Inhibition Of Reductase Activity Research Articles

Synthesis and biological activity of analogs of the antifungal antibiotic UK-2A. I. Impact of picolinamide ring replacement.

The antifungal antibiotic UK-2A strongly inhibits mitochondrial electron transport at the Qi site of the cytochrome bc1 complex. Previous reports have described semi-synthetic modifications of UK-2A to explore the structure-activity relationship (SAR), but efforts to replace the picolinic acid moiety have been limited. Nineteen UK-2A analogs were prepared and evaluated for Qi site (cytochrome c reductase) inhibition and antifungal activity. While the majority are weaker Qi site inhibitors than UK-2A (IC50 , 3.8nM), compounds 2, 5, 13 and 16 are slightly more active (IC50 , 3.3, 2.02, 2.89 and 1.55 nM, respectively). Compared to UK-2A, compounds 13 and 16 also inhibit growth of Zymoseptoria tritici and Leptosphaeria nodorum more strongly, while 2 and 13 provide stronger control of Z. tritici and Puccinia triticina in glasshouse tests. The relative activities of compounds 1-19 are rationalized based on a homology model constructed for the Z. tritici Qi binding site. Physical properties of compounds 1-19 influence translation of intrinsic activity to antifungal growth inhibition and in planta disease control. The 3-hydroxy-4-methoxy picolinic acid moiety of UK-2A can be replaced by a variety of o-hydroxy-substituted arylcarboxylic acids that retain strong activity against Z. tritici and other agriculturally relevant fungi. © 2018 Society of Chemical Industry.

Pistafolin B is the major aldose reductase inhibitor of the pods of tara [Caesalpinia spinose (Molina) Kuntze

Aldose reductase, the pivotal enzyme in the polyol pathway, has been widely investigated as an enzyme critically involved in the onset and progression of various pathologies associated with diabetes mellitus. Investigation of the inhibitory effect of tara [Caesalpinia spinosa (Molina) Kuntze] pods extract on aldose reductase revealed that its n-butanol fraction exhibits excellent aldose reductase inhibitory activity in vitro and ex vivo. Methyl gallate and pistafolin B were isolated from the n-butanol fraction of the tara pod methanolic extract as the main contributors for its aldose reductase inhibition, guided by affinity-based ultrafiltration-high performance liquid chromatography, with pistafolin B being the more potent inhibitor of the two. In vitro and in silico results demonstrated that pistafolin B is a mixed-type inhibitor that can bind to the aldose reductase active site rapidly, preventing substrate access and product formation (IC50, 0.198 mM; Ki, 0.34 mM). Ex vivo experiments indicated that pistafolin B can penetrate the eye lens and successfully inhibit aldose reductase under hyperglycaemic conditions, thus preventing the accumulation of sorbitol and the subsequent osmotic stress.

Review of Medicinal Plants and their Compounds for Aldose Reductase Inhibitory Activity

Review of Medicinal Plants and their Compounds for Aldose Reductase Inhibitory Activity

Ethanol Extract of Evodia rutaecarpa Attenuates Cell Growth through Caspase-Dependent Apoptosis in Benign Prostatic Hyperplasia-1 Cells.

The dried fruits of Evodia rutaecarpa Bentham have been used widely as a herbal medicine for the treatment of inflammatory disorders and abdominal pain. Benign prostatic hyperplasia (BPH) is a nonmalignant disease characterized by overgrowth of prostates. Despite the pharmacological efficacy of the fruits of E. rutaecarpa against various diseases, their effects against BPH have not been reported. Here, we investigated the inhibitory activity of a 70% ethanol extract of E. rutaecarpa (EEER) against BPH, and its underlying mechanisms regarding cell growth of BPH using BPH-1 cells. An in vitro 5α-reductase activity assay showed that EEER exhibited inhibitory activity against 5α-reductase. In BPH-1 cells, EEER treatment inhibited cell viability and reduced the expression of the proliferating cell nuclear antigen proliferating cell nuclear antigen (PCNA), cyclin D1, and phosphor-ERK1/2 proteins. Moreover, EEER also induced apoptosis, with chromatin condensation, apoptotic bodies, and internucleosomal DNA fragmentation. Regarding its underlying mechanisms, EEER exacerbated the activation of caspase-8 and caspase-3 in a concentration-dependent manner and eventually caused the cleavage of PARP. Taken together, these data demonstrated that EEER had a potent 5α-reductase inhibitory activity and that EEER treatment in BPH-1 cells inhibited cell viability via caspase-8- and caspase-3-dependent apoptosis. Therefore, EEER may be a potential phytotherapeutic agent for the treatment of BPH.

