New Glucosidase Inhibitors from an Ayurvedic Herbal Treatment for Type 2 Diabetes: Structures and Inhibition of Human Intestinal Maltase-Glucoamylase with Compounds fromSalacia reticulata

The incidence of diabetes has increased globally in recent years and figures of diabetic patients were estimated to rise up to 642 million by 2040. The disorder is accompanied with various complications if not managed at the early stages, and interlinked high mortality rate and morbidity with time. Different classes of drugs are available for the management of type 2 diabetes but were having certain limitations of their safety. Alphaglucosidase is a family of enzyme originated from the pancreas which plays a role in the anabolism of 80-90% of carbohydrate consumed into glucose. This glucose is absorbed into the blood and results in frank postprandial hyperglycemia and worsens the conditions of diabetic patients which precipitate complications. Inhibition of these enzymes helps to prevent postprandial hyperglycemia and the formation of glycated end products. Alphaglucosidase inhibitors are reported to be more important in adequate control of type 2, but marketed drugs have various side effects, such as poor patient compliance and also expensive. This proves the needs for other class of drugs with better efficacy, safety, patient compliance and economic. In this review, we have emphasized the recent advances in the field of new alpha-glucosidase inhibitors with improved safety and pharmacological profile.

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

Medicinal Chemistry ◽

10.2174/1573406416666200826101205 ◽

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.

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