The triterpenoids and sesquiterpenoids from the plant of Agrimonia pilosa.

A phytochemistry of the whole plant of Agrimonia pilosa led to the discovery of two new nortriterpenoids, agrimonorterpenes A and B (1 and 2), together with one known triterpenoid fupenzic acid (3) and seven known sesquiterpenoids (4-10). The new structures were determined as 19α-hydroxy-2-oxo-nor-A (3)-urs-11,12-dien-28-oic acid (1) and 2, 19ß-dihydroxy-3-oxo-23-noroleana-1, 4, 12-trien-28-oic acid (2) by the spectroscopic data of UV, IR, HR-ESI-MS, and NMR. Notably, the structure of 1 possessed a rare five-membered A- ring. And this is the first time to discover the sesquiterpenoids (4-10) from A. pilosa. Compound 3 displayed the selective cytotoxicity against HCT116, BGC823, and HepG2 cell lines with the IC50 values of 16.31 µM, 21.94 µM, and 23.40 µM, respectively.

Mangosteen xanthone γ-mangostin exerts lowering blood glucose effect with potentiating insulin sensitivity through the mediation of AMPK/PPARγ.

Diabetes mellitus (DM) is concomitant with significant morbidity and mortality and its prevalence is accumulative in worldwide. The conventional antidiabetic agents are known to mitigate the symptoms of diabetes; however, they may also cause side and adverse effects. There is an imperative necessity to conduct preclinical and clinical trials for the discovery of alternative therapeutic agents that can overcome the drawbacks of current synthetic antidiabetic drugs. This study aimed to investigate the efficacy of lowering blood glucose and underlined mechanism of γ-mangostin, mangosteen (Garcinia mangostana) xanthones. The results showed γ-Mangostin had a antihyperglycemic ability in short (2 h)- and long-term (28 days) administrations to diet-induced diabetic mice. The long-term administration of γ-mangostin attenuated fasting blood glucose of diabetic mice and exhibited no hepatotoxicity and nephrotoxicity. Moreover, AMPK, PPARγ, α-amylase, and α-glucosidase were found to be the potential targets for simulating binds with γ-mangostin after molecular docking. To validate the docking results, the inhibitory potency of γ-mangostin againstα-amylase/α-glucosidase was higher than Acarbose via enzymatic assay. Interestingly, an allosteric relationship between γ-mangostin and insulin was also found in the glucose uptake of VSMC, FL83B, C2C12, and 3T3-L1 cells. Taken together, the results showed that γ-mangostin exerts anti-hyperglycemic activity through promoting glucose uptake and reducing saccharide digestion by inhibition of α-amylase/α-glucosidase with insulin sensitization, suggesting that γ-mangostin could be a new clue for drug discovery and development to treat diabetes.

Dibenzazepine-linked isoxazoles: New and potent class of α-glucosidase inhibitors.

α-Glucosidase inhibition is a valid approach for controlling hyperglycemia in diabetes. In the current study, new molecules as a hybrid of isoxazole and dibenzazepine scaffolds were designed, based on their literature as antidiabetic agents. For this, a series of dibenzazepine-linked isoxazoles (33-54) was prepared using Nitrile oxide-Alkyne cycloaddition (NOAC) reaction, and evaluated for their α-glucosidase inhibitory activities to explore new hits for treatment of diabetes. Most of the compounds showed potent inhibitory potency against α-glucosidase (EC 3.2.1.20) enzyme (IC50 = 35.62 ± 1.48 to 333.30 ± 1.67 µM) using acarbose as a reference drug (IC50 = 875.75 ± 2.08 µM). Structure-activity relationship, kinetics and molecular docking studies of active isoxazoles were also determined to study enzyme-inhibitor interactions. Compounds 33, 40, 41, 46, 48-50, and 54 showed binding interactions with critical amino acid residues of α-glucosidase enzyme, such as Lys156, Ser157, Asp242, and Gln353.

Design, synthesis, characterization, enzymatic inhibition evaluations, and docking study of novel quinazolinone derivatives.

