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

2019 ◽  
Vol 15 (1) ◽  
pp. 8-16 ◽  
Author(s):  
Zahra Heydari ◽  
Maryam Mohammadi-Khanaposhtani ◽  
Somaye Imanparast ◽  
Mohammad A. Faramarzi ◽  
Mohammad Mahdavi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kinetic Study ◽  
Inhibitory Activity ◽  
Cycloaddition Reaction ◽  
Competitive Inhibitor ◽  
Biological Evaluation ◽  
Quinoline Derivatives ◽  
Standard Drug

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. </P><P> 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.

Novel coumarin containing dithiocarbamate derivatives as potent α-glucosidase inhibitors for management of type 2 diabetes

2020 ◽  
Vol 16 ◽  
Author(s):  
Marjan Mollazadeh ◽  
Maryam Mohammadi-Khanaposhtani ◽  
Yousef Valizadeh ◽  
Afsaneh Zonouzi ◽  
Mohammad Ali Faramarzi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kinetic Study ◽  
Active Site ◽  
Docking Study ◽  
Secondary Amines ◽  
Molecular Docking Study ◽  
Glucosidase Inhibitors ◽  
Dithiocarbamate Derivatives

Background: α-Glucosidase is a hydrolyze enzyme that plays a crucial role in degradation of carbohydrates and starch to glucose. Hence, α-glucosidase is an important target in the carbohydrate mediated diseases such as diabetes mellitus. Objective: In this study, novel coumarin containing dithiocarbamate derivatives 4a-n were synthesized and evaluated against α-glucosidase in vitro and in silico. Methods: These compounds were obtained of reaction between 4-(bromomethyl)-7-methoxy-2H-chromen-2-one 1, carbon disulfide 2, and primary or secondary amines 3a-n in the presence potassium hydroxide and ethanol at room temperature. In vitro α-glucosidase inhibition and kinetic study of these compounds were performed. Furthermore, docking study of the most potent compounds was also performed by Auto Dock Tools (version 1.5.6). Results: Obtained results showed that all the synthesized compounds exhibited prominent inhibitory activities (IC50 = 85.0 ± 4.0-566.6 ± 8.6 μM) in comparison to acarbose as standard inhibitor (IC50 = 750.0 ± 9.0 µM). Among them, secondary amine derivative 4d with pendant indole group was the most potent inhibitor. Enzyme kinetic study of the compound 4d revealed that this compound compete with substrate to connect to the active site of α-glucosidase and therefore is a competitive inhibitor. Also, molecular docking study predicted that this compound as well interacted with α-glucosidase active site pocket. Conclusion: Our results suggest that the coumarin-dithiocarbamate scaffold can be a promising lead structure for design potent α-glucosidase inhibitors for treatment of type 2 diabetes.

Novel synthesis of dihydropyrimidines for α-glucosidase inhibition to treat type 2 diabetes: In vitro biological evaluation and in silico docking

2014 ◽  
Vol 54 ◽  
pp. 96-104 ◽  
Author(s):  
Muhammad Yar ◽  
Marek Bajda ◽  
Lubna Shahzadi ◽  
Sohail Anjum Shahzad ◽  
Maqsood Ahmed ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
In Silico ◽  
Biological Evaluation ◽  
In Silico Docking ◽  
Novel Synthesis

scholarly journals A Novel Dipeptidyl Peptidase IV Inhibitory Tea Peptide Improves Pancreatic β-Cell Function and Reduces α-Cell Proliferation in Streptozotocin-Induced Diabetic Mice

2019 ◽  
Vol 20 (2) ◽  
pp. 322 ◽  
Author(s):  
Yating Lu ◽  
Peng Lu ◽  
Yu Wang ◽  
Xiaodong Fang ◽  
Jianming Wu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Type 2 Diabetes ◽  
Inhibitory Activity ◽  
Black Tea ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Inhibitory Peptides ◽  
Dpp Iv

