Potent Aldose Reductase Inhibitors Research Articles

Aldose reductase inhibitory potential of different fractions of Houttuynia cordata Thunb

ObjectiveTo evaluate the aldose reductase (AR) inhibitory activity of different fractions from Houttuynia cordata (H. cordata) which used as a medicinal salad for lowering of blood sugar level. MethodsAR inhibitory activity along with protein content was evaluated in vitro in rat lens. Total phenol and flavonoid contents were also determined in all the fractions. ResultsAll the four fractions were found to inhibit lens AR activity, but to different extent. From dose response curve (DRC), aqueous fraction (AQ) was found to be the most effective AR inhibitor followed by ethyl acetate (EA), chloroform (CL) and hexane fraction (HEX). The IC50 values of AQ, EA, CL and HEX were calculated to be (64.62±3.90), (90.69±7.50), (134.59±4.90) and (151.58±3.30) μ g/mL respectively. Quercetin was taken as positive control which exhibited AR inhibition with an IC50 value of (3.21±0.60) μ g/mL in a non-competitive manner. ConclusionThese findings indicated that, AQ fraction of H. cordata exhibited significant inhibitory effect on AR in a non-competitive manner, which may be attributed to the presence of high phenolic and flavonoid contents. Thus, the plant H. cordata may act as a promising source in the treatment of secondary complications like cataract associated with diabetes.

Design of an Amide N-Glycoside Derivative of β-Glucogallin: A Stable, Potent, and Specific Inhibitor of Aldose Reductase

β-Glucogallin (BGG), a major component of the Emblica officinalis medicinal plant, is a potent and selective inhibitor of aldose reductase (AKR1B1). New linkages (ether/triazole/amide) were introduced via high yielding, efficient syntheses to replace the labile ester, and an original two-step (90%) preparation of BGG was developed. Inhibition of AKR1B1was assessed in vitro and using transgenic lens organ cultures, which identified the amide linked glucoside (BGA) as a stable, potent, and selective therapeutic lead toward the treatment of diabetic eye disease.

Alkaloids as Aldose Reductase Inhibitors, with Special Reference to Berberine

Aldose reductase is the rate-limiting enzyme of the polyol pathway that leads to conversion of glucose to sorbitol. Its increased activity, which results in abnormal activation of the polyol pathway, is implicated in the development of long-term complications of diabetes mellitus. Different plant species and their active components have shown potent in vitro and in vivo aldose reductase inhibitory activity. Among different phyto-constituents, alkaloids that contain isoquinoline/bis(isoquinoline)and related ring structures (such as berberine, palmatine, coptisine, and jateorrhizine) have shown very potent aldose reductase inhibitory activity. The structural activity relationship has revealed the importance of hydrophobic and hydrophilic groups of isoquinoline/bis(isoquinoline)for binding to an enzyme. The dioxymethylene group in the D ring (hydrophobic group) of these alkaloids binds tightly to the site adjacent to the anionic binding site (active site), while the methoxyl groups (polar) bind to the site adjacent to the nicotinamide ring of the coenzyme. On the basis of these findings, it may be proposed that the presence of isoquinoline/bis(isoquinoline)ring structures is the most important requirement for alkaloids to behave as potent aldose reductase inhibitors. Thus, other plants may also be screened for the same activity. The present review discusses these isoquinoline/bis(isoquinoline)-based alkaloids as aldose reductase inhibitors that may be used to manage diabetic complications and may substitute for the chemically synthesized aldose reductase inhibitors.

