In vitro α-glucosidase inhibitory activity of phenolic constituents from aerial parts of Polygonum hyrcanicum

Background and the purpose of the study

The early stage of diabetes mellitus type 2 is associated with postprandial hyperglycemia. Hyperglycemia is believed to increase the production of free radicals and reactive oxygen species, leading to oxidative tissue damage. In an effort of identifying herbal drugs which may become useful in the prevention or mitigation of diabetes, biochemical activities of Polygonum hyrcanicum and its constituents were studied.

Methods

Hexane, ethylacetate and methanol extracts of P. hyrcanicum were tested for α-glucosidase inhibitory, antioxidant and radical scavenging properties. Active constituents were isolated and identified from the methanolic extract in an activity guided approach.

Results

A methanolic extract from flowering aerial parts of the plant showed notable α-glucosidase inhibitory activity (IC₅₀ = 15 μg/ml). Thirteen phenolic compounds involving a cinnamoylphenethyl amide, two flavans, and ten flavonols and flavonol 3-O-glycosides were subsequently isolated from the extract. All constituents showed inhibitory activities while compounds 3, 8 and 11 (IC₅₀ = 0.3, 1.0, and 0.6 μM, respectively) were the most potent ones. The methanol extract also showed antioxidant activities in DPPH (IC₅₀ = 76 μg/ml) and FRAP assays (1.4 mmol ferrous ion equivalent/g extract). A total phenol content of 130 mg/g of the extract was determined by Folin-Ciocalteu reagent.

Conclusion

This study shows that P. hyrcanicum contains phenolic compounds with in vitro activity that can be useful in the context of preventing or mitigating cellular damages linked to diabetic conditions.     

The α-amylase and α-glucosidase inhibitory activities of the dichloromethane extracts and constituents of Ferulago bracteata roots

Context: Ferulago (Apiaceae) species have been used since ancient times for the treatment of intestinal worms, hemorrhoids, and as a tonic, digestive, aphrodisiac, or sedative, as well as in salads or as a spice due to their special odors.

Objectives: This study reports the α-amylase and α-glucosidase inhibitory activities of dichloromethane extract and bioactive compounds isolated from Ferulago bracteata Boiss. &; Hausskn. roots.

Materials and methods: The isolated compounds obtained from dichloromethane extract of Ferulago bracteata roots through bioassay-guided fractionation and isolation process were evaluated for their in vitro α-amylase and α-glucosidase inhibitory activities at 5000–400?µg/mL concentrations. Compound structures were elucidated by detailed analyses (NMR and MS).

Results: A new coumarin, peucedanol-2′-benzoate (1), along with nine known ones, osthole (2), imperatorin (3), bergapten (4), prantschimgin (5), grandivitinol (6), suberosin (7), xanthotoxin (8), felamidin (9), umbelliferone (10), and a sterol mixture consisted of stigmasterol (11), β-sitosterol (12) was isolated from the roots of F. bracteata. Felamidin and suberosin showed significant α-glucosidase inhibitory activity (IC₅₀ 0.42 and 0.89?mg/mL, respectively) when compared to the reference standard acarbose (IC₅₀ 4.95?mg/mL). However, none of the tested extracts were found to be active on α-amylase inhibition.

Discussion and conclusions: The present study demonstrated that among the compounds isolated from CH₂Cl₂ fraction of F. bracteata roots, coumarins were determined as the main chemical constituents of this fraction. This is the first report on isolation and characterization of the bioactive compounds from root extracts of F. bracteata and on their α-amylase and α-glucosidase inhibitory activities.     

Constituents from the testas of Castanea mollissima Blume with α-glucosidase inhibitory activity

In the screening of biologically active constituents from medicinal plants, the 75% EtOH extract of the testas of Castanea mollissima Blume showed potent α-glucosidase inhibitory activity. By means of various chromatographic methods, the extract gave a new dammarane-type triterpene 1 along with 17 known compounds. The structure of 1 was determined to be 3β-acetoxy-20-oxo-21-nordammaran-23-oic acid by HRMS and NMR studies including 2D NMR experiments. The new compound and some known compounds showed potent α-glucosidase inhibitory activity with acarbose as a positive control.     

