Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights.

This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications.

CADD Studies in the Discovery of Potential ARI (Aldose Reductase Inhibitors) Agents for the Treatment of Diabetic Complications.

The lack of currently available drugs for treating diabetes complications has stimulated our interest in finding new Aldose Reductase inhibitors (ARIs) with more beneficial biological properties. One metabolic method uses aldose reductase inhibitors in the first step of the polyol pathway to control excess glucose flux in diabetic tissues. Computer-aided drug discovery (CADD) is key in finding and optimizing potential lead substances. AR inhibitors (ARI) have been widely discussed in the literature. For example, Epalrestat is currently the only ARI used to treat patients with diabetic neuropathy in Japan, India, and China. Inhibiting R in patients with severe to moderate diabetic autonomic neuropathy benefits heart rate variability. AT-001, an AR inhibitor, is now being tested in COVID-19 to see how safe and effective it reduces inflammation and cardiac damage. In summary, these results from animal and human studies strongly indicate that AR can cause cardiovascular complications in diabetes. The current multi-center, large-scale randomized human study of the newly developed powerful ARI may prove its role in diabetic cardiovascular disease to establish therapeutic potential. During the recent coronavirus disease (COVID-19) outbreak in 2019, diabetes and cardiovascular disease were risk factors for severely negative clinical outcomes in patients with COVID19. New data shows that diabetes and obesity are among the strongest predictors of COVID-19 hospitalization. Patients and risk factors for severe morbidity and mortality of COVID- 19.

Characterization of the inhibition of aldose reductase with p-coumaric acid ethyl ester.

The inhibition of aldose reductase is an effective strategy to alleviate symptoms of diabetic complications. The p-coumaric acid ethyl ester (p-CAEE) was taken as an example to investigate the inhibition of aldose reductase from p-coumaric acid derivations. The results showed p-CAEE strongly inhibited aldose reductase with the half inhibitory concentration of 1.92 µM, following the noncompetitive manner with a Ki value of 0.94 µM. After binding with p-CAEE, the enzyme showed increased ß-sheet content, and the α-helix content, random coil content, and intrinsic fluorescence strength decreased. p-CAEE bonded with aldose reductase at the anionic, hydrophobic, and selective pockets of the enzyme, via hydrogen bond and hydrophobic interactions with Thr113, Cys80, Trp111, and Leu300, etc. The strong inhibition was related to the high oil-water partition coefficient and special esterify group. This study provides new information to develop aldose reductase inhibitors from p-coumaric acid derivations. PRACTICAL APPLICATIONS: Inhibition of aldose reductase is an effective strategy to alleviate and control the symptoms of diabetic complications. In this study, it has been shown that p-coumaric acid ethyl ester could strongly inhibit the aldose reductase. In addition, the inhibition of aldose reductase was been correlated with structures and oil-water partition coefficients of p-coumaric acid derivatives. It provides a theoretical basis for the development of effective aldose reductase inhibitors.

In-silico Investigations of quinine and quinidine as potential Inhibitors of AKR1B1 and AKR1B10: Functional and structural characterization.

The aberrant expression of aldo keto reductases (AKR1B1 & AKR1B10) has been extensively studied in different types of cancer especially the colon cancer but a very few studies have yet been reported regarding the discovery of inhibitors for the treatment of colon cancer by targeting these isozymes. Therefore, there is a need of selective inhibitors of both targets for the eradication of colon cancer. Currently, the study is focused on the exploration of two quinolone compounds i.e., (S)-(6-Methoxyquinolin-4-yl)[(1S,2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol (Quinidine) and (R)-(6-Methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol (Quinine) as the potential inhibitors of AKR1B1 and AKR1B10 via detailed in-silico approach. The structural properties including vibrational frequencies, dipole moment, polarizability and the optimization energies were estimated using density functional theory (DFT) calculations; where both compounds were found chemically reactive. After that, the optimized structures were used for the molecular docking studies and here quinidine was found more selective towards AKR1B1 and quinine exhibited maximum inhibition of AKR1B10. The results of molecular docking studies were validated by molecular dynamics simulations which provided the deep insight of stability of protein ligand complex. At the end, the ADMET properties were determined to demonstrate the druglikeness properties of both selected compounds. These findings suggested further exploration of both compounds at molecular level using different in-vivo and in-vitro approaches that will lead to the designing of potential inhibitor of AKR1B1/AKR1B10 for curing colon cancer and related malignancies.