Structural Modification of Natural Product Ganomycin I Leading to Discovery of a α-Glucosidase and HMG-CoA Reductase Dual Inhibitor Improving Obesity and Metabolic Dysfunction in Vivo.

It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor (( R, E)-5-(4-( tert-butyl)phenyl)-3-(4,8-dimethylnona-3,7-dien-1-yl)furan-2(5 H)-one, 7d) with improved chemical stability and long-term safety was obtained. Compound 7d showed multiple and strong in vivo efficacies in reducing weight gain, lowering HbAlc level, and improving insulin resistance and lipid dysfunction in both ob/ob and diet-induced obesity (DIO) mice models. Compound 7d was also found to reduce hepatic steatosis in ob/ob model. 16S rRNA gene sequencing, SCFA, and intestinal mucosal barrier function analysis indicated that gut microbiota plays a central and causative role in mediating the multiple efficacies of 7d. Our results demonstrate that 7d is a promising drug candidate for metabolic syndrome.

In vitro and in silico studies of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitory activity of the cowpea Gln-Asp-Phe peptide

Previous studies have shown that cowpea protein positively interferes with cholesterol metabolism. In this study, we evaluated the ability of the fraction containing peptides of <3 kDa, as well as that of the Gln-Asp-Phe (QDF) peptide, derived from cowpea β-vignin protein, to inhibit HMG-CoA reductase activity. We established isolation and chromatography procedures to effectively obtain the protein with a purity above 95%. In silico predictions were performed to identify peptide sequences capable of interacting with HMG-CoA reductase. In vitro experiments showed that the fraction containing peptides of <3 kDa displayed inhibition of HMG-CoA reductase activity. The tripeptide QDF inhibits HMG-CoA reductase (IC50 = 12.8 μM) in a dose-dependent manner. Furthermore, in silico studies revealed the binding profile of the QDF peptide and hinted at the molecular interactions that are responsible for its activity. Therefore, this study shows, for the first time, a peptide from cowpea β-vignin protein that inhibits HMG-CoA reductase and the chemical modifications that should be investigated to evaluate its binding profile.

Trypanothione reductase inhibition and anti-leishmanial activity of all-hydrocarbon stapled α-helical peptides with improved proteolytic stability

Trypanothione reductase (TryR) is a well-established target in the search for novel antitrypanosomal and antileishmanial agents. We have previously identified linear and lactam-bridged 13-residue peptides derived from an α-helical region making up part of the dimeric interface of Leishmania infantum TryR (Li-TryR) which prevent trypanothione reduction by disrupting enzyme dimerization. We now show that i,i + 4 side-chain cross-linking with an all-hydrocarbon staple stabilizes the helical structure of these peptides and significantly improves their resistance to protease cleavage relative to previous linear and cyclic lactam analogues. Interestingly, replacement of the amide bridge by the hydrocarbon staple at the same cyclization positions generates derivatives (2 and 3) that similarly inhibit oxidoreductase activity of the enzyme but unexpectedly stabilize the TryR homodimer. The most proteolytically stable peptide 2 covalently linked to oligoarginines displayed potent in vitro leishmanicidal activity against L. infantum parasites.

