Synthesis, in vitro inhibitory activity, kinetic study and molecular docking of novel N-alkyl-deoxynojirimycin derivatives as potential α-glucosidase inhibitors.

A series of novel N-alkyl-1-deoxynojirimycin derivatives 25 ∼ 44 were synthesised and evaluated for their in vitro α-glucosidase inhibitory activity to develop α-glucosidase inhibitors with high activity. All twenty compounds exhibited α-glucosidase inhibitory activity with IC50 values ranging from 30.0 ± 0.6 µM to 2000 µM as compared to standard acarbose (IC50 = 822.0 ± 1.5 µM). The most active compound 43 was ∼27-fold more active than acarbose. Kinetic study revealed that compounds 43, 40, and 34 were all competitive inhibitors on α-glucosidase with Ki of 10 µM, 52 µM, and 150 µM, respectively. Molecular docking demonstrated that the high active inhibitors interacted with α-glucosidase by four types of interactions, including hydrogen bonds, π-π stacking interactions, hydrophobic interactions, and electrostatic interaction. Among all the interactions, the π-π stacking interaction and hydrogen bond played a significant role in a various range of activities of the compounds.

Determination of Chemical Composition and α-amylase Inhibitory Effect of New Propolis Extracts.

BACKGROUND: Propolis is a resinous mixture collected by honeybees from tree buds and exudates of the plants. Propolis contains aromatic acids, diterpenic acids and phenolic compounds and these components are responsible for its antitumor, anticancer, antiviral and antifungal effects. Propolis can be extracted and the solubility of propolis differs depending on the solvent used in the process of extraction. Solvents used for propolis extraction have a great impact on the propolis extract and should be nontoxic. OBJECTIVE: In this study, raw propolis was extracted by peppermint and clove volatile oils. METHODS: Chemical composition of extracts was determined by using GC-MS equipment. Total phenolic content and antioxidant activity of the extracts were measured. α-amylase inhibitory activity of the extracts was carried out as well. RESULTS: The findings of the present study showed that clove volatile oil is more effective in the extraction of propolis than peppermint volatile oil. The total phenolic content of these extracts was determined as 175.12 and 40.80 mg GAE/mL for clove and peppermint oil propolis extracts, respectively. All extracts contained the same phenolic compounds but the quantity was less in volatile oil extract than in ethanol extract. Both of these extracts showed better α-amylase inhibitory activity than a reference inhibitor, acarbose. CONCLUSION: It could be concluded that propolis extract obtained by using volatile oils could be used as a complementary agent in the treatment of type 2 diabetes mellitus.

In Vitro α-glucosidase Inhibition and Computational Studies of Kaempferol Derivatives from Dryopteris cycanida.

BACKGROUND: Dryopteris cycadina has diverse traditional uses in the treatment of various human disorders which are supported by pharmacological studies. Similarly, the phytochemical studies of this plant led to the isolation of numerous compounds. METHODOLOGY: The present study deals with α-glucosidase inhibition of various kaempferol derivates including kaempferol-3, 4/-di-O-α- L-rhamnopyranoside 1, kaempferol-3, 5-di-O-α-L-rhamnoside 2 and kaempferol-3,7-di-O-α- L-rhamnopyranoside 3. RESULTS: The results showed marked concentration-dependent inhibition of the enzyme when assayed at different concentrations and the IC50 values of compounds 1-3 were 137±9.01, 110±7.33, and 136±1.10 mM, respectively far better than standard compound, acarbose 290±0.54 mM. The computational studies revealed strong docking scores of these compounds and augmented the in vitro assay. CONCLUSION: In conclusion, the isolated kaempferol derivatives 1-3 from D. cycadina exhibited potent α- glucosidase inhibition.

Design, synthesis and biological evaluation of theophylline containing variant acetylene derivatives as α-amylase inhibitors.

A novel pharmacophore with theophylline and acetylene moieties was constructed by using a fragment-based drug design and a series of twenty theophylline containing acetylene conjugates were designed and synthesized, and all the compounds were evaluated by enzyme-based in vitro α-amylase inhibition activity. The in vitro evaluation revealed that most of the compounds displayed good inhibitory activities, and among them nine analogs 13-15, 20, 21 and 24-27 were exhibited more or nearly as equipotent inhibitory activity with IC50 values 1.11 ±â€¯0.07, 1.14 ±â€¯0.17, 1.07 ±â€¯0.01 and 1.21 ±â€¯0.03, 1.33 ±â€¯0.09, 1.17 ±â€¯0.01, 1.05 ±â€¯0.02, 1.61 ±â€¯0.04, 1.02 ±â€¯0.03 µM respectively, as compared with standard, acarbose 1.37 ±â€¯0.26 µM. Further, molecular docking simulation studies were done to identify the interactions and binding mode of synthesized analogs at binding site of α-amylase enzyme (PBD ID: 4GQR). Among the synthesized analogs, two compounds 25 and 27 were selected on the basis of α-amylase inhibition activity and evaluated for in vivo anti-diabetic activity by High Fat Diet-Streptozotocin (HFD-STZ) model in normal rats. At the dose of 10 mg/kg, bw, po these compounds have significantly reduced Plasma Glucose level in rats as compared to pioglitazone. The anti-diabetic activity results showed that the animal treated with the compounds 25 and 27 could better reverse and control the progression of the disease compared to the standard.

Use of acarbose for eliminating the interval between meal consumption and insulin injection in patients with Type 1 diabetes.

This double-blind, placebo-controlled, cross-over study investigated whether acarbose therapy enables patients with Type 1 diabetes to administer insulin injections at the same time as meals without adverse glycaemic consequences, thus negating the need for an injection-meal interval (IMI). The valid-case population was 15. All patients were well controlled on insulin therapy and diet. Each patient underwent four 14-d treatment sequences: IMI of 0 min+acarbose; IMI of 30 min + acarbose; IMI of 0 min + placebo; IMI of 30 min + placebo. There was a 1-wk, placebo-controlled washout period between each treatment. A 50 mg acarbose or placebo tablet was taken with each of three meals for the first 3 d of each treatment; this was increased to 100 mg three times daily on the remaining 11 d. Blood samples were taken between 08.00 and 09.00 h at the end of each treatment sequence, during the fasting state and at the following times after breakfast: 30, 60, 120 and 180 min. The primary target variable was 1-hr postprandial blood glucose level after 14 d. The mean increase in 1-hr postprandial blood glucose level using an IMI of 0 min + acarbose was 51.1+/-53.2 mg/dl, compared with 46.6+/-50.4 mg/dl using a 30-min IMI + placebo. Data provided strong evidence that acarbose prevents the marked increase in postprandial glucose level normally observed when insulin is administered with a meal. Acarbose may thus be useful for patients with Type 1 diabetes who find IMIs inconvenient.