Metabolite profiling,antioxidant, and α-glucosidase inhibitory activities of germinated rice: nuclear-magnetic-resonance-based metabolomics study

In an attempt to profile the metabolites of three different varieties of germinated rice, specifically black (GBR), red, and white rice, a ¹H-nuclear-magnetic-resonance-based metabolomics approach was conducted. Multivariate data analysis was applied to discriminate between the three different varieties using a partial least squares discriminant analysis (PLS-DA) model. The PLS model was used to evaluate the relationship between chemicals and biological activities of germinated rice. The PLS-DA score plot exhibited a noticeable separation between the three rice varieties into three clusters by PC1 and PC2. The PLS model indicated that α-linolenic acid, γ-oryzanol, α-tocopherol, γ-aminobutyric acid, 3-hydroxybutyric acid, fumaric acid, fatty acids, threonine, tryptophan, and vanillic acid were significantly correlated with the higher bioactivities demonstrated by GBR that was extracted in 100% ethanol. Subsequently, the proposed biosynthetic pathway analysis revealed that the increased quantities of secondary metabolites found in GBR may contribute to its nutritional value and health benefits.     

Antidiabetic components of Cassia alata leaves: Identification through α-glucosidase inhibition studies

Context: Cassia alata Linn. [syn. Senna alata (L.) Roxb.] (Caesalpiniaceae) is used for treating various disease conditions including diabetes but its mechanism(s) of action and active principles remain to be elucidated.

Objective: The antidiabetic principles were identified using an in vitro α-glucosidase inhibition study.

Materials and methods: The methanol extract of leaves of C. alata, which showed potent α-glucosidase inhibitory activity (IC₅₀, 63.75?±?12.81 µg/ml), was fractionated. Active fractions were taken for further analysis by a variety of techniques including HPLC and Combiflash chromatography. The identity of the isolated compounds was established by spectroscopic analysis while their potential antidiabetic activity was assessed by in vitro enzyme inhibition studies.

Results: The α-glucosidase inhibitory effect of the crude extract was far better than the standard clinically used drug, acarbose (IC₅₀, 107.31?±?12.31 µg/ml). A subsequent fractionation of the crude extract was made using solvents of ascending polarity (petroleum ether, chloroform, ethyl acetate, n-butanol and water). The ethyl acetate (IC₅₀, 2.95?±?0.47 µg/ml) and n-butanol (IC₅₀, 25.80?±?2.01 µg/ml) fractions which contained predominantly kaempferol (56.7?±?7.7 µM) and kaempferol 3-O-gentiobioside (50.0?±?8.5 µM), respectively, displayed the highest carbohydrate enzyme inhibitory effect.

Discussion: One of the possible antidiabetic mechanisms of action of C. alata is by inhibiting carbohydrate digestion. This is the first report on α-glucosidase activity of kaempferol 3-O-gentiobioside.

Conclusion: Considering the activity profile of the crude extract and isolated bioactive compounds, further in vivo and clinical studies on C. alata extracts and compounds are well merited.     

Diterpenoids from the roots of Euphorbia fischeriana and their inhibitory effects on α-glucosidase

Abstract

Chemical investigation has been performed on the roots of Euphorbia fischeriana, a traditional Chinese medicine. Three diterpenoids were obtained using various chromatographic techniques, and their structures were determined by spectroscopic data including HRESIMS, 1D NMR, 2D NMR, ECD, and calculated ECD, which gave two new diterpenoids, daphnane type (1) and ent-pimarene type (3). Additionally, the isolated compounds (1–3) displayed moderate inhibitory effects against α-glucosidase in an in vitro bioassay.     

Antidiabetic potential and enzyme kinetics of benzothiazole derivatives and their non-bonded interactions with α-glucosidase and α-amylase

Benzothiazole derivatives were synthesized and their antidiabetic potential evaluated using α-glucosidase, α-amylase, non-enzymatic glycosylation of hemoglobin and advanced glycation end product inhibition assays. Compound 3l showed low IC₅₀ values of 0.31, 0.98, 0.59 and 0.19 mM in α-amylase, α-glucosidase, non-enzymatic glycosylation of hemoglobin and AGE inhibition assays, respectively, and outperformed the standard acarbose. Enzyme kinetic studies revealed that it has a K _i of 0.39 and 1.5 mM for α-amylase and α-glucosidase, respectively. The non-bonded interactions of 3l with α-amylase (3OLD) and α-glucosidase (2ZE0) showed that it binds in the active site pocket and is surrounded by residues Asp197, Glu233, Asp300 in 3OLD and Asp199, Glu256, Asp326 in 2ZE0.     