In this study, novel quinazolinone derivatives 7a-n were synthesized and evaluated against metabolic enzymes including α-glycosidase, acetylcholinesterase, butyrylcholinesterase, human carbonic anhydrase I, and II. These compounds exhibited high inhibitory activities in comparison to used standard inhibitors with Ki values in the range of 19.28-135.88 nM for α-glycosidase (Ki value for standard inhibitor = 187.71 nM), 0.68-23.01 nM for acetylcholinesterase (Ki value for standard inhibitor = 53.31 nM), 1.01-29.56 nM for butyrylcholinesterase (Ki value for standard inhibitor = 58.16 nM), 10.25-126.05 nM for human carbonic anhydrase I (Ki value for standard inhibitor = 248.18 nM), and 13.46-178.35 nM for human carbonic anhydrase II (Ki value for standard inhibitor = 323.72). Furthermore, the most potent compounds against each enzyme were selected in order to evaluate interaction modes of these compounds in the active site of the target enzyme. Cytotoxicity assay of the title compounds 7a-n against cancer cell lines MCF-7 and LNCaP demonstrated that these compounds do not show significant cytotoxic effects.

Maltase-glucoamylase inhibition potency and cytotoxicity of pyrimidine-fused compounds: An in silico and in vitro approach.

The prevalence of diabetes mellitus has been incremented in the current century and the need for novel therapeutic compounds to treat this disease has been significantly increased. One of the most promising approaches is to inhibit intestinal alpha glucosidases. Based on our previous studies, four pyrimidine-fused heterocycles (PFH) were selected as they revealed satisfactory inhibitory action against mammalian α-glucosidase. The interaction of these compounds with both active domains of human maltase-glucoamylase (MGAM) and their effect on human Caco-2 cell line were investigated. The docking assessments suggested that binding properties of these ligands were almost similar to that of acarbose by establishing hydrogen bonds especially with Tyr1251 and Arg526 in both C-terminal and N-terminal MGAM, respectively. Also, these compounds indicated a stronger affinity for C-terminal of MGAM. L2 and L4 made tightly complexes with both terminals of MGAM which in turn revealed the importance of introducing pyrimidine scaffold and its hinge compartment. The results of molecular dynamics simulation analyses confirmed the docking data and showed deep penetration of L2 and L4 into the active site of MGAM. Based on cell cytotoxicity assessments, no significant cell death induction was observed. Hence, these functional MGAM inhibitors might be considered as new potential therapeutic compounds in treatment of diabetes and its complications.

Design and synthesis of novel xanthone-triazole derivatives as potential antidiabetic agents: α-Glucosidase inhibition and glucose uptake promotion.

Inhibiting the decomposition of carbohydrates into glucose or promoting glucose conversion is considered to be an effective treatment for type 2 diabetes. Herein, a series of novel xanthone-triazole derivatives were designed, synthesized, and their α-glucosidase inhibitory activities and glucose uptake in HepG2 cells were investigated. Most of the compounds showed better inhibitory activities than the parental compound a (1,3-dihydroxyxanthone, IC50 = 160.8 µM) and 1-deoxynojirimycin (positive control, IC50 = 59.5 µM) towards α-glucosidase. Compound 5e was the most potent inhibitor, with IC50 value of 2.06 µM. The kinetics of enzyme inhibition showed that compounds 5e, 5g, 5h, 6c, 6d, 6g and 6h were noncompetitive inhibitors, and molecular docking results were consistent with the noncompetitive property that these compounds bind to allosteric sites away from the active site (Asp214, Glu276 and Asp349). On the other hand, the glucose uptake assays exhibited that compounds 5e, 6a, 6c and 7g displayed high activities in promoting the glucose uptake. The cytotoxicity assays showed that most compounds were low-toxic to human normal hepatocyte cell line (LO2). These novel xanthone triazole derivatives exhibited dual therapeutic effects of α-glucosidase inhibition and glucose uptake promotion, thus they could be use as antidiabetic agents for developing novel drugs against type 2 diabetes.

Cytotoxicity and biological capacity of sulfur-free lignins obtained in novel biorefining process.

Lignin is one of the most promising and versatile products obtained in biorefineries due to its diverse therapeutic properties such as antimicrobial, antioxidant and anti-inflammatory activity. However, these properties depend on the source of lignin and the way it was isolated from the biomass. In this study, four different lignins are compared (extracted with Aquasolv (ASL1, ASL2), Organosolv (OSL) and Alkali (ALK) processes) for their cellular antioxidant capacity, anti-diabetic activity, free radical scavenging and cytotoxicity. Alkali and Organosolv lignins showed the highest antioxidant capacity 1159.815 µmol TE g-1 and 1463.415 µmol TE g-1, respectively, in agreement with their highest amount of free -OH groups. Additionally, OSL showed the highest inhibition in the antidiabetic assay followed by ASL1 with values for α-amylase of 3.6 mg/ml and 4.3 mg/ml respectively, and α-glucosidase 1.6 mg/ml and 2.5 mg/ml correspondingly. Nevertheless, cell-based assays revealed that ASL has the lowest cytotoxic effect in Caco-2 cells and, thus, is 10 times less cytotoxic than Alkali and OSL. This work suggests the applicability of ASL for high value applications such as cosmetics or pharmaceuticals. INDUSTRIAL RELEVANCE: Industrially, Liquid Hot Water (LHW) and Organosolv processes may appear as promising biorefining technologies in the following years. Lignin produced is free of sulfur, can be labelled as clean and environmentally-friendly and in this study, was proven that LHW lignin is non cytotoxic. The findings in this paper showed that different sources of lignin can be used in product formulation for life science purposes, thus opening a broad spectrum of possibilities for lignin valorisation in biorefineries.

Synthetic heterocyclic candidates as promising α-glucosidase inhibitors: An overview.

α-Glucosidase enzyme inhibition is an effective therapeutic decorum in the treatment of type 2 diabetes mellitus. Since 1990, three α-glucosidase inhibitors are known to exist clinically, Acarbose, Voglibose and Miglitol. Side effects and long synthetic routes to access them forced the researchers to move their focus to discover simple and small heterocyclic motifs that work as promising α-glucosidase inhibitors and may eventually lead to the management of postprandial hyperglycemic condition in T2DM. In this regards, this review deals with recently discovered heterocyclic molecules that have been evaluated to exhibit inhibition of α-glucosidase enzyme.

α-Amylase and α-glucosidase inhibitor effects and pancreatic response to diabetes mellitus on Wistar rats of Ephedra alata areal part decoction with immunohistochemical analyses.

Ephedra alata, known as a medicinal plant in China, was used in this study as aqueous extract from aerial parts, for diabetes mellitus treatment. This study was carried out on two parts, in vitro, we tested the effect of the studied extract on the inhibition of α-glucosidase and α-amylase activities, and in vivo on Wistar male rats receiving alloxan intraperitoneally at a rate of 125 mg/kg. Extract (100, 200, and 300 mg/kg of body weight) was administrated for 28 days by oral gavage. Blood glucose, amylase, lipase, and lipid profile level were determined. Oxidative stress was evaluated by enzymatic activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and by estimation of lipid peroxidation and protein carbonyl (PC) level. Histopathological changes in pancreas were investigated under photonic microscopy using immunohistochemical procedure. Our findings showed that aqueous extract inhibited in vitro both α-glucosidase and α-amylase activities and its use in vivo at 300 mg/kg of body weight restored pancreas weight and weight gain, ameliorated significantly (p Ë‚ 0.05) biochemical parameters; it prevented the increase in lipid and protein oxidation and the decrease in enzymatic and non-enzymatic defense system. Histological study of treated animals showed a comparable healed regeneration of beta cells.

Bioactive cytosporone derivatives isolated from the mangrove-derived fungus Dothiorella sp. ML002.

Three new cytosporone derivatives dothiorelones K-M (1, 2 and 7), together with six known ones (3-6, 8 and 9) were isolated from the mangrove-derived fungus Dothiorella sp. ML002. Their structures were determined by comprehensive 1D, 2D NMR spectroscopic and HR-ESI-MS spectroscopic data. Compounds 1, 2 and 5 displayed inhibitory activities against α-glucosidase with the IC50 values of 22.0, 77.9 and 5.4 µg/mL, respectively. Additionally, compounds 1, 2, and 5 also exhibited antibacterial activities against Staphylococcus aureus (ATCC 6538) with the same MIC values of 50 µg/mL, respectively. The results indicated that cytosporone derivatives will be useful to as diabetes control agents.

Combinatorial peptide library screening for discovery of diverse α-glucosidase inhibitors using molecular dynamics simulations and binary QSAR models.

Human α-glucosidase is an enzyme involved in the catalytic cleavage of the glucoside bond and involved in numerous functionalities of the organism, as well as in the insurgence of diabetes mellitus 2 and obesity. Thus, developing chemicals that inhibit this enzyme is a promising approach for the treatment of several pathologies. Small peptides such as di- and tri-peptides may be in natural organism as well as in the GI tract in high concentration, coming from the digestive process of meat, wheat and milk proteins. In this work, we reported the first tentative hierarchical structure-based virtual screening of peptides for human α-glucosidase. The goal of this work is to discover novel and diverse lead compounds that my act as inhibitors of α-glucosidase such as small peptides by performing a computer aided virtual screening and to find novel scaffolds for further development. Thus, in order to select novel candidates with original structure we performed molecular dynamics (MD) simulations among the 12 top-ranked peptides taking as comparison the MD simulations performed on crystallographic inhibitor acarbose. The compounds with the lower RMSD variability during the MD, were reserved for in vitro biological assay. The selected 4 promising structures were prepared on solid phase peptide synthesis and used for the inhibitory assay, among them compound 2 showed good inhibitory activity, which validated our method as an original strategy to discover novel peptide inhibitors. Moreover, pharmacokinetic profile predictions of these 4 peptides were also carried out with binary QSAR models using MetaCore/MetaDrug applications.

Pyrano[3,2-c]quinoline Derivatives as New Class of α-glucosidase Inhibitors to Treat Type 2 Diabetes: Synthesis, in vitro Biological Evaluation and Kinetic Study.

BACKGROUND: Pyrano[3,2-c]quinoline derivatives 6a-n were synthesized via simple two-step reactions and evaluated for their in vitro α-glucosidase inhibitory activity. METHODS: Pyrano[3,2-c]quinoline derivatives 6a-n derivatives were prepared from a two-step reaction: cycloaddition reaction between 1-naphthyl amine 1 and malonic acid 2 to obtain benzo[h]quinoline-2(1H)-one 3 and reaction of 3 with aryl aldehydes 4 and Meldrum's acid 5. The anti- α-glucosidase activity and kinetic study of the synthesized compounds were evaluated using α-glucosidase from Saccharomyces cerevisiae and p-nitrophenyl-a-D-glucopyranoside as substrate. The α-glucosidase inhibitory activity of acarbose was evaluated as positive control. RESULTS: All of the synthesized compounds, except compounds 6i and 6n, showed more inhibitory activity than the standard drug acarbose and were also found to be non-cytotoxic. Among the synthesized compounds, 1-(2-bromophenyl)-1H-benzo[h]pyrano[3,2-c]quinoline-3,12(2H,11H)-dione 6e displayed the highest α-glucosidase inhibitory activity (IC50 = 63.7 ± 0.5 µM). Kinetic study of enzyme inhibition indicated that the most potent compound, 6e, is a non-competitive inhibitor of α-glucosidase with a Ki value of 72 µM. Additionally, based on the Lipinski rule of 5, the synthesized compounds were found to be potential orally active drugs. CONCLUSION: Our results suggest that the synthesized compounds are promising candidates for treating type 2 diabetes.

TLC Screening Profile of Secondary Metabolites and Biological Activities of Salisapilia tartarea S1YP1 Isolated from Philippine Mangroves.

The Salisapilia species are estuarine oomycetes of the mangrove and saltmarsh ecosystem. To date, reports on the secondary metabolites and biological activities of these microorganisms are wanting. In this study, secondary metabolites in broth ethyl acetate extracts (BEAE) and mycelial ethyl acetate extracts (MEAE) of Salisapilia tartarea S1YP1 isolated from yellow senescent mangrove leaves were screened by Thin Layer Chromatography (TLC). Extracts were assayed for antioxidant, antibacterial, α- glucosidase inhibition, and cytotoxic activity. The TLC detected anthraquinones, anthrones, flavonoids, phenols, and triterpenes in both BEAE and MEAE. Coumarins were detected in BEAE but not in MEAE. Quantifying the total phenolics and total flavonoids content of the extracts in terms of gallic acid and quercetin equivalents, respectively shows that BEAE has higher total phenolic and flavonoid contents than MEAE. BEAE exhibited significant antioxidant activities through measurements of free radical scavenging activity against DPPH, hydroxyl, nitric oxide, and superoxide anion radicals as well as the ability to chelate Fe2+ metal ion. BEAE significantly inhibited in a dose-dependent manner α-glucosidase activity and selectively inhibited HepG2 cell proliferation. Antioxidant, α- glucosidase inhibitory, and cytotoxic activities have not been observed for MEAE. Both BEAE and MEAE do not have antibacterial activity.

Clerodendrum volubile inhibits key enzymes linked to type 2 diabetes but induces cytotoxicity in human embryonic kidney (HEK293) cells via exacerbated oxidative stress and proinflammation.

The toxicity and safety associated with the use of medicinal plants remains a major concern. In this study, the antidiabetic properties of the dichloromethane (DCM) fraction of C. volubile leaves were investigated in vitro. Its cytotoxic effect and mechanism of toxicity were also investigated in Human Embryonic Kidney (HEK293) cells. The fraction was subjected to in vitro antioxidant assays using the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) scavenging and Ferric reducing antioxidant power (FRAP) protocols. Its enzyme-inhibitory properties were investigated on α-glucosidase and α-amylase activities. Gas Chromatography Mass Spectroscopy (GCMS) and Fourier Transform Infrared (FTIR) spectroscopic analysis were used to identify its phytoconstituents. Cytotoxicity was determined via MTT assay. The treated cells were assayed for reduced glutathione (GSH), non-protein thiol, nitric oxide and malondialdehyde (MDA) levels, as well as Superoxide Dismutase (SOD), catalase, myeloperoxidase and ATPase activities. Cell apoptosis and/or morphological changes were determined using the acridine orange and ethidium bromide (AO/EB) dual staining method. The fraction showed significant (p < 0.05) antioxidant and enzyme-inhibitory activity. It showed significant (p < 0.05) cytotoxic effect against HEK293 cells with concomitant depletion of antioxidative and elevation of proinflammatory biomarkers. Morphological changes were examined in the cells with an apoptotic index of 0.84. 1,1-Dodecanediol, diacetate was identified as the most predominant compound, while aromatics and amines as the most functional groups present in the fraction. These results suggest the antidiabetic and cytotoxic effects of C. volubile leaves. The toxicity can be attributed to induced oxidative stress and proinflammation with concomitant depletion of ATP leading to apoptosis of the cells.

New indole based hybrid oxadiazole scaffolds with N-substituted acetamides: As potent anti-diabetic agents.

Current study is based on the sequential conversion of indolyl butanoic acid (1) into ethyl indolyl butanoate (2), indolyl butanohydrazide (3), and 1,3,4-oxadiazole-2-thiol analogs (4) by adopting chemical transformations. In a parallel series of reactions, 2-bromo-N-phenyl/arylacetamides (7a-l) were synthesized by reacting different amines derivatives (5a-l) with 2-bromoacetyl bromide (6) to serve as electrophile. Then, the synthesized electrophiles (7a-l) were treated with nucleophilic 1,3,4-oxadiazole-2-thiol analog (4) to afford a range of N-substituted derivatives (8a-l). The structural confirmation of all the synthetic compounds was carried out by IR, 1H-, 13C NMR, EI-MS, and CHN analysis data. All synthesized molecules (8a-l) were tested for their antidiabetic potential via inhibition of the α-glucosidase enzyme followed by their in silico study. Their cytotoxicity profile was also ascertained via hemolytic activity and all of them possessed very low cytotoxicity. Compounds 8h and 8l were found most active having IC50 values 9.46 ±â€¯0.03 µM and 9.37 ±â€¯0.03 µM, respectively. However, all other molecules also exhibited good to moderate inhibition potential with IC50 values between 12.68 ±â€¯0.04-37.82 ±â€¯0.07, compared to standard acarbose (IC50 = 37.38 ±â€¯0.12 µM), hence can be used as lead molecules for further research in order to get better antidiabetic agents.

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.

Anti-inflammatory and angiogenic activity of polysaccharide extract obtained from Tibetan kefir.

The search for new bioactive molecules is a driving force for research pharmaceutical industries, especially those molecules obtained from fermentation. The molecules possessing angiogenic and anti-inflammatory attributes have attracted attention and are the focus of this study. Angiogenic activity from kefir polysaccharide extract, via chorioallantoic membrane assay, exhibited a pro-angiogenic effect compared with vascular endothelial factor (pro-angiogenic) and hydrocortisone (anti-angiogenic) activity as standards with an EC50 of 192ng/mL. In terms of anti-inflammatory activity determined via hyaluronidase enzyme assay, kefir polysaccharide extract inhibited the enzyme with a minimal activity of 2.08mg/mL and a maximum activity of 2.57mg/mL. For pharmaceutical purposes, kefir polysaccharide extract is considered to be safe because it does not inhibit VERO cells in cytotoxicity assays.