Novel topical esmolol hydrochloride improves wound healing in diabetes by inhibiting aldose reductase, generation of advanced glycation end products, and facilitating the migration of fibroblasts.

Aims/Objectives: Wound healing in people with diabetes is delayed secondary to impaired nitric oxide generation, advanced glycation end products (AGE), and poor migration of epithelial cells. We developed a novel topical esmolol hydrochloride (Galnobax) and assessed its efficacy for wound healing in streptozocin-induced diabetic hairless rat. Methods: All experiments were performed at an animal laboratory and tertiary-care research facility. Ex vivo aldose reductase inhibition was assessed from enzymes obtained from a bacterial culture (spectrophotometer), sorbitol content in homogenized red blood cells, and AGE in glucose and bovine serum by fluorometry following the addition of esmolol in varying concentrations. A scratch assay of human fibroblasts, endothelial cells, and keratinocytes was assessed under a high-glucose environment and after esmolol by phase-contrast microscopy. The efficacy evaluation of the topical application of Galnobax (14 and 20%) or vehicle was conducted in streptozotocin-induced diabetic hairless rats, and endogenous nitrite and hydroxyproline from homogenized wound tissue were measured along with pharmacokinetic and dermal toxicity in Hanford miniature swine. Results: Esmolol inhibited the formation of sorbitol by 59% in erythrocytes in comparison to glucose-induced sorbitol levels. AGE generation in bovine serum albumin was reduced at 1 mM esmolol concentrations (2.6 ± 1.7) compared with control (p < 0.05) and similar to that of diclofenac (2.5 ± 1.3). Esmolol at 1 and 10 µM enhanced the migration of fibroblasts, epithelial cells, and keratinocytes compared with control. The nitric oxide levels (day 7) were 44 and 112% higher with Galnobax (14%) than those of the diabetic group (p < 0.05) and the vehicle control group (p < 0.05), respectively. The days 7 and 14 hydroxyproline in the wound was higher by 22 and 44% following Galnobax (14%) compared with the diabetic and vehicle control groups. The wound area exhibited better reduction with Galnobax at 14% up to day 10 follow-up compared with the controls. The pharmacokinetic and dermal toxicity in miniature swine suggested no significant adverse event with Galnobax. Conclusions: Topical esmolol hydrochloride is a novel, safe, and effective treatment modality that acts through pleotropic mechanisms to hasten wound healing in diabetes.

Syzygium aromaticum bud (clove) essential oil is a novel and safe aldose reductase inhibitor: in silico, in vitro, and in vivo evidence.

PURPOSE: This study aimed to evaluate the antioxidant and antidiabetic properties of clove essential oil (CEO) and to elucidate its mode of action, using selected biochemical targets, relevant to diabetes, and, specifically, its inhibitory effect on the polyol pathway. METHODS: In the current study, CEO was examined for its inhibitory effects on aldose reductase in silico, in vitro, and in vivo, as well as its antioxidative activity. RESULTS: In silico docking studies showed that all the selected major compounds of CEO have an energy change ranging between - 5.5 and - 8.8 kcal/mol and an inhibition constant ranging between 357.08 nM and 93.12 µM. CEO significantly inhibits aldose reductase with an IC50 value of 58.55 ± 5.84 µg/mL in a noncompetitive manner. The supplementation of CEO at 20 mg/kg BW decreases retinal sorbitol dehydrogenase activity via decreased aldose reductase activity in streptozotocin (STZ)-induced diabetic Sprague Dawley rats. Moreover, diabetic rats injected with CEO have exhibited improved levels of glycemia. The IC50 values for ABTS, hydroxyl, and hydrogen peroxide scavenging activities of CEO were found to be 34.42, 277.4, and 39.99 µg/mL, respectively. Reducing power assay and phosphomolybdate assay exhibited a reduction force with the A0.5 values of 50.25 and 140.16 µg/mL, respectively. CONCLUSION: CEO potentially exerts a beneficial effect on diabetes-related complications due to its antioxidant and inhibitory effect on aldose reductase activity.

