Design, synthesis and biological evaluation of selective hybrid coumarin-thiazolidinedione aldose reductase-II inhibitors as potential antidiabetics.

Thiazolidinediones (TZD), benzopyrans are the proven scaffolds for inhibiting Aldose reductase (ALR2) activity and their structural confluence with the retention of necessary fragments helped in designing a series of hybrid compounds 2-(5-cycloalkylidene-2,4-dioxothiazolidin-3-yl)-N-(2-oxo-2H-chromen-3-yl)acetamide (10a-n) for better ALR2 inhibition. The compounds were synthesized by treating substituted 3-(N-bromoacetyl amino)coumarins (9a-d) with potassium salt of 5-cyclo alkylidene-1,3-thiazolidine-2,4-diones (4a-d). The inhibition activity against ALR2 with IC50 values range from 0.012 ± 0.001 to 0.056 ± 0.007 µM. N-[(6-Bromo-3-coumarinyl)-2-(5-cyclopentylidene-2,4-dioxothiazolidin-3-yl)] acetamide (10c) with cyclopentylidene group on one end and the 6-bromo group on the other end showed better inhibitory property (IC50 = 0.012 µM) and selectivity index (324.166) against the ALR2, a forty fold superiority over sorbinil, a better molecule over epalrestat and rest of the analogues exhibited a far superior response over sorbinil and slightly better as compared with epalrestat. It was further confirmed by the insilico studies that compound 10c showed best inhibition activity among the synthesized compounds with a high selectivity index against the ALR2. In invivo experiments, supplementation of compound 10c to STZ induced rats delayed the progression of cataract in a dose-dependent manner warranting its further development as a potential agent to treat thediabetic secondary complications especially cataract.

Design and synthesis of chiral 2H-chromene-N-imidazolo-amino acid conjugates as aldose reductase inhibitors.

Aldose reductase (ALR2) inhibitors provide a viable mode to fight against diabetic complications. ALR2 exhibit plasticity in the active site vicinities and possible shifts in the nearby two supporting alpha helices. Therefore, a novel series of amino acid conjugates of chromene-3-imidazoles (13-15) were designed and synthesized based on natural isoflavonoids. The compounds were identified on the basis of spectral (1H NMR, 13C NMR and MS) data and tested in vitro for ALR2 inhibitory activity with an IC50 value ranges from 0.031 ± 0.082 µM to 4.29 ± 0.55 µM. Our in silico and biochemical studies confirmed that 15e has the best inhibition activity among the synthesized compounds with a high selective index against the Aldehyde reductase (ALR1). Supplementation of 15e to STZ induced rats decreased the blood glucose levels and delayed the progression of cataract in a dose-dependent manner. The present study thus provides novel series of compounds with a promising inhibitor to prevent or delay the cataract progression.

Inhibition of aldose reductase by Aegle marmelos and its protective role in diabetic cataract.

ETHNOPHARMACOLOGICAL RELEVANCE: Aegle marmelos (L.) Corr. Serr. (Aegle marmelos) leaves were extensively used in the Ayurvedic, Unani and Siddha systems of Indian medicine as an anti-diabetic agent, which serves as hypoglycemic agent. However, the significance of this plant on secondary complications of diabetes such as cataract remained unknown. The aim of the study was to investigate the possible anti-cataractous activity of Aegle marmelos against streptozotocin (STZ) induced diabetic cataract in rats. MATERIALS AND METHODS: Aegle marmelos leaf extract was prepared using three different solvents (petroleum ether, ethyl acetate and methanol) and tested for inhibition against rat lens aldose reductase (AR), a key enzyme of polyol pathway. Furthermore, the pharmacological potential of Aegle marmelos extract was investigated against osmotic stress induced opacification of lens in ex vivo organ culture and streptozotocin (STZ) induced diabetic cataract in rats. RESULTS: Ethyl acetate extract of Aegle marmelos inhibited rat lens AR in vitro with an IC50 value of ≈ 15 µg/ml. This extract also prevented the hyperglycemia induced increase in AR activity, sorbitol accumulation and opacification of rat lens in ex vivo lens organ culture. Supplementation of ethyl acetate extract of Aegle marmelos to STZ-induced diabetic rats decreased the blood glucose levels due to hyperglycemia and inhibited the AR activity and delayed cataract progression in dose dependent manner. α-crystallin isolated from diabetic rats fed with Aegle marmelos showed improved chaperone activity than that of isolated from rats naïve to Aegle marmelos. CONCLUSION: This study indicates that ethyl acetate extract of Aegle marmelos has pharmacologically active components with a potential to inhibit rat lens AR and consequential decrease in osmotic stress. Besides this, the present study also demonstrates that the extract prevented loss of antioxidants contributing to the integrity of α-crystallin's chaperone activity and thereby delaying cataract.