Bioactivity-guided isolation of a bioactive compound with α-glucosidase inhibitory activity from the leaves extract of Sauropus androgynus

Naturally-derived antidiabetic medications have been explored as alternatives to the current widely-used drugs which can cause mild to severe side effects. Sauropus androgynus has been traditionally utilized to treat diabetes patients. In this report, a flavonoid glycoside, astragalin (1), was isolated from the leaves extract of S. androgynus using bioassay-guided isolation approach. Enrichment processes using macroporous resins resulted in two enriched fractions with 1 contents of 0.083% and 0.054% for PAD610 and PAD900 fractions, respectively. Compound 1 showed a higher α-glucosidase inhibitory (IC₅₀ = 55.03 ± 0.61 μg/mL) than that of acarbose. In vitro assay for antioxidant and α-glucosidase inhibitory activities showed the greatest inhibition by PAD 610 fractions which has 98.912% and 83.268%, respectively. These findings have shown promising results for further studies on S. androgynus as a potential herbal drug, particularly for the treatment of diabetes.     

Determination of the inhibition profiles of pyrazolyl–thiazole derivatives against aldose reductase and α-glycosidase and molecular docking studies

Aldose reductase (AR) is the first and rate-limiting enzyme of the polyol pathway, which converts glucose to sorbitol in an NADPH-dependent reaction. α-Glycosidase breaks down starch and disaccharides to glucose. Hence, inhibition of these enzymes can be regarded a considerable approach in the treatment of diabetic complications. AR was purified from sheep liver using simple chromatographic methods. The inhibitory effects of pyrazolyl–thiazoles ((3aR,4S,7R,7aS)-2-(4-{1-[4-(4-bromophenyl)thiazol-2-yl]-5-(aryl)-4,5-dihydro-1H-pyrazol-3-yl}phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives; 3a – i ) on AR and α-glycosidase enzymes were investigated. All compounds showed a good inhibitory action against AR and α-glycosidase. Among these compounds, compound 3d exhibited the best inhibition profiles against AR, with a K_i value of 7.09 ± 0.19 µM, whereas compound 3e showed the lowest inhibition effects, with a K_i value of 21.89 ± 1.87 µM. Also, all compounds showed efficient inhibition profiles against α-glycosidase, with K_i values in the range of 0.43 ± 0.06 to 2.30 ± 0.48 µM, whereas the K_i value of acarbose was 12.60 ± 0.78 µM. Lastly, molecular modeling approaches were implemented to predict the binding affinities of compounds against AR and α-glycosidase. In addition, the ADME analysis of the molecules was performed.     

Crystal structures,absolute configurations and molecular docking studies of naftopidil enantiomers as α1D-adrenoceptor antagonists

Chiral drug naftopidil (NAF), a specific α_1D-adrenoceptor (AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers showed the same antagonistic effects on the α_1D-AR, but the binding mechanism of these two stereochemical NAF isomers to the α_1D receptor remained unclear. Herein, we reported the crystallographic structures of optically pure NAF stereoisomers for the first time and unambiguously determined their absolute configurations. The crystal data of R and S enantiomers matched satisfactorily the pharmacophore model for α_1D-selective antagonists. Based on the constructed α_1D homology model, molecular docking studies shed light on the molecular mechanism of NAF enantiomers binding to α_1D-AR. The results indicated that NAF enantiomers exhibited the very similar binding poses and occupied the same binding pocket.     

Xanthones as potential α-glucosidase non-competition inhibitors: Synthesis,inhibitory activities,and in silico studies

α-glucosidase inhibitors (AGIs) were commonly used in clinical for the treatment of type 2 diabetes. Xanthones were naturally occurring antioxidants, and they may also be potential AGIs. In this study, eleven 1,6- and 1,3-substituted xanthone compounds were designed and synthesized, of which four were new compounds. Their α-glucosidase inhibitory activities in vitro and in silico were evaluated. Five xanthone compounds with higher activity than acarbose were screened out, and the xanthones substituted at the 1,6-positions were more likely to be potential α-glucosidase non-competitive inhibitors. The binding mode of xanthones with α-glucosidase was further studied by molecular docking method, and the results showed that the inhibitory effect of non-competitive inhibitors on site 1 of α-glucosidase may be related to the hydrogen bonds formed by the compounds with amino acid residues ASN165, HIS209, TRY207, ASP243, and SER104. This study provided a theoretical basis of the rapid discovery and structural modification of non-competitive xanthone inhibitors of α-glucosidase.     

