title: An efficient synthesis of quinoxalinone derivatives as potent inhibitors of aldose reductase.
abstract: A novel and facile synthesis of quinoxalinone derivatives was developed in which a wide range of 3-chloroquinoxalin-2(1H)-ones as key intermediates can be generated chemo- and regioselectively in good yields from corresponding quinoxaline-2,3(1H,4H)-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 nM. Among them, 2-(3-(4-bromophenoxy)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid and 2-(6-bromo-3-(4-bromophenoxy)-2-oxoquinoxalin-1(2H)-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.
authors.affiliation: Department of Applied Chemistry, Beijing Institute of Technology, Beijing, China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Yang
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Zhang
authors.forename: Bobin
authors.initials: B
authors.lastname: Wu
authors.forename: Mingming
authors.initials: M
authors.lastname: Ma
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Qin
authors.forename: Minlan
authors.initials: M
authors.lastname: He
authors.forename: Saghir
authors.initials: S
authors.lastname: Hussain
authors.forename: Chaojun
authors.initials: C
authors.lastname: Jing
authors.forename: Bing
authors.initials: B
authors.lastname: Ma
authors.forename: Changjin
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D020134:Catalytic Domain; D003920:Diabetes Mellitus / Q000188:drug therapy; D015195:Drug Design; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D011810:Quinoxalines; D000449:Aldehyde Reductase