A Pre-clinical Trial Study: Anti-human Colon Cancer Effect of Thalassiolin B in vitro with Enzymes Inhibition Effects and Molecular Docking Studies.

In this study, it is recorded the inhibition effect of Thalassiolin B on aldose reductase, alpha-glucosidase and alpha-amylase enzymes. In the next step, the molecular docking method was used to compare the biological activities of the Thalassiolin B molecule against enzymes formed from the assembly of proteins. In these calculations, the enzymes used are Aldose reductase, Alpha-Amylase, and Alpha-Glucosidase, respectively. After the docking method, ADME/T analysis of Thalassiolin B molecule was performed to be used as a drug in the pharmaceutical industry. In the MTT assay, the anti-human colon cancer properties of Thalassiolin B against EB, LS1034, and SW480 cell lines were investigated. The cell viability of Thalassiolin B was very low against human colon cancer cell lines without any cytotoxicity on the human normal (HUVEC) cell line. The IC50 of the Thalassiolin B against EB, LS1034, and SW480 were 483, 252, and 236 µg/mL, respectively. Thereby, the best cytotoxicity results and anti-human colon cancer potentials of our Thalassiolin B were observed in the case of the SW480 cell line. Maybe the anti-human colon cancer properties of Thalassiolin B are related to their antioxidant effects.

Ginsenoside Rb1 alleviates diabetic kidney podocyte injury by inhibiting aldose reductase activity.

Panax notoginseng, a traditional Chinese medicine, exerts beneficial effect on diabetic kidney disease (DKD), but its mechanism is not well clarified. In this study we investigated the effects of ginsenoside Rb1 (Rb1), the main active ingredients of Panax notoginseng, in alleviating podocyte injury in diabetic nephropathy and the underlying mechanisms. In cultured mouse podocyte cells, Rb1 (10 µM) significantly inhibited high glucose-induced cell apoptosis and mitochondrial injury. Furthermore, Rb1 treatment reversed high glucose-induced increases in Cyto c, Caspase 9 and mitochondrial regulatory protein NOX4, but did not affect the upregulated expression of aldose reductase (AR). Molecular docking analysis revealed that Rb1 could combine with AR and inhibited its activity. We compared the effects of Rb1 with eparestat, a known aldose reductase inhibitor, in high glucose-treated podocytes, and found that both alleviated high glucose-induced cell apoptosis and mitochondrial damage, and Rb1 was more effective in inhibiting apoptosis. In AR-overexpressing podocytes, Rb1 (10 µM) inhibited AR-mediated ROS overproduction and protected against high glucose-induced mitochondrial injury. In streptozotocin-induced DKD mice, administration of Rb1 (40 mg·kg-1·d-1, ig, for 7 weeks) significantly mitigated diabetic-induced glomerular injuries, such as glomerular hypertrophy and mesangial matrix expansion, and reduced the expression of apoptotic proteins. Collectively, Rb1 combines with AR to alleviate high glucose-induced podocyte apoptosis and mitochondrial damage, and effectively mitigates the progression of diabetic kidney disease.

Synthesis and Aldose Reductase Inhibition Effects of Novel N-Benzyl-4-Methoxyaniline Derivatives.

In the current study, starting from 4-methoxyaniline, four Schiff bases were synthesized from benzaldehydes with Br and OMe. Corresponding N-benzylanilines and their derivatives were obtained from reductions (by NaBH4 ) and substitutions (by acyl and tosyl chlorides) of these bases, respectively. The inhibitory effects of the sixteen compounds, twelve of which were novel compounds are examined. Then, we conducted molecular docking and binary QSAR studies to determine inhibitory-enzyme interactions of compounds that show an inhibitory effect. Our results reveal that methoxyanilline-derived compounds show good biological activities. The most active compound (22) has IC50 values of 2.83 µM. These novel AR enzyme inhibitors may open new avenues for better AR inhibitors in the future.

Biological effects of bis-hydrazone compounds bearing isovanillin moiety on the aldose reductase.

