Novel, Highly Potent Aldose Reductase Inhibitors:  Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic Acid Derivatives

Abstract

Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives were synthesized and tested as a novel class of aldose reductase (ALR2) inhibitors. Each compound was evaluated as a diastereomeric mixture, due to tautomeric equilibria in solution. The parent compound 39 exhibited a good inhibitory activity with an IC(50) value of 0.85 microM, similar to that of the well-known ARI sorbinil (IC(50) 0.50 microM). The concurrent introduction of a halogen and a lipophilic group in the 5- and in the 1-positions, respectively, of the indole nucleus of 39, gave compound 55, cyano[5-fluoro-1-(4-methylbenzyl)-2-oxo-2,3-dihydroindol-3-yl]acetic acid, which displayed the highest activity (IC(50) 0.075 microM, very close to that of tolrestat IC(50) 0.046 microM), with a good selectivity toward ALR2 compared with aldehyde reductase (ALR1) (16.4-fold), and no appreciable inhibitory properties against sorbitol dehydrogenase (SD), or glutathione reductase (GR). The isopropyl ester 59, a prodrug of 55, was found to be almost as effective as tolrestat in preventing cataract development in severely galactosemic rats when administered as an eye drop solution. Docking simulation of 55 into a three-dimensional model of human ALR2 made it possible to formulate the hypothesis that the 2-hydroxy tautomer was the active species binding into the catalytic site of the enzyme. This was fully consistent with the structure-activity relationships within this series of cyanooxoindolylacetic acid derivatives.

A Fluorous, Pummerer Cyclative‐Capture Strategy for the Synthesis of N‐Heterocycles

“…1 5-Chloro-1-methyl-1H-indole-2,3-dione: [37] General procedure D was followed. Thus, treatment of 5-chloro-3- (3,3,4,4,5,5,6,6,7,7,8 5-Fluoro-1-methyl-1H-indole-2,3-dione: [38] General procedure D was followed. Thus, treatment of 8 (0.15 g, 0.23 mmol, 1 equiv) with CAN (0.38 g, 0.70 mmol, 3 equiv) and purification by using fluorous silica (eluting with 80 % MeCN/H 2 O then MeCN) gave the title compound (42 mg, 0.23 mmol, 100 %) as an orange solid.…”

Substituted derivatives of indole acetic acid as aldose reductase inhibitors with antioxidant activity: structure-activity relationship

“…The ALR2 inhibition activities of structurally related derivatives were recorded, namely those of 1-indole butanoic acid with IC 50 values ranging from 7.4 to 37 μmol/l (Sun et al 2003), cyano(2-oxo-2,3-dihydroindole-3-ylidene) acetic acid with IC 50 varying from 0.075 to 5.40 μmol/l (Da Settimo et al 2003) and (3-benzoylindol-1-yl)acetic acid with 38% ALR2 inhibition at 1 μmol/l concentration (Nicolaou and Demopoulos 2003). Mild ALR2 inhibitory activity of 2-phenylindole derivatives was recorded by Suzen et al (2007).…”

“…Other authors recorded the ALR2 inhibition activity of acidic derivatives of structurally related indoles (Da Settimo et al 2003;Nicolaou and Demopoulos 2003;Sun et al 2003;Suzen and Buyukbingol 2003;Suzen et al 2007). The antioxidant activity of indole-based compounds has recently been thoroughly reviewed (Suzen 2006(Suzen , 2007Stolc et al 2006;Suzen et al 2006;Reiter et al 2008;Augustyniak et al 2010;Juranek et al 2010;Shirinzadeh et al 2010).…”

Preliminary evaluation of rat kidney aldose reductase inhibitory activity of 2-phenylindole derivatives: affiliation to antioxidant activity

“…Highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid derivatives (van Zandt et al, 2005), cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives (da Settimo et al, 2003), (2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-yl)-acetic acid (Djoubissie et al, 2006), [5-(4-pyrrol-1-yl-benzoyl)-1H-pyrrol-2-yl)]-acetic acid (Ananostou et al, 2002), 1-(6-hydroxyindole-1-yl)-2,2-dimethylpropan-1-one (Demopoulos et al, 2003), and 5-(3 0 -indolyl)-2-thiohydantoin (Buyukbingol et al, 1994) can be considered as some of the important examples. Recently it has been shown that diabetes is associated with increased oxidative stress (Spycher et al, 1997).…”