Evaluation of in vitro aldose reductase inhibitory potential of alkaloidal fractions of Piper nigrum, Murraya koenigii, Argemone mexicana, and Nelumbo nucifera

Aldose reductase is primarily involved in development of long-term diabetic complications due to increased polyol pathway activity. The synthetic aldose reductase inhibitors are not very successful clinically. Therefore, the natural sources may be exploited for safer and effective aldose reductase inhibitors. In the present study, the aldose reductase inhibitory potential of hydroalcoholic and alkaloidal extracts of Piper nigrum, Murraya koenigii, Argemone mexicana, and Nelumbo nucifera was evaluated. The hydroalcoholic and alkaloidal extracts of the selected plants were prepared. The different concentrations of hydroalcoholic and alkaloidal extracts of these plants were evaluated for their goat lens aldose reductase inhibitory activity using dl-glyceraldehyde as substrate. The aldose reductase inhibitory potential of extracts was assessed in terms of their IC50 value. Amongst the hydroalcoholic extracts, the highest aldose reductase inhibitory activity was shown by P. nigrum (IC50 value 35.64±2.7 μg/mL) followed by M. koenigii (IC50 value 45.67±2.57 μg/mL), A. mexicana (IC50 value 56.66±1.30 μg/mL), and N. nucifera (IC50 value 59.78±1.32 μg/mL). Among the alkaloidal extracts, highest inhibitory activity was shown by A. mexicana (IC50 value 25.67±1.25 μg/mL), followed by N. nucifera (IC50 value 28.82±1.85 μg/mL), P. nigrum (IC50 value 30.21±1.63 μg/mL), and M. koenigii (IC50 value 35.66±1.64 μg/mL). It may be concluded that the alkaloidal extracts of these plants possess potent aldose reductase inhibitory activity and may be therapeutically exploited in diabetes-related complications associated with increased activity of aldose reductase.

Molecular Docking Studies of Novel Arylidene-2, 4-Thiazolidinediones as Potential Aldose Reductase Inhibitors

Diabetes mellitus is a chronic metabolic disease affected a wide range of population all over the world and leads to development of many severe long term complications. Aldose reductase (AR) is the enzyme considered to play a key role in the development of secondary diabetic complications via polyol pathway. AR inhibition has been proposed as a strategy to prevent and delayed such complications. 2,4-thiazolidinedione derivatives being isosteres of hydantoin, emerged as potential AR inhibitors with antidiabetic activity. Therefore, we have designed novel arylidene-2, 4-thiazolidinediones as AR inhibitors using molecular docking technique. Mol-dock score along with re-rank score was the criteria for measuring the affinity of STMG-(1-40) with the AR enzymes. Result of present study will provide a new guideline for the further design of novel potent inhibitors of AR in the management of diabetes along with its complications. Keywords: Diabetic complications, Diabetes, Docking, Aldose reductase, Nephropathy, Thiazolidinedione.

Aldose Reductase Inhibitors of Plant Origin

Diabetic complications are attributed to hyperglycaemic condition which is in turn associated with the polyol pathway and advanced glycation end products. Aldose reductase (AR) is the principal enzyme of polyol pathway which plays a vital role in the development of diabetic complications. AR inhibitory activity can be screened by both in vitro and in vivo methods. In vitro assays for AR enzyme are further classified on the basis of the source of enzyme such as rat lens, rat kidney, cataracted human eye lens, bovine eyes and human recombinant AR enzymes, whereas the in vivo model is based on the determination of lens galactitol levels. A number of synthetic AR inhibitors (ARIs) including tolrestat and sorbinil have been developed, but all of these suffer from drawbacks such as poor permeation and safety issues. Therefore, pharmaceutical companies and many researchers have been carrying out research to find new, potent and safe ARIs from natural sources. Thus, many naturally occurring compounds have been reported to have AR inhibitory activity. The present review attempts to highlight phytochemicals and plant extracts with potential AR inhibitory activity. It also summarizes the classes of compounds which have proven AR inhibitory activity. Phytochemicals such as quercetin, kaempferol and ellagic acid are found to be the most promising ARIs. The exhaustive literature presented in this article clearly indicates the role of plant extracts and phytochemicals as potential ARIs.

