Oxy-imino saccharidic derivatives as a new structural class of aldose reductase inhibitors endowed with anti-oxidant activity

Abstract

Aldose reductase is a key enzyme in the development of long term diabetic complications and its inhibition represents a viable therapeutic solution for people affected by these pathologies. Therefore, the search for effective aldose reductase inhibitors is a timely and pressing challenge. Herein we describe the access to a novel class of oxyimino derivatives, obtained by reaction of a 1,5-dicarbonyl substrate with O-(arylmethyl)hydroxylamines. The synthesised compounds proved to be active against the target enzyme. The best performing inhibitor, compound (Z)-8, proved also to reduce both cell death and the apoptotic process when tested in an in vitro model of diabetic retinopathy made of photoreceptor-like 661w cell line exposed to high-glucose medium, counteracting oxidative stress triggered by hyperglycaemic conditions.

Clinical and Molecular-Genetic Insights into the Role of Oxidative Stress in Diabetic Retinopathy: Antioxidant Strategies and Future Avenues

“…In our opinion, the possibility remains that biotherapies based on the redox changes occurring in diabetics may help to protect the retina. In the latter concern, an interesting spectrum of presumptive factors for DR protection has been ultimately proposed, including outstanding antioxidants [ 50 , 51 , 52 , 53 ].…”

Nature-Inspired O-Benzyl Oxime-Based Derivatives as New Dual-Acting Agents Targeting Aldose Reductase and Oxidative Stress

“…Pursuing our interest in the ARI field [7][8][9][10][11][12] and prompted by our successful experience of turning the flavonoid core into the bioisosteric pyrido [1,2-a]pyrimidin-4-one nucleus, by obtaining potent and selective anti-oxidant ARIs such as 5 (Figure 1) [13], we developed a novel series of polyhydroxylated (E)-benzaldehyde O-benzyl oximes 6-11 (Figure 1) as prototypes of dual-acting ARIs inspired by the stilbene derivative resveratrol A thorough survey of the most recent literature in the ARI field highlights an increasingly interest in natural compounds, mainly represented by polyhydroxylated flavonoids as quercetin (2, Figure 1), chalcones as butein (3, Figure 1), and coumarins as scopoletin (4, Figure 1), obtained from different plant species [2]. Besides fully addressing the current policy of the World Health Organization (WHO), which promotes the integration of traditional herbal medicines into the health care practices of countries [3], the use of these derivatives is justified by their multifunctional profile, which combines a promising ARI activity with a potent anti-oxidant efficacy.…”

Synthesis, Molecular Docking Analysis and Biological Evaluations of Saccharide-Modified Thiadiazole Sulfonamide Derivatives

“…Saccharides have the characteristics of low toxicity, high polarity, and high solubility. In the area of medicinal chemistry, glycol derivatives and glycosyl modification compounds have shown a wide range of pharmacological activities [ 18 , 19 , 20 , 21 , 22 ]. In the research on CA IX inhibitors, saccharide-modified compounds have achieved remarkable success, and various molecules of saccharide-modified CA IX inhibitors have been reported [ 23 , 24 , 25 ].…”