Identification of Novel Aldose Reductase Inhibitors Based on Carboxymethylated Mercaptotriazinoindole Scaffold

Abstract

Fifteen compounds, sharing an indole-1-acetic acid moiety as a common fragment, were selected from commercial databases for testing aldose reductase inhibition. 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (13) was the most promising inhibitor, with an IC50 in the submicromolar range and high selectivity, relative to aldehyde reductase. The crystal structure of aldose reductase complexed with 13 revealed an interaction pattern explaining its high affinity. Physicochemical parameters underline the excellent "leadlikeness" of 13 as a promising candidate for further structure optimizations.

Antioxidant action of 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid, an efficient aldose reductase inhibitor, in a 1,1′-diphenyl-2-picrylhydrazyl assay and in the cellular system of isolated erythrocytes exposed totert-butyl hydroperoxide

“…Compound 1 belongs to a group of novel carboxymethylated mercapto-triazino-indole derivatives, recently projected as aldose reductase inhibitors. 39 The biological activity of 1 was characterized with an IC 50 in submicromolar range for aldose reductase inhibition and high selectivity in relation to congeneric aldo-keto reductases. In addition, physicochemical properties of 1 corresponding to excellent 'drug-likeness' render the compound a prospective agent with a therapeutic potential in the treatment of diabetic complications.…”

“…This finding is in agreement with preferred thione tautomeric forms of 1 at neutral pH shown before. 39 Analogically, 2-mercaptopyrimidines, 44 substituted 1,2,4-triazole-3-thiones, 45 and the mercaptoimidazole derivative ergothioneine 46 exist in water solutions predominantly in the thione tautomer forms.…”

A Novel Carboxymethylated Mercaptotriazinoindole Inhibitor of Aldose Reductase Interferes With the Polyol Pathway in Streptozotocin-Induced Diabetic Rats

“…64 acid (CMTI) was characterized by a corresponding IC 50 value in a submicromolar region. A reasonable degree of selectivity with respect to the closely related aldehyde reductase and AKR1B10 oxidoreductase (Stefek et al 2015) was recorded.…”

“…Recently novel carboxymethylated mercaptotriazinoindoles have been identified as efficient inhibitors of aldose reductase (Stefek et al 2015). Of them, 3-mercapto- 5H-1,2,4-triazino[5,6-b]indole-5-acetic Vol.…”

“…The study was approved by the Ethics Committee of the Institute and performed in accordance with the Principles of Laboratory Animal Care (NIH publication 83-25, revised 1985) and the Slovak law regulating animal experiments (Decree 289, Part 139, July 9th 2003). The CMTI substance was provided by Matrix Scientific (Columbia, SC, USA) in 99.5 % purity, determined by the LC-MS technique (Stefek et al 2015).…”