Chalcones and their pyrazine analogs: synthesis, inhibition of aldose reductase, antioxidant activity, and molecular docking study

Chalcones and their pyrazine analogs synthesized by Claisen–Schmidt condensation were tested for inhibition of aldose reductase, which is the key enzyme in the development of secondary diabetic complications. The most active compounds exerted IC50 values within the micromolar scale, and their interactions with the enzyme were described in a molecular docking study. Antioxidant activity of several representative compounds was explored in DPPH (2,2-diphenyl-1-picrylhydrazyl) assay, revealing significant scavenging for 4-hydroxy-substituted derivatives endowed with electron-donating methoxy substituent in position 3 of the ring B. To conclude, the novel chalcones hydroxylated and methoxylated in the B-ring and their pyrazine analogs exhibited significant aldose reductase inhibition activity, albeit lower in comparison with the reference epalrestat. Medium antioxidant activity (not exceeding the antioxidant efficacy of the standard Trolox) was shown by the representative compounds tested.

Inhibition of aldose reductase activity by Cannabis sativa chemotypes extracts with high content of cannabidiol or cannabigerol

Aldose reductase (ALR2) is a key enzyme involved in diabetic complications and the search for new aldose reductase inhibitors (ARIs) is currently very important. The synthetic ARIs are often associated with deleterious side effects and medicinal and edible plants, containing compounds with aldose reductase inhibitory activity, could be useful for prevention and therapy of diabetic complications. Non-psychotropic phytocannabinoids exert multiple pharmacological effects with therapeutic potential in many diseases such as inflammation, cancer, diabetes. Here, we have investigated the inhibitory effects of extracts and their fractions from two Cannabis sativa L. chemotypes with high content of cannabidiol (CBD)/cannabidiolic acid (CBDA) and cannabigerol (CBG)/cannabigerolic acid (CBGA), respectively, on human recombinant and pig kidney aldose reductase activity in vitro.A molecular docking study was performed to evaluate the interaction of these cannabinoids with the active site of ALR2 compared to known ARIs.The extracts showed significant dose-dependent aldose reductase inhibitory activity (>70%) and higher than fractions. The inhibitory activity of the fractions was greater for acidic cannabinoid-rich fractions. Comparative molecular docking results have shown a higher stability of the ALR2-cannabinoid acids complex than the other inhibitors. The extracts of Cannabis with high content of non-psychotropic cannabinoids CBD/CBDA or CBG/CBGA significantly inhibit aldose reductase activity. These results may have some relevance for the possible use of C. sativa chemotypes based preparations as aldose reductase inhibitors.

Determination of flavonoids in Acer okamotoanum and their aldose reductase inhibitory activities

Plants in the genus Acer include medicinal plants and deciduous tree species in which several bioactive compounds have been isolated. In this study, flavonoids were isolated from the aerial parts of Acer okamotoanum by open column chromatography and identified by spectroscopic analysis as afzelin, quercitrin, and isoquercitrin. Among these flavonoids, quercitrin and isoquercitrin exhibited potent aldose reductase inhibitory activity (IC50 value of 0.40 and 0.63 μM, respectively). Almost all studied tissues of Acer spp. contained high amounts of quercitrin. The leaf of A. mono had the highest amount of quercitrin (61.90 μg g−1). Our results demonstrated that Acer species contain high concentrations of flavonoids with promising aldose reductase inhibitory activity that could be utilized to develop novel therapeutics for diabetic disorders.