Effect on α-glucosidase inhibition and antioxidant activities of butyrolactone derivatives from Aspergillus terreus MC751

Butyrolactone I and II from Aspergillus terreus MC751 as well as three synthetic butyrolactone I derivatives were assessed for α-glucosidase inhibitory and antioxidant activities. Butyrolactone I (1), which has a prenyl side chain and an alpha hydroxy-lactone group, was the most potent α-glucosidase inhibitor and also had antioxidant activities with IC₅₀ values of 52.17 ± 5.68 and 51.39 ± 3.68 μM, respectively. In contrast, butyrolactone II (2) lacking a prenyl side chain was the most potent antioxidant with an IC₅₀ of 17.64 ± 6.41 μM, but was less active against α-glucosidase. Acetylation of all hydroxyl groups of butyrolactone I significantly decreased both the α-glucosidase inhibitory and antioxidant activity. The prenyl and alpha hydroxy-lactone groups seem to have a synergic effect on the inhibitory activity but not antioxidant activity. This is the first structure–activity relationship report on the α-glucosidase inhibition and antioxidant activity by butyrolactone derivatives.     

Chemical constituents and their acetyl cholinesterase inhibitory and antioxidant activities from leaves of Acanthopanax henryi: potential complementary source against Alzheimer’s disease

The aim of this study was to investigate chemical constituents of the leaves of Acanthopanax henryi, and their antioxidant, acetyl cholinesterase inhibitory activities. Caffeoyl quinic acid derivates and flavonoids were obtained from A. henry, through column chromatography technologies, and the content of major constituents was determined by the HPLC–UV method. Anti-oxidant activity of the isolated metabolites was evaluated by free radical scavenging (DPPH, ABTS radicals) and superoxide anion scavenging. The results showed that di-caffeoyl quinic acid derivates had stronger antioxidant activity than positive controls (ascorbic acid, trolox and allopurinol). Acetyl cholinesterase inhibitory activity was estimated on the constituents, among which, quercetin, 4-caffeoyl-quinic acid and 4,5-caffeoyl quinic acid were found to have strong acetyl cholinesterase inhibitory activity with IC₅₀ values ranging from 62.6 to 121.9 μM. The present study showed that some of the tested constituents from the leaves of A. henryi exhibit strong antioxidant and acetyl cholinesterase inhibitory effects. This suggest that the leaves of A. henryi can be used as a new natural complementary source of acetyl cholinesterase inhibitors and anti-oxidant agents, thus being a promising potential complementary source against Alzheimer’s disease.     

Molecular docking and inhibition studies of α-amylase activity by labdane diterpenes from Alpinia nigra seeds

Wide varieties of synthetic drugs are available for combating type 2 diabetes but are not free of associated side effects. Commercially available antidiabetic drugs are known to be potent inhibitors of α-amylase which reduce postprandial hyperglycaemia. Here, we have investigated Alpinia nigra seed extracts and the isolated two labdane diterpenes (I and II) for the α-amylase inhibitory activity. These labdane type diterpenes showed more promising inhibitory effects (IC₅₀ value 24.3 ± 2.05 and 15.167 ± 0.52 μM for compound I and II, respectively) against α-amylase than the standard inhibitor, acarbose. For both compounds, the mode of enzymatic inhibition was found to be non-competitive with K _i 13.303 ± 0.065 and 12.19 ± 0.099 μM, respectively. Molecular docking studies revealed that both I and II bind the human pancreatic α-amylase in the active site cleft similar to the acarbose. Among all the compounds under investigation, acarbose and compound II were found to have the highest MolDock and re-rank score. Further molecular dynamic simulation studies also supports the docking results obtained for both I and II. This is the first report on α-amylase inhibitory effect of the two labdane diterpenes with their potential candidature as future antidiabetic drugs of herbal origin.     

The α-glucosidase inhibitory activity of avicularin and 4-O-methyl gallic acid isolated from Syzygium myrtifolium leaves

Diabetes Mellitus is the main cause of death on a global scale. In 2019, there were 463 million people with diabetes, and WHO predicts that by 2030, there will be 578 million. As an antidiabetic agent, α-glucosidase inhibitors are one of the methods employed to reduce the prevalence of diabetes. Diabetes is traditionally treated with Syzygium as a primary material, medicine, fruit, ornamental plant, and source of carpentry. This investigation aimed to examine the inhibitory effect of seven species of Syzygium against α-glucosidase enzyme using an in vitro assay and isolate active substances and ascertain their concentrations in each sample. As a solvent, ethanol was used in maceration to extract the substance. Afterward, the extract underwent a series of fractionation techniques, including liquid–liquid extraction, vacuum liquid chromatography, column chromatography, and preparative Thin Layer Chromatography (TLC) for purification and isolation. The compound's structures were elucidated using TLC, UV–Visible spectrophotometry, and nuclear magnetic resonance (NMR) spectroscopy. Based on concentrations of 100 and 200 µg/mL, Syzygium myrtifolium exhibited the most significant inhibitory effect, followed by other species of Syzygium. The proportion of ethyl acetate had the strongest activity (IC₅₀ 0.40 ± 0.02 µg/mL) contrasted to positive control acarbose (IC₅₀ 55.39 ± 0.67 g/mL) and quercitrin (IC₅₀ 6.47 ± 0.40 µg/mL). Avicularin and 4-O-methyl gallic acid were discovered in the ethyl acetate fraction of Syzygium myrtifolium with IC₅₀ values of 17.05 ± 0.75 µg/mL and 25.19 ± 0.21 µg/mL, respectively. As α-glucosidase inhibitory, the results of this study indicate Syzygium myrtifolium can be used as a dietary supplement to manage hyperglycemia.     