Dipeptidyl peptidase IV (DPP-IV) inhibitors occupy a growing place in the drugs used for the management of type 2 diabetes. Recently, food components, including food-derived bioactive peptides, have been suggested as sources of DPP-IV inhibitors without side effects. Chinese black tea is a traditional health beverage, and it was used for finding DPP-IV inhibitory peptides in this study. The ultra-filtrated fractions isolated from the aqueous extracts of black tea revealed DPP-IV inhibitory activity in vitro. Four peptides under 1 kDa were identified by SDS-PAGE and LC-MS/MS (Liquid Chromatography-Mass Spectrometry-Mass Spectrometry) from the ultra-filtrate. The peptide II (sequence: AGFAGDDAPR), with a molecular mass of 976 Da, showed the greatest DPP-IV inhibitory activity (in vitro) among the four peptides. After administration of peptide II (400 mg/day) for 57 days to streptozotocin (STZ)-induced hyperglycemic mice, the concentration of glucagon-like peptide-1 (GLP-1) in the blood increased from 9.85 ± 1.96 pmol/L to 19.22 ± 6.79 pmol/L, and the insulin level was increased 4.3-fold compared to that in STZ control mice. Immunohistochemistry revealed the improved function of pancreatic beta-cells and suppressed proliferation of pancreatic alpha-cells. This study provides new insight into the use of black tea as a potential resource of food-derived DPP-IV inhibitory peptides for the management of type 2 diabetes.

INHIBITORY POTENCY OF WITHANIA SOMNIFERA EXTRACTS AGAINST DPP-4: AN IN VITRO EVALUATION

2017 ◽  
Vol 15 (1) ◽  
pp. 11
Author(s):  
Praveen Kumar Kempegowda ◽  
Farhan Zameer ◽  
Chethan Kumar Narasimashetty ◽  
Shiva Prasad Kollur ◽  
Satish Kumar Murari
Keyword(s):  
Type 2 Diabetes ◽  
13C Nmr ◽  
Inhibitory Activity ◽  
Withania Somnifera ◽  
Methanol Extract ◽  
Nmr Studies ◽  
1H And 13C Nmr ◽  
Rp Hplc

Background: Pharmacologic treatments for type 2 diabetes are based upon increasing insulin availability and improving sensitivity to insulin. Nowadays, glucagon like peptide-1 (GLP-1) based therapies aims at glucose control through DPP-4 inhibitors. DPP-4 is a transmembrane glycoprotein belongs to prolyl oligopeptidase family, with the specificity of removing X-Pro or X-Ala dipeptides from the N-terminus of polypeptides. GLP-1 effect by stimulating glucose-dependent insulin release from the pancreatic islets, inhibit inappropriate post-meal glucagon release and slow gastric emptying promoting leaky gut. The current study investigated DPP-4 inhibitory activity of catechin, isolated from Withania somnifera (WS), for ethnopharmacological treatment of type 2 diabetes and aimed to increase availability of GLP-1and sensitivity to insulin. Materials and Methods: Young and matured fresh roots, leaves, and fruits of WS plant extract were considered and were systematically evaluated for DPP-4 inhibitory activity using in vitro method, enzyme kinetics, phytochemical analysis, RP-HPLC, LCMS and 1H and 13C NMR method and structure-activity relationship (SAR) studies. Results: In this study, methanol (100% and 80%) extracts of WS matured root exhibited maximum DPP-4 inhibitory activity when compared to other extracts. The maximum DPP-4 inhibitory activity was found in 100% methanol extract of matured root. Phytobioactive was purified by RP-HPLC. The compound purified was found to be flavonoid and was characterized (LCMS, 1H and 13C NMR studies), identified as catechin. Auxiliary, molecular docking was performed using Ligand Fit method using PatchDock package. The study revealed the binding affinity of catechin with DPP-4 to be -6.601 kcal/mol with 13 hydrogen interactions with the receptor and was very similar to the standard potent blockers withaferin A and others (cuscohygrine, scopoletin, sitoindoside IV, tropine), further confirming its hyperglycemic potency. Conclusion: The study reveals that, 100% methanol extract of WS matured roots contains the compound- catechin, which exhibits DPP-4 inhibitory activity resulting in increased level of bioactive GLP-1 and GIP. In this background, we concluded that the WS will be a better source for further development as new antidiabetic drugs.

Phenolic bioactives from developmental stages of highbush blueberry (Vaccinium corymbosum) for hyperglycemia management using in vitro models

2015 ◽  
Vol 95 (4) ◽  
pp. 653-662 ◽  
Author(s):  
Susan Cheplick ◽  
Dipayan Sarkar ◽  
Prasanta Bhowmik ◽  
Kalidas Shetty
Keyword(s):  
Type 2 Diabetes ◽  
Antioxidant Activity ◽  
Inhibitory Activity ◽  
Developmental Stages ◽  
Vaccinium Corymbosum ◽  
In Vitro Models ◽  
In Vitro Assays ◽  
Highbush Blueberry

Cheplick, S., Sarkar, D., Bhowmik, P. and Shetty, K. 2015. Phenolic bioactives from developmental stages of highbush blueberry (Vaccinium corymbosum) for hyperglycemia management using in vitro models. Can. J. Plant Sci. 95: 653–662. Blueberry is a rich source of soluble phenolics as well as human health relevant antioxidants. Phenolic-linked bioactive functionality of blueberry for type 2 diabetes management was screened during fruit maturation, especially from green to ripening stages using in vitro assays. Green fruit showed the highest total soluble phenolic content, whereas all three developmental stages of blueberry fruit exhibited high total antioxidant activity. Overall, ripe fruit had higher α-amylase and α-glucosidase inhibitory activity than green or green/pink fruit, and showed significant potential to improve glucose metabolism through in vitro assays. High phenolic-linked antioxidant activity along with moderate to high α-amylase and α-glucosidase inhibitory activity in ripe blueberry indicated its potential relevance as part of diet-based prevention and management of early stages of hyperglycemia associated with development of type 2 diabetes. This in vitro screening study provides a biochemical rationale and dietary strategy to develop the right blueberry cultivar and stage of fruit development for further validation in animal and clinical studies.

2,4-Dioxochroman Moiety Linked to 1,2,3-triazole Derivatives as Novel α-glucosidase Inhibitors: Synthesis, In vitro Biological Evaluation, and Docking Study

2020 ◽  
Vol 24 (17) ◽  
pp. 2019-2027 ◽  
Author(s):  
Marjan Mollazadeh ◽  
Maryam Mohammadi-Khanaposhtani ◽  
Yousef Valizadeh ◽  
Afsaneh Zonouzi ◽  
Mohammad Ali Faramarzi ◽  
...  
Keyword(s):  
In Silico ◽  
Click Reaction ◽  
Docking Study ◽  
Competitive Inhibitor ◽  
Biological Evaluation ◽  
Binding Energies ◽  
Standard Drug ◽  
In Silico Docking ◽  
Glucosidase Inhibitors

In this study, a novel series of 2,4-dioxochroman-1,2,3-triazole hybrids 8a-l was synthesized by click reaction. These compounds were screened against α-glucosidase through in vitro and in silico evaluations. All the synthesized hybrids exhibited excellent α-glucosidase inhibition in comparison to standard drug acarbose. Representatively, 3-((((1-(3,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)methylene)chroman-2,4- dione 8h with IC50 = 20.1 ± 1.5 μM against α-glucosidase, was 37-times more potent than acarbose. Enzyme kinetic study revealed that compound 8h was a competitive inhibitor against α-glucosidase. In silico docking study on chloro derivatives 8h, 8g, and 8i were also performed in the active site of α -glucosidase. Evaluations on obtained interaction modes and binding energies of these compounds confirmed the results obtained through in vitro α-glucosidase inhibition.

scholarly journals Inhibitory Effect of Fisetin on α-Glucosidase Activity: Kinetic and Molecular Docking Studies

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5306
Author(s):  
Beiyun Shen ◽  
Xinchen Shangguan ◽  
Zhongping Yin ◽  
Shaofu Wu ◽  
Qingfeng Zhang ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Competitive Inhibitor ◽  
Inhibitory Effect ◽  
Docking Studies ◽  
Molecular Docking Studies ◽  
Ic50 Value ◽  
Cotinus Coggygria

The inhibition of α-glucosidase is a clinical strategy for the treatment of type 2 diabetes mellitus (T2DM), and many natural plant ingredients have been reported to be effective in alleviating hyperglycemia by inhibiting α-glucosidase. In this study, the α-glucosidase inhibitory activity of fisetin extracted from Cotinus coggygria Scop. was evaluated in vitro. The results showed that fisetin exhibited strong inhibitory activity with an IC50 value of 4.099 × 10−4 mM. Enzyme kinetic analysis revealed that fisetin is a non-competitive inhibitor of α-glucosidase, with an inhibition constant value of 0.01065 ± 0.003255 mM. Moreover, fluorescence spectrometric measurements indicated the presence of only one binding site between fisetin and α-glucosidase, with a binding constant (lgKa) of 5.896 L·mol−1. Further molecular docking studies were performed to evaluate the interaction of fisetin with several residues close to the inactive site of α-glucosidase. These studies showed that the structure of the complex was maintained by Pi-Sigma and Pi-Pi stacked interactions. These findings illustrate that fisetin extracted from Cotinus coggygria Scop. is a promising therapeutic agent for the treatment of T2DM.