Synthesis of organic nitrates of luteolin as a novel class of potent aldose reductase inhibitors

Aldose reductase (AR) plays an important role in the design of drugs that prevent and treat diabetic complications. Aldose reductase inhibitors (ARIs) have received significant attentions as potent therapeutic drugs. Based on combination principles, three series of luteolin derivatives were synthesised and evaluated for their AR inhibitory activity and nitric oxide (NO)-releasing capacity in vitro. Eighteen compounds were found to be potent ARIs with IC50 values ranging from (0.099±0.008) μM to (2.833±0.102) μM. O7-Nitrooxyethyl-O3′,O4′-ethylidene luteolin (La1) showed the most potent AR inhibitory activity [IC50=(0.099±0.008) μM]. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure–activity relationship studies suggested that introduction of an NO donor, protection of the catechol structure, and the ether chain of a 2-carbon spacer as a coupling chain on the luteolin scaffold all help increase the AR inhibitory activity of the resulting compound. This class of NO-donor luteolin derivatives as efficient ARIs offer a new concept for the development and design of new drug for preventive and therapeutic drugs for diabetic complications.

Prospecting for novel plant-derived molecules of Rauvolfia serpentina as inhibitors of Aldose Reductase, a potent drug target for diabetes and its complications.

Aldose Reductase (AR) is implicated in the development of secondary complications of diabetes, providing an interesting target for therapeutic intervention. Extracts of Rauvolfia serpentina, a medicinal plant endemic to the Himalayan mountain range, have been known to be effective in alleviating diabetes and its complications. In this study, we aim to prospect for novel plant-derived inhibitors from R. serpentina and to understand structural basis of their interactions. An extensive library of R. serpentina molecules was compiled and computationally screened for inhibitory action against AR. The stability of complexes, with docked leads, was verified using molecular dynamics simulations. Two structurally distinct plant-derived leads were identified as inhibitors: indobine and indobinine. Further, using these two leads as templates, 16 more leads were identified through ligand-based screening of their structural analogs, from a small molecules database. Thus, we obtained plant-derived indole alkaloids, and their structural analogs, as potential AR inhibitors from a manually curated dataset of R. serpentina molecules. Indole alkaloids reported herein, as a novel structural class unreported hitherto, may provide better insights for designing potential AR inhibitors with improved efficacy and fewer side effects.

X-ray structure of the V301L aldo–keto reductase 1B10 complexed with NADP+ and the potent aldose reductase inhibitor fidarestat: Implications for inhibitor binding and selectivity

Only one crystal structure is currently available for tumor marker AKR1B10, complexed with NADP+ and tolrestat, which is an aldose reductase inhibitor (ARI) of the carboxylic acid type. Here, the X-ray structure of the complex of the V301L substituted AKR1B10 holoenzyme with fidarestat, an ARI of the cyclic imide type, was obtained at 1.60Å resolution by replacement soaking of crystals containing tolrestat. Previously, fidarestat was found to be safe in phase III trials for diabetic neuropathy and, consistent with its low in vivo side effects, was highly selective for aldose reductase (AR or AKR1B1) versus aldehyde reductase (AKR1A1). Now, inhibition studies showed that fidarestat was indeed 1300-fold more selective for AR as compared to AKR1B10, while the change of Val to Leu (found in AR) caused a 20-fold decrease in the IC50 value with fidarestat. Structural analysis of the V301L AKR1B10-fidarestat complex displayed enzyme-inhibitor interactions similar to those of the AR-fidarestat complex. However, a close inspection of both the new crystal structure and a computer model of the wild-type AKR1B10 complex with fidarestat revealed subtle changes that could affect fidarestat binding. In the crystal structure, a significant motion of loop A was observed between AR and V301L AKR1B10, linked to a Phe-122/Phe-123 side chain displacement. This was due to the presence of the more voluminous Gln-303 side chain (Ser-302 in AR) and of a water molecule buried in a subpocket located at the base of flexible loop A. In the wild-type AKR1B10 model, a short contact was predicted between the Val-301 side chain and fidarestat, but would not be present in AR or in V301L AKR1B10. Overall, these changes could contribute to the difference in inhibitory potency of fidarestat between AR and AKR1B10.

