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An Efficient Synthesis of Quinoxalinone Derivatives as Potent Inhibitors of Aldose Reductase
Author(s) -
Yang Yanchun,
Zhang Shuzhen,
Wu Bobin,
Ma Mingming,
Chen Xin,
Qin Xiangyu,
He Minlan,
Hussain Saghir,
Jing Chaojun,
Ma Bing,
Zhu Changjin
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200054
Subject(s) - aldose reductase , side chain , quinoxaline , chemistry , acetic acid , stereochemistry , ether , docking (animal) , chemical synthesis , enzyme , combinatorial chemistry , organic chemistry , in vitro , biochemistry , medicine , nursing , polymer
A novel and facile synthesis of quinoxalinone derivatives was developed in which a wide range of 3‐chloroquinoxalin‐2(1 H )‐ones as key intermediates can be generated chemo‐ and regioselectively in good yields from corresponding quinoxaline‐2,3(1 H ,4 H )‐diones. This new protocol is arguably superior, as it allows the design and preparation of a variety of bioactive quinoxaline‐based compounds, which are particularly effective in the treatment of diabetes and its complications. Through this procedure, a new class of quinoxalinone‐based aldose reductase inhibitors were synthesized successfully. Most of the inhibitors, with an N1‐acetic acid head group and a substituted C3‐phenoxy side chain, proved to be potent and selective. Their IC 50 values ranged from 11.4 to 74.8 n M . Among them, 2‐(3‐(4‐bromophenoxy)‐7‐fluoro‐2‐oxoquinoxalin‐1(2 H )‐yl)acetic acid and 2‐(6‐bromo‐3‐(4‐bromophenoxy)‐2‐oxoquinoxalin‐1(2 H )‐yl)acetic acid were the most active. Structure–activity relationship and molecular docking studies highlighted the importance of the ether spacer in the C3‐phenoxy side chains, and provided clear guidance on the contribution of substitutions both at the core structure and the side chain to activity.