br Introduction Diabetes mellitus DM is a chronic metabolic

Introduction Diabetes mellitus (DM) is a chronic metabolic disorder characterized by elevated levels of glucose in the blood. Type 1 diabetes is characterized by insufficient insulin production and needs a daily administration of insulin. Actually, no prevention is known for Type 1 diabetes. Type 2 diabetes normally occurs in adults, only recently seen also in children, and results from an ineffective use by the body of the insulin produced. Healthy lifestyle and body weight, and regular physical activity are recommended to prevent or delay the onset of Type 2 diabetes. The World Health Organization (WHO) estimates that 422million people worldwide suffer from diabetes. In 2012 1.5million deaths were directly caused by this pathology and it is believed that it will be the 7th leading cause of death in 2030. Diabetes can be successfully controlled by the administration of insulin and/or effective oral antidiabetic drugs; however it remains a significant cause of morbidity and mortality because of the gradual development of debilitating complications such as cardiovascular disease, neuropathy, nephropathy, retinopathy, cataracts, which negatively affect the quality of life and life expectancy of diabetic patients. These complications arise from chronic hyperglycemia, which is the initiating cause of diabetic tissue damage. In fact, diabetes selectively damages 1295 that does not efficiently reduce the glucose transport inside the cell when these are exposed to hyperglycemia, such as endothelial cells and mesangial cells, leading to high glucose levels inside the cell.2, 3, 4 Among the hypotheses that have been proposed the most accredited theory supported by experimental and clinical evidence suggests that the pathogenic mechanisms leading to diabetes complications is connected to glucose metabolism via the activation of the polyol pathway. In normal physiological conditions, glucose is phosphorylated by hexokinase while in hyperglycemic conditions the excess of glucose is metabolized through the polyol pathway. Aldose reductase (alditol: NADP+ oxidoreductase, EC1.1.1.2, ALR2), is a monomeric ubiquitous cytoplasmatic protein member of the aldo-keto reductase super family (AKR) which consists of several enzymes that perform oxidoreduction reactions on a wide variety of substrates.6, 7 ALR2 is a widely expressed enzyme. It has been identified in various tissues like the brain, kidney, liver, lens and skeletal muscle tissue. ALR2 is the first and rate-limiting enzyme in the polyol pathway of glucose metabolism8, 9 and normally catalyzes the reduction of toxic aldehydes in cells to inactive alcohols; but when the concentration of glucose in the cell becomes too high it also catalyzes the NADPH-dependent reduction of glucose to sorbitol which is later oxidized to fructose by sorbitol dehydrogenase (SDH), with NAD+ as the cofactor (Fig. 1). In pathological conditions the accumulation of the high concentration of sorbitol inside the cell causes osmotic stress and it has been postulated that it contributes to the development of diabetic complications. In hyperglycemic conditions an increase in the activity of ALR2 causes oxidative stress due to imbalance in the ratios of NADPH/NADP+ and NADH/NAD+ that may mediate the pathogenesis of several diabetic complications like caractogenesis, retinopathy, nephropathy, neuropathy and microangiopathy.8, 11, 12 It has been demonstrated that the polyol pathway has a central role in ischemic injury in fact, the increase of ALR2 activity is detrimental under ischemic conditions and impedes functional and metabolic recovery during reperfusion. Recently, its implication has been established in inflammatory and neoplastic processes.13, 14, 15 In this context, the inhibition of ALR2 is a promising therapeutic strategy useful in preventing or delaying the onset of diabetes complications and controlling their evolution. During the last decades extensive efforts have been directed towards the development of aldose reductase inhibitors (ARIs) as therapeutic tools for the prevention and/or arrest of the progression of long-term diabetic complications.17, 18 Many compounds belonging to structurally different classes have been identified as potent in vitro ALR2 inhibitors. Generally, these inhibitors contain a cyclic amide group, such as in sorbinil, fidarestat, minalrestat, ranirestat, or acetic acid moiety, like in tolrestat, alrestatin, epalrestat, zopolrestat, but also phenolic groups as in quercetin (Fig. 2).