Effects of Long-Term Treatment with Ranirestat, a Potent Aldose Reductase Inhibitor, on Diabetic Cataract and Neuropathy in Spontaneously Diabetic Torii Rats

We evaluated ranirestat, an aldose reductase inhibitor, in diabetic cataract and neuropathy (DN) in spontaneously diabetic Torii (SDT) rats compared with epalrestat, the positive control. Animals were divided into groups and treated once daily with oral ranirestat (0.1, 1.0, 10 mg/kg) or epalrestat (100 mg/kg) for 40 weeks, normal Sprague-Dawley rats, and untreated SDT rats. Lens opacification was scored from 0 (normal) to 3 (mature cataract). The combined scores (0–6) from both lenses represented the total for each animal. DN was assessed by measuring the motor nerve conduction velocity (MNCV) in the sciatic nerve. Sorbitol and fructose levels were measured in the lens and sciatic nerve 40 weeks after diabetes onset. Cataracts developed more in untreated rats than normal rats (P < 0.01). Ranirestat significantly (P < 0.01) inhibited rapid cataract development; epalrestat did not. Ranirestat significantly reversed the MNCV decrease (40.7 ± 0.6 m/s) in SDT rats dose-dependently (P < 0.01). Epalrestat also reversed the prevented MNCV decrease (P < 0.05). Sorbitol levels in the sciatic nerve increased significantly in SDT rats (2.05 ± 0.10 nmol/g), which ranirestat significantly suppressed dose-dependently, (P < 0.05, <0.01, and <0.01); epalrestat did not. Ranirestat prevents DN and cataract; epalrestat prevents DN only.

&lt;i&gt;In silico&lt;/i&gt; docking studies of aldose reductase inhibitory activity of commercially available flavonoids

The primary objective of this study was to investigate the aldose reductase inhibitory activity of flavonoids using in silico docking studies. In this perspective, flavonoids like biochanin, butein, esculatin, fisetin and herbacetin were selected. Epalrestat, a known aldose reductase inhibitor was used as the standard. In silico docking studies were carried out using AutoDock 4.2, based on the Lamarckian genetic algorithm principle. The results showed that all the selected flavonoids showed binding energy ranging between -9.33 kcal/mol to -7.23 kcal/mol when compared with that of the standard (-8.73 kcal/mol). Inhibition constant (144.13 µM to 4.98 µM) and intermolecular energy (-11.42 kcal/mol to -7.83 kcal/mol) of the flavonoids also coincide with the binding energy. All the selected flavonoids contributed aldose reductase inhibitory activity because of its structural properties. These molecular docking analyses could lead to the further development of potent aldose reductase inhibitors for the treatment of diabetes.

Synthesis and biological evaluation of new piplartine analogues as potent aldose reductase inhibitors (ARIs)

As a continuation of our efforts directed towards the development of anti-diabetic agents from natural sources, piplartine was isolated from Piper chaba, and was found to inhibit recombinant human ALR2 with an IC50 of 160 μM. To improve the efficacy, a series of analogues have been synthesized by modification of the styryl/aromatic and heterocyclic ring functionalities of this natural product lead. All the derivatives were tested for their ALR2 inhibitory activity, and results indicated that adducts 3c, 3e and 2j prepared by the Michael addition of piplartine with indole derivatives displayed potent ARI activity, while the other compounds displayed varying degrees of inhibition. The active compounds were also capable of preventing sorbitol accumulation in human red blood cells.

