[1,2,4]Triazino[4,3-a]benzimidazole Acetic Acid Derivatives:  A New Class of Selective Aldose Reductase Inhibitors

Abstract

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.

Aldose reductase structures: implications for mechanism and inhibition

“…Generally, these inhibitors contain either a cyclic imide group, such as a spirohydantoin group [52] or a spirosuccinimide group [53], or an acetic acid moiety [54]. The best known of the spirohydantoin-contain- Multi-author Review Article 755 Rakowitz et al [63] synthesised diphenylmethyleneaminooxycarboxylic acids as novel ARIs and then prepared ester derivatives of the most active analogue (IC 50 = 33 mM) for evaluation as prodrugs; various esters tested showed different propensity for stability or ease of cleavage and hydrolysis.…”

“…Rastelli et al [96] carried out such a study on a class of inhibitors, 7-hydroxy-2-substituted-4H-1-benzopyran-4-one, which they had previously reported to be potent and selective inhibitors of ALR2 [54]. The relative binding energies of three analogues of 7-hydroxy-2-benzyl-4H-1-benzopyran-4-one were predicted by FEP simulations.…”

Geometrically Constrained Analogues of N‐Benzylindolylglyoxylylamides: [1, 2, 4]Triazino[4, 3‐a]benzimidazol‐4(10H)‐one Derivatives as Potential New Ligands at the Benzodiazepine Receptor

“…The synthetic procedure employed to prepare the triazinobenzimidazole derivatives 14, 15 involved the reaction of the appropriate 2-hydrazinobenzimidazole 16, 17 [14,15] with diethylketomalonate in refluxing absolute ethanol. For the synthesis of amide derivatives 4-12, the ester intermediate 14 was allowed to react with the appropriate amine in refluxing xylene.…”

“…The following compounds were prepared in accordance with reported procedures: [1,2,4]triazino [4,3-a]benzimidazol-3,4(10H)-dione 13 [13,15]; 2-hydrazino benzimidazole 16 [14,15]; 1-methyl-2-hydrazinobenzimidazole 17 [14,15]. [1,2,4]triazino [4,3-a]…”

Recent advances on the synthesis of azoles, azines and azepines fused to benzimidazole

“…Pyridobenzimidazoles have also anxiolytic activity in humans, [11][12][13] and pyrimidobenzimidazoles were anti-rheumatic agents. 14 Also, 1,2,4-triazinobenzimidazoles were found to be aldose reductase inhibitors 15 and to possess antimicrobial activity. 16 There are a large number of pharmacologically interesting benzimidazole molecules fused to a five membered rings containing one heteroatom (pyrrolobenzimidazoles), two heteroatoms (pyrazolo-, imidazo-, oxazolo-, and thiazolo-benzimidazoles) and three heteroatoms (triazolo-, thiadiazolo-and oxadiazolo-benzimidazoles).…”