapeutic use*
Diabetes Mellitus, Experimental / drug therapy
Diabetic Nephropathies / drug therapy*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / therapeutic use*
HEK293 Cells
Humans
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / metabolism
Hypoglycemic Agents / therapeutic use*
Mice
Molecular Docking Simulation
Molecular Structure
Protein Binding
Structure-Activity Relationship

Substances

Antioxidants
Benzoxazoles
Enzyme Inhibitors
Hypoglycemic Agents
benzoxazolone
Aldehyde Reductase