Design, Synthesis and Structure-Activity Relationship Study of Aldose Reductase Inhibitors Based on Quinoxalinone Structure

被引：0
|
作者：
Ma B. [1 ]
Fan Z. [1 ]
Wang X. [1 ]
Li C. [1 ]
Zhu C. [1 ]
机构：
[1] School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing
来源：
Beijing Ligong Daxue Xuebao/Transaction of Beijing Institute of Technology | 2021年 / 41卷 / 04期
关键词：
Aldose reductase inhibitors; Inhibitory activity; Molecular docking; Quinoxalinone;
D O I：
10.15918/j.tbit1001-0645.2020.006
中图分类号：
学科分类号：
摘要：
A series of aldose reductase(ALR2) inhibitor candidates were designed and synthesized based on quinoxalin-2(1H)-one, and a carboxyl group was introduced at N1 position. Moreover, the side chain at C3 position was modified. All compounds were tested for ALR2 inhibitory activity, showing significant inhibition. The results also show that, among them, 2-(3-(4-hydroxyphenylpropenyl)-2-oxoquinoxaline-1(2H) -alkyl) acetic acid(4d) demonstrate the most potent inhibitory activity with an IC50 value of 93 nmol/L, being equal to epalrestat(IC50=83 nmol/L), which is the only commercial aldose reductase inhibitor(ARI). In addition, molecular docking experiments reveal that compound 4d can bind tightly to the active site of aldose reductase. © 2021, Editorial Department of Transaction of Beijing Institute of Technology. All right reserved.
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页码：445 / 450
页数：5
相关论文
共 15 条
  • [1] COSCONATI S, MARINELLI L, LA Motta C, Et al., Pursuing aldose reductase inhibitors through in situ cross-docking and similarity-based virtual screening, Journal of Medicinal Chemistry, 52, 18, pp. 5578-5581, (2009)
  • [2] GABBAY K H, MEROLA L O, FIELD R A, Et al., Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes, Science, 151, 3707, pp. 209-210, (1966)
  • [3] BROWNLEE M., Biochemistry and molecular cell biology of diabetic complications, Nature, 414, 6865, pp. 813-820, (2001)
  • [4] KADOR P F, KINOSHITA J H., Role of aldose reductase in the development of diabetes-associated complications, The American Journal of Medicine, 79, 5A, pp. 8-12, (1985)
  • [5] KADOR P F., The role of aldose reductase in the development of diabetic complications, Medicinal Research Reviews, 8, 3, pp. 325-352, (1988)
  • [6] COSTANTINO L, RASTELLI G, CIGNARELLA G, Et al., New aldose reductase inhibitors as potential agents for the prevention of long-term diabetic complications, Expert Opinion on Therapeutic Patents, 7, 8, pp. 843-858, (1997)
  • [7] SINGH D C P, HASHIM S R, SINGHAL R G., Synthesis and antimicrobial activity of some new thioether derivatives of quinoxaline, E-Journal of Chemistry, 8, 2, pp. 635-642, (2011)
  • [8] WILLARDSEN J A, DUDLEY D A, CODY W L, Et al., Design, synthesis, and biological activity of potent and selective inhibitors of blood coagulation factor Xa, Journal of Medicinal Chemistry, 47, 16, pp. 4089-4099, (2004)
  • [9] HAN Z F, HAO X, MA B, Et al., A series of pyrido [2, 3-b] pyrazin-3(4H)-one derivatives as aldose reductase inhibitors with antioxidant activity, European Journal of Medicinal Chemistry, 121, pp. 308-317, (2016)
  • [10] QIN X Y, HAO X, HAN H, Et al., Design and synthesis of potent and multifunctional aldose reductase inhibitors based on quinoxalinones, Journal of Medicinal Chemistry, 58, 3, pp. 1254-1267, (2015)
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