Aldose reductase (ALR2), one of the metabolically important enzymes, catalyzes the formation of sorbitol from glucose in the polyol pathway. ALR2 inhibition is required to prevent diabetic complications. In the present study, the novel bis-hydrazone compounds bearing isovanillin moiety (GY1-12) were synthesized, and various chromatographic methods were applied to purify the ALR2 enzyme. Afterward, the inhibitory effect of the synthesized compounds on the ALR2 was screened in vitro. All the novel bis-hydrazones demonstrated activity in nanomolar levels as AR inhibitors with IC50 and KI values in the range of 12.55-35.04 nM, and 13.38-88.21 nM, respectively. Compounds GY-11, GY-7, and GY-5 against ALR2 were identified as the highly potent inhibitors, respectively, and were superior to the standard drug, epalrestat. Moreover, a comprehensive ligand-receptor interactions prediction was performed using ADME-Tox, Glide XP, and MM-GBSA modules of Schrödinger Small-Molecule Drug Discovery Suite to elucidate the novel bis-hydrazone derivatives, potential binding modes versus the ALR2. As a result, these compounds with ALR2 inhibitory effects may be potential alternative agents that can be used to treat or prevent diabetic complications.

A pilot open-label study of aldose reductase inhibition with AT-001 (caficrestat) in patients hospitalized for COVID-19 infection: Results from a registry-based matched-control analysis.

BACKGROUND AND AIMS: Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway. We hypothesized that aldose reductase inhibition with AT-001 might reduce viral inflammation and risk of adverse outcomes in diabetic patients with COVID-19. METHODS: We conducted an open-label prospective phase 2 clinical trial to assess safety, tolerability and efficacy of AT-001 in patients hospitalized with COVID-19 infection, history of diabetes mellitus and chronic heart disease. Eligible participants were prospectively enrolled and treated with AT-001 1500 mg BID for up to 14 days. Safety, tolerability, survival and length of hospital stay (LOS) were collected from the electronic medical record and compared with data from two matched control groups (MC1 and MC2) selected from a deidentified registry of COVID-19 patients at the same institution. RESULTS: AT-001 was safe and well tolerated in the 10 participants who received the study drug. In-hospital mortality observed in the AT-001 group was 20% vs. 31% in MC1 and 27% in MC2. Mean LOS observed in the AT-001 group was 5 days vs. 10 days in MC1 and 25 days in MC2. CONCLUSIONS: In hospitalized patients with COVID-19 and co-morbid diabetes mellitus and heart disease, treatment with AT-001 was safe and well tolerated. Exposure to AT-001 was associated with a trend of reduced mortality and shortened LOS. While the observed trend did not reach statistical significance, the present study provides the rationale for investigating potential benefit of AT-001 in COVID 19 affected patients in future studies.

Identification of a new class of potent aldose reductase inhibitors: Design, microwave-assisted synthesis, in vitro and in silico evaluation of 2-pyrazolines.

Aldose reductase (AR) acts as a multi-disease target for the design and development of therapeutic agents for the management of diabetic complications as well as non-diabetic diseases. In the search for potent AR inhibitors, the microwave-assisted synthesis of twenty new compounds with a 1,3-diaryl-5-(4-fluorophenyl)-2-pyrazoline moiety as a common fragment in their structure (1-20) was carried out efficiently. Compounds 1-20 were subjected to in vitro studies, which were conducted to assess their AR inhibitory effects and cytotoxicity towards L929 mouse fibroblast (normal) cells. Among these compounds, 1-(3-bromophenyl)-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (20) was identified as the most promising AR inhibitor with an IC50 value of 0.160 ± 0.005 µM exerting competitive inhibition with a Ki value of 0.019 ± 0.001 µM as compared to epalrestat (IC50 = 0.279 ± 0.001 µM; Ki = 0.801 ± 0.023 µM) and quercetin (IC50 = 4.120 ± 0.123 µM; Ki = 6.082 ± 0.272 µM). Compound 20 displayed cytotoxicity towards L929 cells with an IC50 value of 18.75 ± 1.06 µM highlighting its safety as an AR inhibitor. Molecular docking studies suggested that π-π stacking interactions occurred between the m-bromophenyl moiety of compound 20 and Trp21. Based on in silico pharmacokinetic studies, compound 20 was found to possess favorable oral bioavailability and drug-like properties. It can be concluded that compound 20 is a potential orally bioavailable AR inhibitor for the management of diabetic complications as well as non-diabetic diseases.

