quercetin and Galactosemias

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.

Topics: Acetates; Aldehyde Reductase; Animals; Cataract; Enzyme Inhibitors; Galactosemias; Humans; Indoles; Models, Molecular; Ophthalmic Solutions; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship

Acetic acid derivatives of [1,2,4]triazino[4,3-a]benzimidazole (TBI) were synthesized and tested in vitro and in vivo as a novel class of aldose reductase (ALR2) inhibitors. Compound 3, (10-benzyl[1,2,4]triazino[4,3-a]benzimidazol-3,4(10H)-dion-2-yl)acetic acid, displayed the highest inhibitory activity (IC(50) = 0.36 microM) and was found to be effective in preventing cataract development in severely galactosemic rats when administered as an eyedrop solution. All the compounds investigated were selective for ALR2, since none of them inhibited appreciably aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The activity of 3 was lowered by inserting various substituents on the pendant phenyl ring, by shifting the acetic acid moiety from the 2 to the 3 position of the TBI nucleus, or by cleaving the TBI system to yield benzimidazolylidenehydrazines as open-chain analogues. A three-dimensional model of human ALR2 was built, taking into account the conformational changes induced by the binding of inhibitors such as zopolrestat, to simulate the docking of 3 into the enzyme active site. The theoretical binding mode of 3 was fully consistent with the structure-activity relationships in the TBI series and will guide the design of novel ALR2 inhibitors.

Topics: Acetates; Aldehyde Reductase; Animals; Benzimidazoles; Binding Sites; Cataract; Enzyme Inhibitors; Galactosemias; Humans; Models, Molecular; Ophthalmic Solutions; Protein Binding; Rats; Stereoisomerism; Structure-Activity Relationship; Triazines