rac- and meso-Cyclohexanoids: Their α-, β-glycosidases,antibacterial, antifungal activities,and molecular docking studies

An efficient and versatile synthesis method has been postulated for hydroxymethylated rac - and meso-cyclohexanoid derivatives. The synthesis of these stereoisomers was achieved easily with traditional methods using hexahydroisobenzofuran 6 , prepared from commercially available cis-hydrophthalic anhydride. The study, involving diastereoselective epoxidation and cis-hydroxylation, was conducted to obtain epoxy-, cis-, and trans-diol-furans 7, 8 , and 9 . After sulfamic acid-catalyzed ring-opening reaction of the epoxide and furan rings, rac- and meso-tetraacetates 14, 15 , and 16 were afforded. Hydrolysis of acetate groups with ammonia in absolute methanol yielded the desired tetrols rac -17 , meso -18 , and meso -19 . All structures, after purification by chromatographic methods and elucidation by spectral techniques, were screened against α- and β-glucosidases. Compounds 7, 8, 10, 17, 18 , and 19 were also evaluated for their antibacterial and antifungal activity against some selected synthesized compounds with varying degrees of inhibitory effects on the growth of different pathogenic microorganisms by the well-diffusion method. In addition, Saccharomyces cerevisiae α-glucosidase molecular modeling studies were performed for all rac- and meso-compounds 7, 8, 10, 17, 18 , and 19 .     

Anti-insulin resistance effect of constituents from Senna siamea on zebrafish model,its molecular docking,and structure–activity relationships

Journal of Natural Medicines - Senna siamea has been used as an antidiabetic drug since antiquity. With regard to traditional Thai medicine, the use of S. siamea was described for diabetes therapy....     

Design of potent human steroid 5α-reductase inhibitors: 3D-QSAR CoMFA, CoMSIA and docking studies

3D-QSAR CoMFA, CoMSIA and docking studies were performed on a set of 4-azasteroidal human steroid 5α-reductase inhibitors. The models developed using maximal common substructure-based alignment was found to be reliable and significant with good predictive r ² value. CoMSIA model developed using combination of steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor features has shown r _cv ²  = 0.564 with six optimum components, r _ncv ²  = 0.945, F value = 101.196, r _Pred ²  = 0.693 and SEE = 0.209. The contour plots obtained has shown a favourable effect of bulkier groups at C-17 position. Docking studies indicates the importance of bulkier groups at C-17 position for favourable activity. The study further helps in design of potent inhibitors of the enzyme.     

Quantitative analysis of neosalacinol and neokotalanol,another two potent α-glucosidase inhibitors from Salacia species,by LC-MS with ion pair chromatography

A quantitative analytical method for the highly polar sulfonium pseudo-sugar constituents neosalacinol (3) and neokotalanol (4), another two potent α-glucosidase inhibitors isolated from Ayurvedic traditional medicine Salacia species, was developed by employing an ion pair reagent upon chromatographic separation. The optimum conditions for separation and detection of these two constituents were achieved on an ODS column (3-μm particle size, 2.1-mm i.d. × 100 mm) with 5 mM undecafluorohexanoic acid–MeOH (99:1, v/v) as the mobile phase and using MS equipped with an electrospray ionization source. More than ten samples of Salacia from different origins were analyzed, and the results indicated that the assay was reproducible and precise and could be readily utilized for evaluation of α-glucosidase inhibitory activity of Salacia species. By combining this assay with the quantitative analytical method previously developed for salacinol (1) and kotalanol (2), a more precise and strict evaluation of α-glucosidase inhibitory activities of extracts from Salacia species (R = 0.959 for maltase and 0.795 for sucrase) was achieved.