Naphtho[1,2-d]isothiazole Acetic Acid Derivatives as a Novel Class of Selective Aldose Reductase Inhibitors

Abstract

Acetic acid derivatives of naphtho[1,2-d]isothiazole (NiT) were synthesized and tested as novel aldose reductase (ALR2) inhibitors. The parent compound 11 exhibited a fair inhibitory activity (IC(50) = 10 muM), which was enhanced by 2 orders of magnitude by introducing a second carboxylic group at position 4 (13 and 14: IC(50) = 0.55 and 0.14 muM, respectively). Substitution of the acetic acid function with an apolar group gave inactive (29) or poorly active (25, 26, 30) compounds, thus demonstrating that the 2-acetic group is involved in the enzyme pharmacophoric recognition while the 4-carboxylic moiety has only an accessory role. The potent compounds 11, 13, 14, 26 all proved to be selective for ALR2, since none of them inhibited aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The isopropyl ester 31, a prodrug of 14, was found to be effective in preventing cataract development in severely galactosemic rats, when administered as an eyedrop solution. The theoretical binding mode of 13 and 14, obtained by docking simulations into the ALR2 crystal structure, was fully consistent with the structure-activity relationships in the NiT series.

Functional Oil from Black Seed Differentially Inhibits Aldose-reductase and Ectonucleotidase Activities by Up-regulating Cellular Energy in Haloperidol-induced Hepatic Toxicity in Rat Liver

“…Aldose reductase activity was assayed by estimating the consumption of NADPH as described by Da Settimo et al 15 . Briefly, the reaction mixture contained 4.67 mmol/L D,L-glyceraldehyde as substrate, 0.11 mmol/L NADPH, 0.067 mol/L phosphate buffer pH 6.2 , and 0.05 mL of the enzyme preparation rat liver homogenate in a total volume of 1.5 mL.…”

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

“…Ponalrestat was withdrawn from clinical trials due to lack of efficacy. Besides, a number of potent ARIs were recently designed and synthesized based on various chemical core structures including (benzothiazol-2-yl)methylindole (lidorestat) [36], naphtho [1,2-d]isothiazole [55], oxadiazole [56], aromatic thiadiazine-1,1-dioxide [57,58], and quinoxalinone [59]. All of them bear a chemical group of acetic acid on the core.…”

Synthesis and Activity of a New Series of(Z)-3-Phenyl-2-benzoylpropenoic Acid Derivatives as Aldose Reductase Inhibitors

“…In these last molecules a planar aromatic structure with a carboxylic or another acidic proton appears to be essential for the inhibitory effect [2,3]. Chalcones, considered as the precursor of flavonoids and isoflavonoids, are abundant in edible plants [4], and have also been shown to display a diverse array of pharmacological activities, such as anti-protozoal [5], anti-inflammatory [6], anticancer [7] and antihyperglycemic properties [8].…”