Identification of quinoxalin-2(1H)-one Derivatives as a Novel Class of Multifunctional Aldose Reductase Inhibitors

Abstract

Aim: Targeting aldose reductase and oxidative stress with quinoxalin-2(1H)-one derivatives having a 1-hydroxypyrazole head as the bioisosteric replacement of carboxylic acid. Methodology & results: Aldose reductase inhibition, selectivity and antioxidant potency of all the synthesized compounds were evaluated, and binding modes were studied by molecular docking. Most of the derivatives showed potent and selective aldose reductase inhibition, and among them 13d was the most active (IC₅₀ = 0.107 μM), suggesting success of the bioisosteric strategy. Phenolic 3,4-dihydroxyl compound 13f showed strong antioxidant ability even comparable to that of the well-known antioxidant Trolox. Conclusion: The present study identified the excellent bioisostere of the 1-hydroxypyrazole head group along with phenolic hydroxyl and vinyl spacer in C3 side chain on constructing quinoxalinone-based multifunctional aldose reductase inhibitors.

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Keywords: :

• 1-hydroxypyrazole
• aldehyde reductase
• aldose reductase
• antioxidant activity
• diabetic complications
• molecular docking
• multifunctional inhibitors
• oxidative stress
• quinoxalinones
• structure–activity relationships

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/epi-2016-0184

Financial & competing interests disclosure

This work was supported by the National Natural Science Foundation of China (grant no. 21272025 and 21572021), the Research Fund for the Doctoral Program of Higher Education of China (grant no. 20111101110042), Beijing Natural Science Foundation (grant no. 7142096) and Funding for school-level research projects of Yancheng Instidude of Technology (grant no. xjr2019013). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations