Α-glycosidase Inhibitory Activity Research Articles

LC-ESI-MS/MS-Based Comparative Metabolomic Study, Antioxidant and Antidiabetic Activities of Three Lobelia Species: Molecular Modeling and ADMET Study.

The hydroethanol (70%) extracts of three Lobelia species (L. nicotianifolia, L. sessilifolia, and L. chinensis) were analyzed using LC-ESI-MS/MS. Forty-five metabolites were identified, including different flavonoids, coumarin, polyacetylenes, and alkaloids, which were the most abundant class. By applying Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA) based on LC-ESI-MS/MS analysis, the three species were completely segregated from each other. In addition, the three Lobelia extracts were tested for their antioxidant activities using a DPPH assay and as antidiabetic agents against α-glycosidase and α-amylase enzymes. L. chinensis extract demonstrated significant antioxidant activity with an IC50 value of 1.111 mg/mL, while L. nicotianifolia showed mild suppressing activity on the α-glycosidase activity with an IC50 value of 270.8 μg/mL. A molecular simulation study was performed on the main compounds to predict their potential antidiabetic activity and pharmacokinetic properties. The molecular docking results confirmed the α-glycosidase inhibitory activity of the tested compounds, as seen in their binding mode to the key amino acid residues at the binding site compared to that of the standard drug acarbose. Furthermore, the predictive ADMET results revealed good pharmacokinetic properties of almost all of the tested compounds. The biological evaluation results demonstrated the promising activity of the tested compounds, aligned with the in silico results.

Evaluation of Antidiabetic, Antioxidant and Anti-Hyperlipidemic Effects of Solanum indicum Fruit Extract in Streptozotocin-Induced Diabetic Rats.

Globally, diabetes mellitus is the most common cause of premature mortality after cardiovascular diseases and tobacco chewing. It is a heterogeneous metabolic disorder characterised by the faulty metabolism of carbohydrates, fats and proteins as a result of defects in insulin secretion or resistance. It was estimated that approximately 463 million of the adult population are suffering from diabetes mellitus, which may grow up to 700 million by 2045. Solanum indicum is distributed all over India and all of the tropical and subtropical regions of the world. The different parts of the plant such as the roots, leaves and fruits were used traditionally in the treatment of cough, asthma and rhinitis. However, the hypoglycaemic activity of the plant is not scientifically validated. The present study aimed to evaluate the antioxidant, antidiabetic and anti-hyperlipidaemic activity of methanolic fruit extract of Solanum indicum (SIE) in streptozotocin (STZ) induced diabetic rats. Experimentally, type II diabetes was induced in rats by an i.p. injection of STZ at a dose of 60 mg/kg. The effect of the fruit extract was evaluated at doses of 100 and 200 mg/kg body weight in STZ-induced diabetic rats for 30 days. The oral administration of fruit extract caused a significant (p < 0.05) reduction in the blood glucose level with a more prominent effect at 200 mg/kg. The fruit extract showed dose-dependent α-amylase and α-glycosidase inhibitory activity. It reduced the serum cholesterol and triglyceride levels remarkably in diabetic rats compared to normal. The extract showed the reduced activity of endogenous antioxidants, superoxide dismutase, glutathione peroxidase and catalase in the liver of STZ diabetic rats. The result confirmed that the fruit extract of Solanum indicum showed a dose-dependent blood glucose lowering effect and significantly reduced elevated blood cholesterol and triglycerides. It prevented oxidative stress associated with type II diabetes in STZ rats.

Identification of sesquiterpene glycosides from Dendrobium nobile and their α-glycosidase and α-amylase inhibitory activities

Dendrobium nobile is a traditional Chinese medicine and functional food in China, with anti-aging, immunity-enhancing, glucose-lowering and lipid-lowering health functions. In recent years, the research value of D. nobile has attracted the attention of more and more experts and scholars. Today, phytochemical investigation of the stems of Dendrobium nobile Lindl., led to the isolation of five sesquiterpene glycosides, including dendromoniliside D (1), dendronobiloside A (2), dendronobiloside C (3), dendronobiloside D (4), dendroside G (5) and their α-amylase and α-glycosidase inhibitory activities were also investigated. Among them, dendromoniliside D (1), dendroside G (5) were first isolated from D. nobile. And dendronobiloside A (2) and dendronobiloside C (3) exhibited better inhibitory activity against α-glycosidases, respectively. In the case of α-amylase inhibition, dendroside G (5) has a relatively good effect. These results suggest that sesquiterpene glycosides of D. nobile have potential hypoglycemic activity and deserve further research and development.