Development of coumarin-thiosemicarbazone hybrids as aldose reductase inhibitors: Biological assays, molecular docking, simulation studies and ADME evaluation.

The over expression of aldose reductase (ALR2) in the state of hyperglycemia causes the conversion of glucose into sorbitol and initiates polyol pathway. Accumulation of sorbitol in insulin insensitive tissue like peripheral nerves, glomerulus and eyes, induces diabetic complications like neuropathy, nephropathy and retinopathy. For the treatment of diabetic complications, the inhibition of aldose reductase (ALR2) is a promising approach. A series of coumarin-based thiosemicarbazone derivatives was synthesized as potential inhibitor of aldose reductase. Compound N-(2-fluorophenyl)-2-(1-(2-oxo-2H-chromen-3-yl)ethylidene)hydrazinecarbiothioamide (3n) was found to be the most promising inhibitor of ALR2 with an IC50 in micromolar range (2.07 µM) and high selectivity, relative to ALR1. The crystal structure of ALR2 complexed with 3n explored the types of interaction pattern which further demonstrated its high affinity. Compound 3n has excellent lead-likeness, underlined by its physicochemical parameters, and can be considered as a likely prospect for further structural optimization to get a drugable molecule.

Aldose Reductase: a cause and a potential target for the treatment of diabetic complications.

Diabetes mellitus, a disorder of metabolism, results in the elevation of glucose level in the blood. In this hyperglycaemic condition, aldose reductase overexpresses and leads to further complications of diabetes through the polyol pathway. Glucose metabolism-related disorders are the accumulation of sorbitol, overproduction of NADH and fructose, reduction in NAD+, and excessive NADPH usage, leading to diabetic pathogenesis and its complications such as retinopathy, neuropathy, and nephropathy. Accumulation of sorbitol results in the alteration of osmotic pressure and leads to osmotic stress. The overproduction of NADH causes an increase in reactive oxygen species production which leads to oxidative stress. The overproduction of fructose causes cell death and non-alcoholic fatty liver disease. Apart from these disorders, many other complications have also been discussed in the literature. Therefore, the article overviews the aldose reductase as the causative agent and a potential target for the treatment of diabetic complications. So, aldose reductase inhibitors have gained much importance worldwide right now. Several inhibitors, like derivatives of carboxylic acid, spirohydantoin, phenolic derivatives, etc. could prevent diabetic complications are discussed in this article.

Non-carboxylic acid inhibitors of aldose reductase based on N-substituted thiazolidinedione derivatives.

In search of dually active PPAR-modulators/aldose reductase (ALR2) inhibitors, 16 benzylidene thiazolidinedione derivatives, previously reported as partial PPARγ agonists, together with additional 18 structural congeners, were studied for aldose reductase inhibitory activity. While no compounds had dual property, our efforts led to the identification of promising inhibitors of ALR2. Eight compounds (11, 15-16, 20-24, 30) from the library of 33 compounds were identified as potent and selective inhibitors of ALR2. Compound 21 was the most effective and selective inhibitor with an IC50 value of 0.95 ± 0.11 and 13.52 ± 0.81 µM against ALR2 and aldehyde reductase (ALR1) enzymes, respectively. Molecular docking and dynamics studies were performed to understand inhibitor-enzyme interactions at the molecular level that determine the potency and selectivity. Compound 21 was further subjected to in silico and in vitro studies to evaluate the pharmacokinetic profile. Being less acidic (pKa = 9.8), the compound might have a superior plasma membrane permeability and reach the cytosolic ALR2. This fact together with excellent drug-likeness criteria points to improved bioavailability compared to the clinically used compound Epalrestat. The designed compounds represent a novel group of non-carboxylate inhibitors of aldose reductase with an improved physicochemical profile.

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications.

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure-activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of 'drug-likeness". Novel promising structures of putative multifunctional ARIs/AOs are designed.

Synthesis of indole-substituted thiosemicarbazones as an aldose reductase inhibitor: an in vitro, selectivity and in silico study.

Aim: Indole is an important component of many drug molecules, and its conjugation with thiosemicarbazone moiety would be advantageous in finding lead compounds for the development of diabetic complications. Methodology: We have designed, synthesized and evaluated a series of 17 indole-thiosemicarbazones (3a-q) as aldose reductase (ALR2) and aldehyde reductase (ALR1) inhibitors. Results: After in vitro evaluation, all indole-thiosemicarbazones showed significant inhibition against both enzyme ALR1 and ALR2 with IC50 in range of 0.42-20.7 and 1.02-19.1 µM, respectively. The docking study was also carried out to consider the putative binding of molecules with the target enzymes. Conclusion: Compound 3f was found to be most active and selective for ALR2. The indole-thiosemicarbazones series described here has selective hits for diabetes-mellitus-associated complications.

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.

Protective Effect of Aldo-keto Reductase 1B1 Against Neuronal Cell Damage Elicited by 4'-Fluoro-α-pyrrolidinononanophenone.

Chronic exposure to cathinone derivatives increases the risk of severe health hazards, whereas little is known about the detailed pathogenic mechanisms triggered by the derivatives. We have recently shown that treatment with α-pyrrolidinononanophenone (α-PNP, a highly lipophilic cathinone derivative possessing a long hydrocarbon main chain) provokes neuronal cell apoptosis and its 4'-fluorinated analog (F-α-PNP) potently augments the apoptotic effect. In this study, we found that neuronal SK-N-SH cell damage elicited by F-α-PNP treatment is augmented most potently by pre-incubation with an AKR1B1 inhibitor tolrestat, among specific inhibitors of four aldo-keto reductase (AKR) family members (1B1, 1C1, 1C2, and 1C3) expressed in the neuronal cells. In addition, forced overexpression of AKR1B1 remarkably lowered the cell sensitivity to F-α-PNP toxicity, clearly indicating that AKR1B1 protects from neurotoxicity of the derivative. Treatment of SK-N-SH cells with F-α-PNP resulted in a dose-dependent up-regulation of AKR1B1 expression and activation of its transcription factor NF-E2-related factor 2. Metabolic analyses using liquid chromatography/mass spectrometry/mass spectrometry revealed that AKR1B1 is hardly involved in the F-α-PNP metabolism. The F-α-PNP treatment resulted in production of reactive oxygen species and lipid peroxidation byproduct 4-hydroxy-2-nonenal (HNE) in the cells. The enhanced HNE level was reduced by overexpression of AKR1B1, which also lessened the cell damage elicited by HNE. These results suggest that the AKR1B1-mediated neuronal cell protection is due to detoxification of HNE formed by F-α-PNP treatment, but not to metabolism of the derivative.

Synthesis, molecular modeling, selective aldose reductase inhibition and hypoglycemic activity of novel meglitinides.

In the present study, a novel generation of selective aldose reductase ALR2 inhibitors with significant hypoglycemic activities was designed and modulated based on rhodanine scaffold joined to an acetamide linker in between two lipophilic moieties. The synthesis of the novel compounds was accomplished throughout simple chemical pathways. Molecular docking was performed on B-cell membrane protein SUR1, aldehyde reductase ALR1 and aldose reductase ALR2 active sites. Compounds 10B, 11B, 12B, 15C, 16C, 26F and 27F displayed the highest hypoglycemic activities with 80.7, 85.2, 87, 82.3, 83.5, 81.4 and 85.3% reduction in blood glucose levels, respectively. They were more potent than the standard hypoglycemic agent repaglinide with 65.4% reduction in blood glucose level. Compounds 12B and 15C with IC50 0.29 and 0.35 µM were more potent than the standard ALR2 inhibitor epalrestat with IC50 0.40 µM. They were selective towards ALR2 over ALR1 134 and 116 folds, respectively. Molecular docking studies matched with the in-vitro and in-vivo results to elucidate the dual activities of both compounds 12B and 15C as potent antagonists for ALR2 over ALR1 and good agonists for the SUR1 protein.