Designing of acyl sulphonamide based quinoxalinones as multifunctional aldose reductase inhibitors

Yunpeng Ji; Xin Chen; Huan Chen; Xin Zhang; Zhenya Fan; Lina Xie; Bing Ma; Changjin Zhu

doi:10.1016/j.bmc.2019.03.015

Designing of acyl sulphonamide based quinoxalinones as multifunctional aldose reductase inhibitors

Bioorg Med Chem. 2019 Apr 15;27(8):1658-1669. doi: 10.1016/j.bmc.2019.03.015. Epub 2019 Mar 7.

Authors

Yunpeng Ji¹, Xin Chen², Huan Chen¹, Xin Zhang¹, Zhenya Fan¹, Lina Xie¹, Bing Ma³, Changjin Zhu⁴

Affiliations

¹ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081 Beijing, China.
² ME Genomics Inc., Software Industry Base, Shenzhen 518061, China.
³ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081 Beijing, China. Electronic address: mabing@bit.edu.cn.
⁴ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081 Beijing, China. Electronic address: zcj@bit.edu.cn.

PMID: 30858026
DOI: 10.1016/j.bmc.2019.03.015

Abstract

A series of quinoxalinone scaffold-based acyl sulfonamides were designed as aldose reductase inhibitors and evaluated for aldose reductase (ALR2)/aldehyde reductase (ALR1) inhibition and antioxidation. Compounds 9b-g containing styryl side chains at C3-side exhibited good ALR2 inhibitory activity and selectivity. Of them, 9g demonstrated the most potent inhibitory activity with an IC₅₀ value of 0.100 μM, and also exhibited excellent antioxidant activity, even comparable to the typical antioxidant Trolox. Compounds 9 had higher lipid-water partition coefficients relative to the carboxylic acid compounds 8, indicating that they may have better lipophilicity and membrane permeability. Structure-activity relationship (SAR) studies found that acyl trifluoromethanesulfonamide group at N1 and the C3-dihydroxystyryl side chain were the key structure for improving the aldose reductase inhibitory activity and antioxidant activity.

Keywords: Acyl trifluoromethanesulfonamide; Aldose reductase inhibitor; Antioxidant; Lipid-water partition coefficient; Molecular docking; Quinoxalinone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aldehyde Reductase / antagonists & inhibitors*
Aldehyde Reductase / chemistry
Aldehyde Reductase / metabolism
Antioxidants / chemistry
Antioxidants / pharmacology
Drug Design
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Humans
Molecular Docking Simulation
Quinoxalines / chemistry*
Quinoxalines / pharmacology*
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / pharmacology

Substances

Antioxidants
Enzyme Inhibitors
Quinoxalines
Sulfonamides
Aldehyde Reductase