An Efficient Synthesis of Quinoxalinone Derivatives as Potent Inhibitors of Aldose Reductase

A novel and facile synthesis of quinoxalinone derivatives was developed in which a wide range of 3-chloroquinoxalin-2(1H)-ones as key intermediates can be generated chemo- and regioselectively in good yields from corresponding quinoxaline-2,3(1H,4H)-diones. This new protocol is arguably superior, as it allows the design and preparation of a variety of bioactive quinoxaline-based compounds, which are particularly effective in the treatment of diabetes and its complications. Through this procedure, a new class of quinoxalinone-based aldose reductase inhibitors were synthesized successfully. Most of the inhibitors, with an N1-acetic acid head group and a substituted C3-phenoxy side chain, proved to be potent and selective. Their IC(50) values ranged from 11.4 to 74.8 nM. Among them, 2-(3-(4-bromophenoxy)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid and 2-(6-bromo-3-(4-bromophenoxy)-2-oxoquinoxalin-1(2H)-yl)acetic acid were the most active. Structure-activity relationship and molecular docking studies highlighted the importance of the ether spacer in the C3-phenoxy side chains, and provided clear guidance on the contribution of substitutions both at the core structure and the side chain to activity.

Discovery of potential aldose reductase inhibitors using in silico docking studies

The primary objective of this study was to investigate the aldose reductase inhibitory activity of flavonoids using in silico docking studies. In this perspective, flavonoids like Apigenin, Baicalin, Daidzein, Epigallocatechin, Galangin, Genistein, Hesperitin, Naringenin, and Scopoletin were selected. Epalrestat, a known aldose reductase inhibitor was used as the standard. In silico docking studies were carried out using AutoDock 4.2, based on the Lamarckian genetic algorithm principle. In the docking studies, three important parameters like binding energy, inhibition constant and intermolecular energy were determined. The results showed that all the selected flavonoids showed binding energy ranging between −9.91 kcal/mol to −7.52 kcal/mol when compared with that of the standard (−8.73 kcal/mol). Intermolecular energy (−11.40 kcal/mol to −8.71 kcal/mol) and inhibition constant (54.78 nM to 3.10 μM) of the flavonoids also coincide with the binding energy. All the selected flavonoids contributed aldose reductase inhibitory activity because of its functional groups. These molecular docking analyses could lead to the further development of potent aldose reductase inhibitors for the treatment of diabetes.

Evaluation of in vitro aldose reductase inhibitory potential of different fraction of Hybanthus enneaspermus Linn F. Muell

Objective To evaluate the aldose reductase inhibitory (ARI) activity of different fractions of Hybanthus enneaspermus for potential use in diabetic cataract Methods Total phenol and flavonoid content of different fractions was determined. ARI activity of different fractions in rat lens was investigated in vitro Results The results showed significant level of phenolic and flavonoid content in ethyl acetate fraction [total phenol (212.15±0.79 mg/g), total flavonoid (39.11±2.27 mg/g)] and aqueous fraction [total phenol (140.62±0.57 mg/g), total flavonoid (26.07±1.49 mg/g)] as compared with the chloroform fraction [total phenol (68.56±0.51 mg/g), total flavonoid (13.41±0.82 mg/g)] and petrolium ether fraction [total phenol (36.68±0.43 mg/g), total flavonoid (11.55±1.06 mg/g)]. There was a significant difference in the ARI activity of each fraction, and it was found to be the highest in ethyl acetate fraction [IC 50 (49.26±1.76 μg/mL)] followed by aqueous extract [IC 50 (70.83±2.82 μg/mL)] and it was least in the petroleum ether fraction [IC 50 (118.89±0.71 μg/mL)]. Chloroform fraction showed moderate activity [IC 50 (98.52±1.80 μg/mL)]. Conclusions Different fractions showed significanct amount of ARI activity, where in ethyl acetate fraction it was found to be maximum which may be due to its high phenolic and flavonoid content. The extract after further evaluation may be used in the treatment of diabetic cataract.