Rapid screening of α-glucosidase inhibitors in Hypericum perforatum L. using bio-affinity chromatography coupled with UPLC/MS.

α-glucosidase inhibitors (AGIs) are widely used for the treatment of type 2 diabetes, but their side effects have made it to develop novel and alternative AGIs immediately. In this study, the extract of Hypericum perforatum L. (HPE) has been confirmed to have α-glucosidase inhibitory activity in vitro and in vivo. Seven active compounds, rutin, hyperoside, isoquercitrin, avicularin, quercitrin, quercetin, and biapigenin, were screened based on a bio-affinity chromatography column with α-glucosidase enzyme-conjugated solid phase and UPLC/MS, which exhibited excellent α-glycosidase inhibitory effects by the determined IC50 values. The mechanism of α-glycosidase inhibitory activity of biapigenin was studied for the first time. The results showed that biapigenin was a high-potential, reversible, and mixed enzyme inhibitor. Analysis by molecular docking further revealed that hydrophobic interactions were generated by interactions between biapigenin and amino acid residues LYS156, PHE303, PHE314, and LEU313. In addition, hydrogen bonding occurred between biapigenin and α-glucosidase amino acid residues ASP307, SER241, and LYS156. This research identified that biapigenin could be a novel AGI and further applied to the development of potential anti-diabetic drugs. Furthermore, our studies established a rapid in vitro screening method for AGIs from plants.

Novel PEPPSI-type N-heterocyclic carbene palladium(II) complexes: Synthesis, characterization, in silico studies and enzyme inhibitory properties against some metabolic enzymes

In this study, a series of PEPPSI-type N-heterocyclic carbene palladium(II) complexes 3a-e were synthesized using amine functionalized benzimidazolium salts 2a-e as N-heterocyclic carbene precursors. These complexes were characterized by FT-IR, 1H NMR and 13C NMR spectroscopy, elemental analysis and mass spectrometry. Also, the molecular and crystal structure of 3b has been determined by the single-crystal X-ray diffraction method. According to the structural analysis, the geometry of the palladium center of the complex adopts a slightly distorted square planar environment. The benzimidazolium salts 2a-e and their palladium(II) complexes 3a-e were screened for human carbonic anhydrase I, II (hCAs I and II), and α-glycosidase inhibitory activities. Results indicated that all the synthetic compounds exhibited potent inhibitory activities against all targets as compared to the standard inhibitors, revealed by IC50 values. Ki values of 2a-e and 3a-e for hCA I, hCA II, and α-glycosidase enzymes were obtained in the ranges 1.17 ± 0.11–65.50 ± 8.20 µM, 1.02 ± 0.08–57.60 ± 6.41 µM, and 118.86 ± 11.92–509.21 ± 26.61 nM, respectively. Besides these, molecular docking calculations of potent compounds 2b, 2d, 2e, 3a, 3b, 3c and 3e towards human carbonic anhydrase I (hCA I), human carbonic anhydrase II (hCA II), and α-glycosidase (α-Gly) were presented using AutoDock 4. Among the compounds discussed, compounds 3c, 3a, 2e and 2b have the best binding affinity for α-Gly (-9.87, −9.77, −9.04 and −8.63 kcal/mol); compounds 3e, 3b, 2d and 2e turn out to have the second-best binding affinity (-8.80, −8.74, −8.39 and −7.57 kcal/mol) against hCA II. Lastly, compounds showing the lowest binding affinity for hCA I enzyme are 3e, 3b, 2d and 2e, respectively. These findings show that especially NHC-palladium(II) complexes 3a-e are more active for all three enzyme structures than their N-heterocyclic carbene precursors 2a-e and may be potential candidates for the discovery and development of effective inhibitors for the related enzymes in the future.

Water Caltrop (Trapa quadrispinosa Roxb.) Husk Improves Oxidative Stress and Postprandial Blood Glucose in Diabetes: Phenolic Profiles, Antioxidant Activities and α-Glycosidase Inhibition of Different Fractions with In Vitro and In Silico Analyses.

The aim of this study was to investigate the phenolic profiles, antioxidant activities and α-glycosidase inhibitory activities of three different phenolic fractions from water caltrop (Trapa quadrispinosa Roxb.) husk and to further explore the predominant compounds and their mechanisms on α-glycosidase inhibition by virtual screening and molecular dynamics. A total of 29 substances were identified and quantified in this study. Tannins were the main constituents of water caltrop husk extract. All of the free phenolic (FP), esterified phenolic (EP) and insoluble-bound phenolic (BP) fractions exhibited good antioxidant activities, and the BP had the highest radical scavenging ability with IC50 values of 0.82 ± 0.12 μg/mL (ABTS) and 1.15 ± 0.02 μg/mL (DPPH), respectively (p < 0.05). However, compared with the EP and BP, the FP showed the strongest inhibition towards the α-glycosidase and the IC50 value of FP was 1.43 ± 0.12 μg/mL. The 1,2,6-trigalloylglucose and α-glycosidase complex had better root mean square deviations (RMSD) stability via molecular dynamics simulation study. Results obtained from this study may provide a good potential natural resource for the improvement of oxidative stress injury and blood glucose control in diabetes mellitus, which could expand the use of water caltrop husk and improve its economic value.

Phenolic characterization, antioxidant and α-glycosidase inhibitory activities of different fractions from Prinsepia utilis Royle seed shell using in vitro and in silico analyses

Phenolic characterization, antioxidant and α-glycosidase inhibitory activities of different fractions from Prinsepia utilis Royle seed shell using in vitro and in silico analyses

A Biochemical Approach for Hedysarum candidissimum from Turkey: Screening Phytochemicals, Evaluation of Biological Activites, and Molecular Docking Study.

This study was designed to screen the phytochemical composition and investigate the biological activities of Hedysarum candidissimum extracts and also support the results with molecular docking studies. LC/MS/MS analysis revealed the presence of 22 phytochemical constituents (mainly phenolic acids, flavonoids, and flavonoid glycosides) in the plant structure. The methanol extract exhibited the strongest antioxidant activity among all the extracts with its strong DPPH radical scavenging and iron reducing capacity, as well as high phenolic and flavonoid contents. Additionally, it was found to be the most promising acetylcholinesterase (AChE: IC50 : 93.26 μg/mL) and α-glycosidase (AG: IC50 : 28.57 μg/mL) inhibitory activities, supported by the major phenolics of the species through in silico studies. Ethyl acetate extract had the strongest cytotoxic effect on HT-29 (IC50 : 63.03 μg/mL) and MDA-MB-453 (IC50 : 95.36 μg/mL) cancer cell lines. Both extracts exhibited considerable apoptotic and anti-migrative effects on HT-29 cells. The investigations provide phyto-analytical and bio-pharmacological results which can be extended by in vivo studies in the future.

The effect of balanities aeqyptiaca defatted protein meal and protein concentrate supplemented diet on biochemical and molecular stability of diabetic wister albino rat

Balanites aeqyptiaca (BA) seeds were toasted at 70 °C, milled and the oil expelled to resolve to meal which were defatted to resolve to defatted balanites aeqyptiaca (BA) protein meal and (BA) protein concentrate respectively. These were subjected to analysis using standard methods. There exist marked trend between defatted balanites aeqyptiaca protein meal, protein concentrate and incidences of diabetes. This work investigated the anti- diabetic effects of balanites aeqyptiaca defatted protein meal and concentrate supplemented diets in streptozotocin (STZ)-induced diabetic rats. The rats were fattened for two weeks with high fat diet (HFD) to introduce Hyperglycemia and then made diabetic by intraperitoneal administration of STZ (35 mg/kg body weight) and fed diets containing 5 % defatted balanites aeqyptiaca protein meal (DAPM) and 5 % balanites aeqyptiaca protein concentrate (APC) for 14 days. The effect of the diet on blood glucose, serum glutathione peroxidase (GPx), glutathione transferase (GSH), thiobarbituric acid reactive species (TBARS), α-amylase and intestinal α-glucosidase activities were investigated. There was marked increase in the blood glucose, TBARS, pancreatic α-amylase and intestinal α-glycosidase with corresponding decrease in serum GPx and GSH contents in diabetic rats control groups. These trends were however, reversed in diabetic rats fed diet supplemented with the balanites aeqyptiaca protein meals for 14 days. The meals from defatted and protein concentrate inhibit α-amylase and α-glycosidase inhibitory activity in vivo. Thus, the anti-diabetes properties of the defatted meal and protein concentrate may be attributed to the influence of its constituent phytochemicals on starch digestion as well as endogenous enzymes activities. The study revealed that defatted aduwa meal and proteins concnentrate demonstrated potentials used as functional ingredients in food materials and could also increase income access of low resource populace.

New taraxasterane-type triterpenes from Diaphragma juglandis Fructus

Phytochemical investigation into the Diaphragma juglandis Fructus led to the isolation of four new taraxasterane-type triterpenes (1–4). The structures of 1–4 were elucidated by extensive analyses through HRESIMS, NMR and X-ray single-crystal diffraction analysis. In addition, the α-glycosidase inhibitory activities of 1–4 were evaluated and further analysis by molecular docking experiments were adopted to reveal the structure-activity relationship.

The Chemical Constituents of Diaphragma Juglandis Fructus and Their Inhibitory Effect on α-Glucosidase Activity

In our current investigation, 37 constituents (1–37), including 11 megastigmanes (1–11), 17 flavonoids (12–28) and 9 phenylpropanoids (29–37), were isolated from a 70%-EtOH extract of Diaphragma juglandis Fructus. Among them, compounds 1–3, 12 and 29 were new compounds and their structures were elucidated on the basis of physicochemical evidence and meticulous spectroscopic analysis (NMR, HRESIMS and CD). Compounds 13, 16, 21 and 28 showed moderate inhibitory effect on α-glycosidase inhibitory activities, with IC50 values being in the range of 29.47–54.82 µM and stronger than the positive control (acarbose, 60.01 ± 4.82 µM).

Pentacyclic Triterpenoids from Sabia discolor Dunn and Their α-Glycosidase Inhibitory Activities.

Four new pentacyclic triterpenoids named Sabiadiscolor A–D (1 and 7–9) together with eleven known ones were isolated by repeated column chromatography. Their structures were identified and characterized by NMR and MS spectral data as 6 oleanane-type pentacyclic triterpenoids (1–6), 7 ursane-type ones (7–13), and 2 lupanane-type ones (14–15). Except for compound 15, all other compounds were isolated from Sabia discolor Dunn for the first time. Their α-glycosidase inhibitory activities were evaluated, which showed that compounds 1, 3, 8, 9, 13, and 15 implied remarkable activities with IC50 values ranging from 0.09 to 0.27 μM, and the preliminary structure–activity relationship was discussed.

Iboga-type alkaloids with Indolizidino[8,7-b]Indole scaffold and bisindole alkaloids from Tabernaemontana bufalina Lour

Phytochemical investigation on the aerial parts of Tabernaemontana bufalina Lour. (Apocynaceae) led to the identification of four undescribed monoterpenoid indole alkaloids named taberbufamines A−D, an undescribed natural product, and fourteen known indole alkaloids. The structures of the undescribed alkaloids were established by spectroscopic and computational methods, and their absolute configurations were further determined by quantum chemical TDDFT calculations and the experimental ECD spectra. Taberbufamines A and B possessed an uncommon skeleton incorporating an indolizidino [8,7-b]indole motif with a 2-hydroxymethyl-butyl group attached at the pyrrolidine ring. Biosynthetically, Taberbufamines A and B might be derived from iboga-type alkaloid through rearrangement. Vobatensine C showed significant bioactivity against A-549, Bel-7402, and HCT-116 cells with IC50 values of 2.61, 1.19, and 1.74 μM, respectively. Ervahanine A showed antimicrobial activity against Bacillus subtilis, Mycobacterium smegmatis, and Helicobacter pylori with MIC values of 4, 8, and 16 μg/mL, respectively. 19(S)-hydroxyibogamine was shown as butyrylcholinesterase inhibitor (IC50 of 20.06 μM) and α-glycosidase inhibitor (IC50 of 17.18 μM), while tabernamine, ervahanine B, and ervadivaricatine B only showed α-glycosidase inhibitory activities with IC50 values in the range of 0.95–4.61 μM.

