Design, synthesis, in vitro and in silico investigation of aldose reductase inhibitory effects of new thiazole-based compounds

Abstract

Aldose reductase (AR) catalyzes the NADPH-dependent reduction of glucose to sorbitol in the polyol pathway, which plays an important role in the development of diabetic complications including cataract, retinopathy, nephropathy, and neuropathy. AR has been considered as an important target to heal these long-term diabetic complications and for this reason the development of new AR inhibitors is an important approach in modern medicinal chemistry. In the current study, new 4-aryl-2-[2-((3,4-dihydro-2H-1,5-benzodioxepine-7-yl)methylene)hydrazinyl]thiazole derivatives (1-12) were synthesized and screened for their inhibitory effects on AR which was purified by diverse chromatographic methods with a yield of 1.40% and a specific activity of 2.00 EU/mg. All compounds were determined as promising AR inhibitors with the Ki values in the range of 0.018 +/- 0.005 mu M-3.746 +/- 1.321 mu M compared to the quercetin (Ki = 7.025 +/- 1.780 mu M). In particular, 4(4-cyanophenyl)-2-[2-((3,4-dihydro-2H-1,5-benzodioxepin-7-yl)methylene)hydrazinyl]thiazole (3) was detected as the most potential AR inhibitor in this series with the Ki value of 0.018 +/- 0.005 mu M and the compound showed competitive AR inhibition. The cytotoxic effects of compounds 1-12 were investigated on L929 mouse fibroblast (healthy) cells using MTT assay and all these compounds were defined as non-cytotoxic agents against L929 cells. Molecular docking studies, which were employed to determine the affinity of compounds 1-12 into the active site of AR, highlighted that the thiazole scaffold of all these compounds presented pi-pi stacking interactions with Trp20 and Phe122. According to both in vitro and in silico assays, these potential AR inhibitors may have great importance in the prevention of diabetic microvascular conditions.