Pass and Swiss ADME collaborated in silico docking approach to the synthesis of certain pyrazoline spacer compounds for dihydrofolate reductase inhibition and antimalarial activity

&lt;p class="Abstract"&gt;New series of pyrazoline spacer compounds were prepared by the reaction between benzimidazole chalcones and (2-methyl-5-nitro-imidazole-1-yl)-acetic acid hydrazide by the sensible use of Michael addition. The building blocks used for the synthesis of pyrazoline derivatives were opted by using virtual screening by molinspiration search engine. The hypothetically resulted pyrazoline spacer compounds from this list are checked for their reliability on other in silico drug designing online web services like PASS online bioactivity, Swiss ADME predictor. The docking study on final four pyrazoline compounds was carried out using Accelrys Discovery Studio 3.5. These synthesized compounds were, later, characterized with the help of UV, IR, mass and &lt;sup&gt;1&lt;/sup&gt;H NMR techniques. These compounds were further screened for their in vitro antimalarial effect. The PASS, Swiss ADME assisted docking approach and the use of combo heterocyclic ring with pyrazoline scaffold were found to be beneficial to derive and synthesize effective antimalarial agents in the present study.&lt;/p&gt;&lt;p class="Abstract"&gt;&lt;strong&gt;Video Clip of Methodology&lt;/strong&gt;:&lt;/p&gt;&lt;p class="Abstract"&gt;6 min 20 sec: &lt;a href="https://www.youtube.com/v/RWwaZuG1j9E"&gt;Full Screen&lt;/a&gt; &lt;a href="https://www.youtube.com/watch?v=RWwaZuG1j9E"&gt;Alternate&lt;/a&gt;&lt;/p&gt;

Ex vivo and in silico Molecular Docking Studies of Aldose Reductase Inhibitory Activity of Apigenin from Morus indica L.

Objective: An investigation on Aldose Reductase Enzyme (ALR) inhibitory activity of apigenin (API) isolated from Morus indica L. was evaluated by ex vivo and molecular docking studies. Materials and Methods: The inhibitory efficacy of API from M. indica was evaluated against ALR in lens tissue of mice by ex vivo and their binding mechanism through molecular docking was carried out by AutoDock. Results: The API (10-50 µg mL-1) concentration exhibited significant inhibition (p ≤ 0.05) of ALR enzyme in a dose dependent manner with IC50 value of 39.23 µg mL-1. The positive control aminoguanidine (AG) at 10 mM inhibited 42.96% of ALR. The molecular docking studies revealed that API showed better binding energy (-9.15 kJ mol-1) when compared to AG (-3.78 kJ mol1 ). Molecular interaction analysis showed that API interrupts the proton donation mechanism which is necessary for the catalytic activity of ALR by forming H-bond with Trp20 (proton donor). Conclusion: The ALR inhibition potential offered by API was further confirmed through molecular docking studies. The present findings support the pharmacological application of API for the treatment of diabetes cataract. Key words: Mulberry, Antiglycation, Retinopathy, Eye lens.

Dihydrofolate reductase (DHFR) inhibition and molecular modeling study of some 6-bromo- or 6,8-dibromo-quinazolin-4(3H)-ones

Objectives: The dihydrofolate reductase (DHFR) inhibitory activity of 6-bromo- and 6,8-dibromo-quinazolin-4(3H)-ones (7–25) were studied to define the structural features and requirements that enhance selectivity and specificity for the proper binding to the enzyme active site. Methods: Compounds 7–25 were tested for their in vitro DHFR inhibition. As an appli - cation of the use of DHFR inhibitors, in vitro antitumor activity using disease-oriented human cell lines assay was performed. Key findings: Compounds 19, 20, and 22 showed remarkable DHFR inhibitory activity, inhibitory concentration (IC 50 0.6, 0.2, and 0.1 μM, respectively). Compounds 12, 17, 18, 20, and 24 proved to be broad spectrum antitumor with median IC 50 values of 0.6, 0.6, 0.5, 0.6, and 0.7 μM, respectively. Molecular docking study results revealed that the active DHFR inhibitors 22 and 20 bind to DHFR with similar amino acid residues as methotrexate, especially Arg 28. Conclusions: The mono-bromo series proved to be more active than the di-bromo coun - terparts and the 3-(2-hydrazinyl-acetyl)- is more active than its 3-(acetohydrazide) isoster. The investigated compounds could be used as template model for further optimization.