IN VITRO SCREENING OF ACTINIOPTERIS DICHOTOMA FOR ENZYME INHIBITORY ACTIVITY RELATED TO TYPE 2 DIABETES

INDIAN DRUGS ◽  
2016 ◽  
Vol 53 (06) ◽  
pp. 70-73
Author(s):  
M Telagari ◽  
◽  
K. K. Hullatti
Keyword(s):  
Type 2 Diabetes ◽  
Inhibitory Activity ◽  
Skin Diseases ◽  
In Vitro Screening ◽  
Glucosidase Activity ◽  
Ic50 Values ◽  
Calculated Fraction

Actiniopteris dichotoma Mett. (Pteridaceae) is documented in Ayurveda for treatment of Prameha (Diabetes), Atisara and skin diseases. However, the antidiabetic properties of this plant have not been fully validated using scientific tools. The present study screens the A. dichotoma extract and fractions for enzyme inhibitory (α–amylase and α–glucosidase) activity related to type 2 diabetes. The extract was prepared using cold maceration followed by Soxhlation and finally fractionated the combined extracts. Different concentrations (0.1–0.5 mg/mL) of extract and four fractions were subjected to enzyme inhibitory assays. The absorbance was measured at 540 and 405 nm and IC50 values were calculated. Fraction 2 has shown highest α–amylase and α–glucosidase inhibitory activity, (IC50 values are 0.131 and 0.114 mg/mL) which was comparable with acarbose (0.125 and 0.093 mg/mL). Hence, further studies may throw light on the antidiabetic potential of A. dichotoma especially in the management of T2D.

Design, Synthesis, Molecular Docking and Biological Evaluation of 1-(benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol Derivatives as Antiproliferative Agents

2019 ◽  
Vol 16 (10) ◽  
pp. 837-845
Author(s):  
Sandhya Jonnala ◽  
Bhaskar Nameta ◽  
Murthy Chavali ◽  
Rajashaker Bantu ◽  
Pallavi Choudante ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Mouse Skin ◽  
Coupling Reaction ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Design Synthesis

A class of 1-((benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol derivatives (4a-t) has been synthesized in good yields through a three component coupling reaction. The newly synthesized compounds were evaluated for their in vitro antiproliferative activity against five cell lines such as DU145 (human prostate cancer), MDA-MB-B231 (human breast cancer), SKOV3 (human ovarian cancer), B16-F10 (mouse skin melanoma) and CHO-K1 (Chinese hamster ovary cells), a noncancerous cell line. In vitro inhibitory activity indicates that compounds 4a, 4b, 4c, 4d, 4g, 4j, and 4o exhibited potent anti-proliferative behavior. Among them, compounds 4g, 4j and 4o found to be the most active members exhibiting remarkable growth inhibitory activity. Molecular docking facilitates to investigate the probable binding mode and key active site interactions in tubulins α and β proteins. The docking results are complementary to experimental results.

Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Design, Synthesis and Biological Evaluation

2020 ◽  
Vol 16 ◽  
Author(s):  
Reema Abu Khalaf ◽  
Shorooq Alqazaqi ◽  
Maram Aburezeq ◽  
Dima Sabbah ◽  
Ghadeer Albadawi ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Biological Evaluation ◽  
Ligand Docking ◽  
Biological Assessment ◽  
Hypoglycemic Agents ◽  
Binding Affinities ◽  
Oral Hypoglycemic Agents ◽  
Design Synthesis ◽  
Dpp Iv

Background: Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduces the deterioration of gut-derived endogenous incretin hormones that are secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of pancreas. Objective: In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors was carried out. The target compounds were docked to study the molecular interactions and binding affinities against DPP-IV enzyme. Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed. Results: In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 µM concentration, where compound 3d harboring ortho-fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669 and Y752 backbones. Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

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