title: Design and synthesis of potent and multifunctional aldose reductase inhibitors based on quinoxalinones.
abstract: Quinoxalin-2(1H)-one based design and synthesis produced several series of aldose reductase (ALR2) inhibitor candidates. In particular, phenolic structure was installed in the compounds for the combination of antioxidant activity and strengthening the ability to fight against diabetic complications. Most of the series 6 showed potent and selective effects on ALR2 inhibition with IC50 values in the range of 0.032-0.468 μM, and 2-(3-(2,4-dihydroxyphenyl)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (6e) was the most active. More significantly, most of the series 8 revealed not only good activity in the ALR2 inhibition but also potent antioxidant activity, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid (8d) was even as strong as the well-known antioxidant Trolox at a concentration of 100 μM, verifying the C3 p-hydroxystyryl side chain as the key structure for alleviating oxidative stress. These results therefore suggest an achievement of multifunctional ALR2 inhibitors having both potency for ALR2 inhibition and as antioxidants.
authors.affiliation: Department of Applied Chemistry, Beijing Institute of Technology , Zhongguancun South Street, 100081 Beijing, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Qin
authors.forename: Xin
authors.initials: X
authors.lastname: Hao
authors.forename: Hui
authors.initials: H
authors.lastname: Han
authors.forename: Shaojuan
authors.initials: S
authors.lastname: Zhu
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Yang
authors.forename: Bobin
authors.initials: B
authors.lastname: Wu
authors.forename: Saghir
authors.initials: S
authors.lastname: Hussain
authors.forename: Shagufta
authors.initials: S
authors.lastname: Parveen
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* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011810:Quinoxalines; D000449:Aldehyde Reductase