Synthesis and aldose reductase inhibitory activity of substituted 2(1H)-benzimidazolone- and oxindole-1-acetic acids

Howard, HR; Sarges, Reinhard; Siegel, TW; Ta, Beyer

doi:10.1016/0223-5234(92)90112-e

Cited by 24 publications

(5 citation statements)

References 38 publications

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“…As part of an ongoing effort to identify potent and selective ARIs, in view of our long experience in indole chemistry, − we decided to support the acetic acid residue, essential for the inhibition of the enzyme, with the 2-oxoindole nucleus. It has been reported in the literature that potent in vitro inhibition of ALR2 has been observed with a number of acetic acid or spiro-hydantoin derivatives of oxoindole. At first, following a published procedure, we prepared the 2-oxoindol-3-ylacetic acid 60 (Chart ) and evaluated its ALR2 inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2003

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2003

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“…All the synthesized compounds were found active in general, but their coupled products with HES were found even more active, as expected. 2,3-Dihydro-3-(4-nitrobenzensulfonyl)-2-oxo-1Hbenzimidazolone (17) was found most potent of all the synthesized compounds with a 54% reduction in blood glucose level of the rats as compared to 41% reduction produced by tolbutamide and 38% by glucophage. On coupling with HES 10100 , the activity increased further to 67% reduction in blood glucose level as compared to 54% by the drug itself.…”

Section: ■ Conclusionmentioning

confidence: 94%

“…15 In addition, a wide variety of other biochemical and pharmacological properties of these compounds have also been demonstrated. They antagonize neurotransmitters, 16 inhibit aldose reductase, 17 show antiulcer and antisecretory properties, 18 enhance pulmonary surfactant secretion, and modulate ion channels. 19 Several of these compounds show activity against leukemia.…”

Section: ■ Introductionmentioning

confidence: 99%

Conjugates of Degraded and Oxidized Hydroxyethyl Starch and Sulfonylureas: Synthesis, Characterization, and in Vivo Antidiabetic Activity

et al. 2014

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Orally administered drugs usually face the problem of low water solubility, low permeability, and less retention in bloodstream leading to unsatisfactory pharmacokinetic profile of drugs. Polymer conjugation has attracted increasing interest in the pharmaceutical industry for delivering such low molecular weight (Mw) drugs as well as some complex compounds. In the present work, degraded and oxidized hydroxyethyl starch (HES), a highly biocompatible semisynthetic biopolymer, was used as a drug carrier to overcome the solubility and permeability problems. The HES was coupled with synthesized N-arylsulfonylbenzimidazolones, a class of sulfonylurea derivatives, by creating an amide linkage between the two species. The coupled products were characterized using GPC, FT-IR, (1)H NMR, and (13)C NMR spectroscopy. The experiments established the viability of covalent coupling between the biopolymer and N-arylsulfonylbenzimidazolones. The coupled products were screened for their in vivo antidiabetic potential on male albino rats. The coupling of sulfonylurea derivatives with HES resulted in a marked increase of the hypoglycemic activity of all the compounds. 2,3-Dihydro-3-(4-nitrobenzensulfonyl)-2-oxo-1H-benzimidazole coupled to HES10100 was found most potent with a 67% reduction in blood glucose level of the rats as compared to 41% reduction produced by tolbutamide and 38% by metformin.

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“…Alternatively, the sodium salt of compound 234 was treated with tert-butyl bromoacetate and the product 235 was hydrolyzed with trifluoroacetic acid to give the final acid 237, retaining the double bond. Oxindole derivatives 233, 236, and 237 are in vitro inhibitors of aldose reductase 96 which is a key component of the procedure 97,98 in which an increase in the flux of glucose through the polyol pathway is implicated in the development of chronic complications in diabetes. 99 In another study, compound 238 was synthesized via exhaustive methylation of oxindole.…”

Section: Scheme 71mentioning

confidence: 99%

Oxindole as starting material in organic synthesis

Ziarani¹,

Gholamzadeh²,

Lashgari³

et al. 2013

Arkivoc

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Synthesis and aldose reductase inhibitory activity of substituted 2(1H)-benzimidazolone- and oxindole-1-acetic acids

Cited by 24 publications

References 38 publications

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

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

Conjugates of Degraded and Oxidized Hydroxyethyl Starch and Sulfonylureas: Synthesis, Characterization, and in Vivo Antidiabetic Activity

Oxindole as starting material in organic synthesis

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