Comparison of the chemical composition and antioxidant, anti-inflammatory, α-amylase and α-glycosidase inhibitory activities of the supernatant and cream from black tea infusion.

Tea cream is a kind of turbid substance commonly existing in tea infusion and tea beverage upon cooling. Herein, a comparative study was conducted on the supernatant and cream from black tea infusion in terms of antioxidant, anti-inflammatory and enzyme inhibitory activities, and chemical composition. Ultraviolet-visible (UV-vis) spectrometry and high-performance liquid chromatography (HPLC) analysis showed that the contents of protein, polyphenols, theaflavins, thearubigins, theabrownins, and caffeine in cream were significantly higher than those in the supernatant. The contents of Al, Ca, Cu, and Fe elements in cream were higher than those in the supernatant. However, higher levels of monosaccharides and free amino acids were detected in the supernatant compared with cream. The ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) based metabolomics analysis revealed that the main marker compounds between the supernatant and the cream were organic acids, phenolic acids, and flavan-3-ols and their oxidation products, flavonol glycosides and amino acids. The cream showed better antioxidant and anti-inflammatory, as well as α-amylase and α-glycosidase inhibitory activities than the supernatant, because it contained higher contents of polyphenols than the supernatant. The present study expanded the new vision towards the cream of black tea infusion.

Hexahydroazulene-2(1H)-one Sesquiterpenoids with Bridged Cyclobutane, Oxetane, and Tetrahydrofuran Rings from the Stems of Daphne papyracea with α-Glycosidase Inhibitory Activity.

Chemical investigation of an alcoholic extract from the stem of Daphne papyracea ("Xuehuagou") led to the isolation of the tetracyclic sesquiterpenoid daphnepapytone A (1), containing a unique caged skeleton with a cyclobutane ring having three tetrasubstituted chirality centers. Also isolated were new guaiane sesquiterpenoids, namely, daphnepapytones B-H (2-8), and one 1,5-diphenylpentanone 2-hydroxy-5-oxo-daphneone (9), together with 26 known compounds. The cyclic metabolites share a 5-isoprenyl-hexahydroazulene-2(1H)-one skeleton with different substitution patterns and a bridged cyclobutane, oxetane, or tetrahydrofuran ring. The planar structures and relative configuration of the new compounds were elucidated on the basis of spectroscopic analysis aided by DFT 13C NMR calculations. The absolute configurations of 1-7 were determined by X-ray single-crystal diffraction or TDDFT-ECD calculations. Daphnepapytones A and C (1 and 3), 2-hydroxy-5-oxodaphneone (9), daphnenone (10), daphneone (11), and 3-methyldaphneolone (12) showed α-glycosidase inhibitory activity, with IC50 values of 159.0, 102.3, 139.3, 43.3, 145.0, and 126.1 μM, respectively.

γ-Glutamyl-β-phenylethylamine, a novel α-glucosidase and α-amylase inhibitory compound from Termitomyces robustus, an edible Nigerian mushroom

Termitomyces species are known edible mushrooms in Nigeria, believed to have exceptional culinary and nutraceutical properties. Methanol extract from fruiting bodies of Termitomyces robustus was evaluated for antidiabetic activity using in vitro α-amylase and α-glucosidase assays. The isolation and structural elucidation of metabolites from the T. robustus extract afforded five compounds including a new natural product γ-glutamyl-β-phenylethylamine 3 and four known phenyl derivatives: tryptophan 1, 4-hydroxyphenylacetic acid 2, 4-hydroxyphenylpropionic acid 4, and phenyllactic acid 5. Structures were elucidated from analyses of spectroscopic data (1 D and 2 D NMR, HRESIMS) and all isolated compounds were tested for α-amylase and α-glycosidase inhibitory activity. The in vitro assay established crude extract to possess α- amylase and α-glucosidase inhibition with IC50 of 78.05 µg/mL and 86.10 µg/mL, respectively. The isolated compounds compared favourably with the standard drug, acarbose with IC50 ranging from 6.18-15.08 µg/mL and 18.28-44.63 µg/mL for α-amylase and glucosidase, respectively.