Synthesis and biological evaluation of stilbene derivatives coupled to NO donors as potential antidiabetic agents

The work is focused on the design of drugs that prevent and treat diabetes and its complications. A novel class of stilbene derivatives were prepared by coupling NO donors of alkyl nitrate and were fully characterised by NMR and other techniques. These compounds were tested in vitro activity, including α-glucosidase inhibitory activity, aldose reductase (AR) inhibitory activity and advanced glycation end products (AGEs) formation inhibitory activity. A class of modified compounds could play a significant effect for treatment of diabetic complications. Target compounds 3e and 7c offered a potential drug design concept for the development of therapeutic or preventive agents for diabetes and its complications.

Evaluation of Aldose Reductase, Protein Glycation, and Antioxidant Inhibitory Activities of Bioactive Flavonoids in Matricaria recutita L. and Their Structure-Activity Relationship.

The inhibitory activities of Matricaria recutita L. 70% methanol extract were evaluated by isolating and testing 10 of its compounds on rat lens aldose reductase (RLAR), advanced glycation end products (AGEs), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging. Among these compounds, apigenin-7-O-β-D-glucoside, luteolin-7-O-β-D-glucoside, apigenin-7-O-β-D-glucuronide, luteolin-7-O-β-D-glucuronide, 3,5-O-di-caffeoylquinic acid, apigenin, and luteolin showed potent inhibition, and their IC50 values in RLAR were 4.25, 1.12, 1.16, 0.85, 0.72, 1.72, and 1.42 μM, respectively. Furthermore, these compounds suppressed sorbitol accumulation in rat lens under high-glucose conditions, demonstrating their potential to prevent sorbitol accumulation ex vivo. Notably, luteolin-7-O-β-D-glucuronide and luteolin showed antioxidative as well as AGE-inhibitory activities (IC50 values of these compounds in AGEs were 3.39 and 6.01 μM). These results suggest that the M. recutita extract and its constituents may be promising agents for use in the prevention or treatment of diabetic complications.

Dihydroxanthyletin-type coumarins from Angelica decursiva that inhibits the formation of advanced glycation end products and human recombinant aldose reductase.

The formation of advanced glycation end-products (AGE) and aldose reductase activity have been implicated in the development of diabetic complications. The present study was aimed to evaluate human recombinant aldose reductase (HRAR) and AGE inhibitory activity of seven natural dihydroxanthyletin-type coumarins, 4-hydroxy Pd-C-III (1), 4'-methoxy Pd-C-I (2), Pd-C-I (3), Pd-C-II (4), Pd-C-III (5), decursidin (6), and (+)-trans-decursidinol (7) from Angelica decursiva. Coumarins 1-7 showed potent HRAR and AGE inhibitory activities with ranges of IC50 values of 1.03-21.31 and 0.41-5.56µM, respectively. In the kinetic study for HRAR enzyme inhibition, coumarins 1, 3, 4, and 7 were competitive-type inhibitors, 6 was a mixed-type inhibitor, whereas 2 and 5 were noncompetitive-type inhibitors. Furthermore, we also predicted the docking interactions of HRAR with coumarins 1-7 using AutoDock Vina, and as a result, the simulated enzyme-inhibitor complexes exhibited negative binding energies (Autodock Vina=-9.6 to -8.1kcal/mol for HRAR), indicating a high affinity and tight binding capacity for the HRAR active site. Our results clearly indicate the potential HRAR and AGE formation inhibitory activities of dihydroxanthyletin-type coumarins, which could be further explored to develop therapeutic modalities for the treatment of diabetes and related complications.

Novel quinazolinone-based 2,4-thiazolidinedione-3-acetic acid derivatives as potent aldose reductase inhibitors.

