Potent, orally active aldose reductase inhibitors related to zopolrestat: surrogates for benzothiazole side chain

Abstract In this work, isatin was employed as the scaffold to design aldose reductase inhibitors with antioxidant activity. Most of the isatin derivatives were proved to be excellent in the inhibition of aldose reductase (ALR2) with IC 50 values at submicromolar level, and (E)-2-(5-(4-methoxystyryl)-2,3-dioxoindolin-1-yl) acetic acid (9g) was identified as the most effective with an IC 50 value of 0.015 μM. Moreover, compounds 9a-h with styryl side chains at the C5 position of isatin showed potent antioxidant activity. Particularly, the phenolic compound 9h demonstrated similar antioxidant activity with the well-known antioxidant Trolox. Structure-activity relationship and molecular docking studies showed that the acetic acid group at N1 and C5 p-hydroxystyryl side chain were the key structures to increase the aldose reductase inhibitory activity and antioxidant activity.

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Syntheses of tolrestat analogs containing additional substituents in the ring and their evaluation as aldose reductase inhibitors. Identification of potent, orally active 2-fluoro derivatives

Journal of Medicinal Chemistry ◽

10.1021/jm00112a029 ◽

1991 ◽

Vol 34 (8) ◽

pp. 2504-2520 ◽

Cited By ~ 10

Author(s):

Jay Wrobel ◽

Jane Millen ◽

Janet Sredy ◽

Arlene Dietrich ◽

Beverly J. Gorham ◽

...

Keyword(s):

Aldose Reductase ◽

Aldose Reductase Inhibitors ◽

Reductase Inhibitors ◽

Orally Active ◽

Fluoro Derivatives

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Benzothiazol-2-ylcarboxylic acids with diverse spacers: A novel class of potent, orally active aldose reductase inhibitors

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/s0960-894x(97)00287-4 ◽

1997 ◽

Vol 7 (13) ◽

pp. 1677-1682 ◽

Cited By ~ 4

Author(s):

Tomoji Aotsuka ◽

Naoki Abe ◽

Kanako Fukushima ◽

Naoki Ashizawa ◽

Motoyuki Yoshida

Keyword(s):

Aldose Reductase ◽

Aldose Reductase Inhibitors ◽

Reductase Inhibitors ◽

Orally Active

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Identification of quinoxalin-2(1H)-one derivatives as a novel class of multifunctional aldose reductase inhibitors

Future Medicinal Chemistry ◽

10.4155/fmc-2019-0194 ◽

2019 ◽

Vol 11 (23) ◽

pp. 2989-3004 ◽

Cited By ~ 2

Author(s):

Xin Hao ◽

Xiangyu Qin ◽

Xin Zhang ◽

Bing Ma ◽

Gang Qi ◽

...

Keyword(s):

Aldose Reductase ◽

Side Chain ◽

Head Group ◽

Binding Modes ◽

Aldose Reductase Inhibition ◽

Aldose Reductase Inhibitors ◽

Reductase Inhibitors ◽

Bioisosteric Replacement ◽

Antioxidant Potency ◽

And Oxidative Stress

Aim: Targeting aldose reductase and oxidative stress with quinoxalin-2(1 H)-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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