Identification of novel aldose reductase inhibitors based on carboxymethylated mercapto-triazino-indole scaffold
Marta Šoltésová Prnová 1
Ivana Miláčková 1
Michal Staško 1
Jana Balleková 1
Magdaléna Májeková 1
Milan Štefek 1
1 Institute of experimental pharmacology and toxicology, Slovak Academy of Sciences
|Section:||Organic, bioorganic and pharmaceutical chemistry, pharmacology|
The etiology of diabetic complications involves the polyol pathway which degrades excessive glucose by aldose reductase (ALR2). On the basis of our previous work, where we observed significant inhibition of ALR2 by 1-indole acetic acid, we searched for novel ARIs (aldose reductase inhibitors) in databases of purchasable compounds. The database consists of 19 compounds therefore 15 is indole-1-acetic acid moiety as a common fragment in their structure. Among the studied compounds, 5-carboxy-3-mercapto-1,2,4-triazino-[5,6-b]indole (compound 13) was identified as the most promising inhibitor of ALR2.
The enzyme ALR2 was isolated from rat eye lenses and aldehyde reductase (ALR1) was isolated from their kidneys. Inhibition activities of the compounds were determined by following decrease of the absorbance of NADPH. Rat lenses and erythrocytes for uptake determination was isolated form male Wistar rats 8 - 9 weeks old, weighing 200 - 230 g. The distribution ratios D in 1-octanol/buffer systems, defined by total concentration of a solute in organic phase divided by that in aqueous phase.
Analysis of the enzyme kinetics for the most efficient derivative 13 showed uncompetitive inhibition. Molecular "docking" identified key interactions with specific amino acid residues of the ALR2 binding site. The highest selectivity in relation to ALR1, characterized by selectivity factor around 400. At the organ level, compound 13 attenuated sorbitol accumulation in isolated rat eye lenses and RBC as a result of its inhibition of glucose flux through the polyol pathway, which indicates that the drug is readily taken up by the eye lens and interferes with cytosolic ALR2. The partiation coefficient (D) of 13 was given around 0.012 recorded in the system water/octanol at pH 7.4. Molecular obesity indices, in addition to the structural parameters fitting „the rule of three“, along with water solubility, points to an excellent „lead-likeness“ of compound 13, with prospects of further structure optimizations.
The compound 13 represents an effective and selective aldose reductase inhibitor with a favourable parameters of molecular obesity. This consequently shows promise in pharmacological use for the prevention of diabetic complications.