In vitro and in vivo anti-diabetic and hepatoprotective effects of edible pods of Parkia roxburghii and quantification of the active constituent by HPLC-PDA.

ETHNOPHARMACOLOGICAL RELEVANCE: Parkia roxburghii G. Don. is a traditional medicinal plant and its pods are extensively used as food and medicine. It is believed by the traditional healers to have medicinal properties to treat diabetes, hypertension and urinary tract infections (Jamaluddin et al., 1994). MATERIALS AND METHODS: The methanolic extract of pods of P roxburghii and fractions were screened for their α-glucosidase and α-amylase inhibitory activity. Anti-hyperglycemic effects were studied on streptozotocin (45mg/kg b.w.) induced diabetes in albino rats (seven groups, n=7 n=6), using different doses for 14 days. Plasma glucose concentration (HbA1c) was analysed using whole blood, while SGOT, SGPT, TG, TC and uric acid were analysed using serum, employing commercial kits. Quantitative analysis of the major active constituent was carried out by HPLC-PDA. RESULTS: Bioactivity guided chemical investigation of the edible pods of P roxburghii identified sub-fraction EA-Fr 5 which significantly inhibited α-glucosidase (IC50 0.39±0.06 µgmL(-1)), reduced the blood glucose level to normal, and lowered the elevated levels of liver function enzymes SGOT and SGPT in STZ-induced diabetic rats. EA-Fr 5 was found to contain epigallocatechin gallate (1) and hyperin (2) which exhibited significantly higher α-glucosidase inhibitory potency with IC50 0.51±0.09 and 0.71±0.03µM respectively. EA-Fr 5 contained 379.82±2.90mg/g of EGCG, the major active constituent which manifests a broad spectrum of biological activities. CONCLUSION: The present investigation for the first time reports the occurrence of EGCG and hyperin in P roxburghii and substantiates the traditional use of pods of P roxburghii as dietary supplement for management of diabetes with significantly promising α-glucosidase inhibitory potency and anti-hyperglycemic as well as hepatoprotective effects.

Effect of Cadmium Ion on alpha-Glucosidase: An Inhibition Kinetics and Molecular Dynamics Simulation Integration Study.

α-Glucosidase is a critical metabolic enzyme that produces glucose molecules by catalyzing carbohydrates. The aim of this study is to elucidate biological toxicity of Cd(2+) based on α-glucosidase activity and conformational changes. We studied Cd(2+)-mediated inactivation as well as conformational modulation of α-glucosidase by using kinetics coupled with simulation of molecular dynamics. The enzyme was significantly inactivated by Cd(2+) in a reversibly binding behavior, and Cd(2+) binding induced a non-competitive type of inhibition reaction (the K i was calculated as 0.3863 ± 0.033 mM). Cd(2+) also modulated regional denaturation of the active site pocket as well as overall partial tertiary structural change. In computational simulations using molecular dynamics, simulated introduction of Cd(2+) induced in a depletion of secondary structure by docking Cd(2+) near the saccharides degradation at the active site, suggesting that Cd(2+) modulating enzyme denaturation. The present study elucidated that the binding of Cd(2+) triggers conformational changes of α-glucosidase as well as inactivates catalytic function, and thus suggests an explanation of the deleterious effects of Cd(2+) on α-glucosidase.

Synthesis, α-glucosidase inhibitory, cytotoxicity and docking studies of 2-aryl-7-methylbenzimidazoles.

Benzimidazole analogs 1-27 were synthesized, characterized by EI-MS and (1)HNMR and their α-glucosidase inhibitory activities were found out experimentally. Compound 25, 19, 10 and 20 have best inhibitory activities with IC50 values 5.30±0.10, 16.10±0.10, 25.36±0.14 and 29.75±0.19 respectively against α-glucosidase. Compound 6 and 12 has no inhibitory activity against α-glucosidase enzyme among the series. Further studies showed that the compounds are not showing any cytotoxicity effect. The docking studies of the compounds as well as the experimental activities of the compounds correlated well. From the molecular docking studies, it was observed that the top ranked conformation of all the compounds fit well in the active site of the homology model of α-glucosidase.