Targeting aldose reductase enzyme with 2,4-thiazolidinedione-3-acetic acid derivatives having a bulky hydrophobic 3-arylquinazolinone residue. All the target compounds were structurally characterized by different spectroscopic methods and microanalysis, their aldose reductase inhibitory activities were evaluated, and binding modes were studied by molecular modeling. All the synthesized compounds proved to inhibit the target enzyme potently, exhibiting IC50 values in the nanomolar/low nanomolar range. Compound 5i (IC50=2.56nM), the most active of the whole series, turned out to be almost 70-fold more active than the only marketed aldose reductase inhibitor epalrestat. This work represents a promising matrix for developing new potential therapeutic candidates for prevention of diabetic complications through targeting aldose reductase enzyme. [Formula: see text].

HMG-CoA Reductase Inhibitory Activity of Gnetum gnemon Seed Extract and Identification of Potential Inhibitors for Lowering Cholesterol Level

Objectives: Melinjo (Gnetum gnemon) seeds have been known to have some biological properties. One of them is ant hypercholesterolemia. The present study investigated in vitro and in silico methods to predict potential antihypercholesterolemic of the Melinjo seed extracts of through HMG-CoA reductase inhibitory activity. Methods: Melinjo seed powders were successively extracted by reflux method using five solvents with gradient polarity including: n-hexane, dichloromethane, ethyl acetate and methanol. All extracts were evaluated in vitro using HMG-CoA Reductase assay kit, to analyze the inhibitory activity. Molecular docking of the phytochemical content of the seeds were carried out using Auto Dock Vina, and also Ligand Scout to analyses interaction between ligand and receptor. Results: Dichloromethane extract demonstrated the highest inhibitory activity against HMG-CoA reductase with IC50 value is 0.40 μg/mL, followed by that of ethyl acetate extract. UPLC-MS analyses showed that dichloromethane extract contained trans-resveratrol, piceid, gnetin C, gnetol, isorhapontigenin, ɛ-viniferin, gnemonol L, and gnemonol M. Molecular docking studies demonstrated that dimer of resveratrol such as gnemonol L, gnemosida, and ɛ-viniferin have better free binding energy than that of monomer. piceid, gnetin C, gnemonol L, and gnemonol M could be considered as HMG-CoA reductase inhibitor. Conclusion: Gnetum gnemon seed extract showed strong HMG-CoA reductase activity. Resveratrol dimer promises as a potential lead compound to design/synthesize anti-cholesterol. Key words: Gnetum gnemon, Melinjo, HMG-CoA Reductase, Resveratrol, Stilbene, Molecular Docking.

Aldose reductase inhibitory activity studies of THERACURMIN

THERACURMIN a commercially available nano-dispersion of curcumin used to treat after effects of alcohol has been evaluated for in vitro ARI activity on Aldose reductase isolated from the bovine lens. As envisaged, the product displays better ARI activity with IC50 value of 3 μM. The observed ARI activity of THERACURMIN is of therapeutic significance as the limited bioavailability of curcumin limits its clinical use.

Exploration of thioxothiazolidinone–sulfonate conjugates as a new class of aldehyde/aldose reductase inhibitors: A synthetic and computational investigation

In the present study, the pharmacophore integration methodology provided an efficient access to a new library of thioxothiazolidinone–sulfonate conjugates (8a–r) from easily available synthetic precursors. The approach was excellently high yielding with flexible structural sites for chemical modifications. The designed hybrid scaffolds were assessed for aldehyde/aldose reductase inhibition activities. The results for the in vitro bioassays were promising with the identification of compound 8e as the lead and selective candidate for ALR2 inhibition with an IC50 value of 0.468±0.003µMas compared to 3.1±0.2µM for the standard (sorbinil), whereas compound 8o demonstrated high inhibitory potency for both ALR2 and ALR1 enzymes. Molecular modeling analysis of the potent compounds provided further insight into the biological properties where detailed binding mode analysis revealed that the conjugates (8a–r) were found stabilized in the active site of the enzymes through the development of a number of interactions with catalytic residues.