Cassane diterpenoids from Caesalpinia pulcherrima and their anti-inflammatory and α-glycosidase inhibitory activities

Three undescribed cassane-type diterpenoids (CAs), caesalpulcherrins K-M (1–3), together with three known ones (4–6) were isolated from the aerial parts of Caesalpinia pulcherrima (L.) Sw (Fabaceae). Their structures were elucidated via analysis of NMR (1 D and 2 D) and HRESIMS data. The character for caesalpulcherrin K possessing the olefin bond at C-11 and C-12 in its cassane skeleton was observed, which belonged to a small group among more than 450 CAs. That is, only fifteen derivatives have been reported up to now, to our knowledge. Biological evaluation revealed that compounds 1–6 exhibited moderate anti-inflammatory activity, with an IC50 value from 6.04 ± 0.34 to 8.92 ± 0.65 μM. Furthermore, compounds 5 and 6 exhibited significant α-glucosidase inhibitory activity at 10 μM.

Rapid prediction method of α-Glycosidase inhibitory activity of Coreopsis tinctoria extract from different habitats by near infrared spectroscopy

α-Glucosidase is one of the main enzymes causing elevated blood glucose, and Coreopsis tinctoria extract can be used as a natural inhibitor of α-Glucosidase. Therefore, a new method was proposed for predicting the inhibitory activity on α-Glucosidase of Coreopsis tinctoria extract based on near infrared spectroscopy. The absorbance of the inhibitory system was measured by ultraviolet spectroscopy, which was used to study the inhibitory activity on a-glucosidase of Coreopsis tinctoria extract. The near infrared spectra of the solid samples were collected. By selecting spectral preprocessing and optimizing spectral bands, a rapid prediction model of the inhibitory activity was established by partial least squares regression. The root mean square error of cross-validation (RMSECV), correlation coefficient (R) value and the ratio of prediction to deviation (RPD) value were used as indicators of the evaluation model. The near infrared spectrum model was established by combining the best spectral preprocessing of the continuous wavelet transform (CWT) and the best spectral band. The root mean square error of cross-validation (RMSECV) of this model was 0.815%, the correlation coefficient (R) value was 0.942, and the ratio of prediction to deviation (RPD) was 3.0. The root mean square error of prediction (RMSEP) of the model by prediction set was 0.819%, the correlation coefficient (R) value was 0.950, and the RPD was 3.2. The model shows that the fitting relationship between the predicted inhibition value and the reference inhibition value of the near infrared spectral model is good. The results showed that there was a good correlation between near infrared spectroscopy and the inhibitory activity of Coreopsis tinctoria extract. Thus, the established model was robust and effective and could be used for rapid quantification of α-Glucosidase inhibitory activity. The prediction method is simple and rapid, and can be extended to study the inhibition of other medicinal plants.

Hyperpatulones C-G, new spirocyclic polycyclic polyprenylated acylphloroglucinols from the leaves of Hypericum patulum

Five new spirocyclic polycyclic polyprenylated acylphloroglucinols, Hyperpatulones C-G (1–5), were obtained from the leaves of Hypericum patulum. Their structures were characterized by the comprehensive analysis of their IR, NMR, CD spectra and HRESIMS data. All the new compounds were evaluated for the α-glycosidase inhibitory activities. Among them, compounds 3–5 showed α-glucosidase inhibitory activities, with IC50 values of 14.06–37.69 μM.

Design and synthesis of phenoxymethybenzoimidazole incorporating different aryl thiazole-triazole acetamide derivatives as α-glycosidase inhibitors.

A novel series of phenoxymethybenzoimidazole derivatives (9a-n) were rationally designed, synthesized, and evaluated for their α-glycosidase inhibitory activity. All tested compounds displayed promising α-glycosidase inhibitory potential with IC50 values in the range of 6.31 to 49.89 μM compared to standard drug acarbose (IC50 = 750.0 ± 10.0 μM). Enzyme kinetic studies on 9c, 9g, and 9m as the most potent compounds revealed that these compounds were uncompetitive inhibitors into α-glycosidase. Docking studies confirmed the important role of benzoimidazole and triazole rings of the synthesized compounds to fit properly into the α-glycosidase active site. This study showed that this scaffold can be considered as a highly potent α-glycosidase inhibitor. Supplementary InformationThe online version contains supplementary material available at 10.1007/s11030-021-10310-7.