1,2-Benzothiazine 1,1-dioxide carboxylate derivatives as novel potent inhibitors of aldose reductase

Due to the importance of aldose reductase (ALR2) as a potential drug target in the treatment of diabetic complications, there are increasing interests in design and synthesis of ALR2 inhibitors. Here, we prepared 1,2-benzothiazine 1,1-dioxide acetic acid derivatives and investigated their inhibition activity. Most of these derivatives were found to be active with IC50 values ranging from 0.11μM to 10.42μM, and compound 8d, 2-[2-(4-bromo-2-fluorobenzyl)-1,1-dioxido-2H-1,2-benzothiazin-4(3H)-ylidene]acetic acid, showed the most potent inhibition activity. Further, SAR and docking studies suggest that in comparison with the α,β-unsaturated derivatives, the saturated carboxylic acid derivatives had a greater binding affinity with the enzyme and thus an enhanced inhibition activity. Therefore, development of more powerful ARIs based on benzothiazine 1,1-dioxide by stereo-controlled synthesis could be expected.

ChemInform Abstract: Design and Synthesis of Potent and Selective Aldose Reductase Inhibitors Based on Pyridylthiadiazine Scaffold.

AbstractSeveral newly synthesized pyrido[2,3‐e]‐[1,2,4]thiadiazine 1,1‐dioxide derivatives (VII) are found to be potent aldose reductase inhibitors with compound (VIId) exhibiting the highest activity.

Curcumin analogues as possible anti-proliferative & anti-inflammatory agents

A series of novel curcumin analogues has been designed, synthesized and tested in vitro/ in vivo as potential multi-target agents. Their anti-proliferative and anti-inflammatory activities were studied. Compounds 1b and 2b were stronger inhibitors of soybean lipoxygenase (LOX) than curcumin. Analogue 1b was also the most potent aldose reductase (ALR2) inhibitor. Two compounds, ( 1a and 1f) exhibited in vivo anti-inflammatory activity comparable to that of indomethacin, whereas derivative 1i exhibited even higher activity. The derivatives were also tested for their anti-proliferative activity using three different human cancer cell lines. Compounds 1a, 1b, 1d and 2b exhibited significant growth inhibitory activity as compared to curcumin, against all three cancer cell lines. Lipophilicity was determined as R M values using RPTLC and theoretically. The results are discussed in terms of the structural characteristics of the compounds. Docking simulations were performed on LOX and ALR2 inhibitor 1b and curcumin. Compound 1b is well fitted in the active site of ALR2, binding to the ALR2 enzyme in a similar way to curcumin. Allosteric interactions may govern the LOX-inhibitor binding.

Design and synthesis of potent and selective aldose reductase inhibitors based on pyridylthiadiazine scaffold

A series of pyrido[2,3- e]-[1,2,4]-thiadiazine 1,1-dioxide acetic acid derivatives were synthesized and tested for their inhibitory activity against aldose reductase (ALR2). These derivatives were found to be potent aldose reductase inhibitors with IC 50 values ranging from 0.038 μM to 11.29 μM. Most but not all of them showed a strong ALR2 inhibition activity and significant selectivity, which were further supported by docking studies. Of these inhibitors, compound 7d exhibited highest inhibition activity. Structure–activity relationship studies indicate the requirement of N2-benzyl group with electron-withdrawing substituents and N4-acetic acid group in the pyridothiadiazine scaffold.

Antihyperglycaemic and aldose reductase inhibitory potential of Acacia catechu hard wood and Tectona grandis leaves

The ethanolic extract of Acacia catechu hard wood (Ac) and the ethanolic as well as aqueous extracts of Tectona grandis leaves (Tg) showed marked antihyperglycaemic activity in both normoglycaemic and streptozotocin-induced diabetic rats at 250 mg/kg dose levels. The ethanolic and aqueous extracts of Ac and Tg also showed marked inhibition on AR from eye lens of normal rats with IC 50 values of 9.30 and 9.08 and 3.05, 4.51 μg/ml, respectively. The ethanolic as well as aqueous extracts of both Ac and Tg also showed marked inhibition on AR from eye lens of STZ-induced diabetic rats with IC50 values of 4.70 and 4.91 and 4.71 and 4.83 μg/ml. These results suggest that Acacia catechu hard wood and Tectona grandis leaves could be a new approach in the development of therapeutic or preventive agents for diabetic late-stage complications.