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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Novel Coumarin Containing Dithiocarbamate Derivatives as Potent α-Glucosidase Inhibitors for Management of Type 2 Diabetes

Author(s): Marjan Mollazadeh, Maryam Mohammadi-Khanaposhtani, Yousef Valizadeh, Afsaneh Zonouzi, Mohammad A. Faramarzi, Mitra Kiani, Mahmood Biglar, Bagher Larijani, Haleh Hamedifar , Mohammad Mahdavi * and Mir Hamed Hajimiri*

Volume 17, Issue 3, 2021

Published on: 26 August, 2020

Page: [264 - 272] Pages: 9

DOI: 10.2174/1573406416666200826101205

Price: $65

Abstract

Background: α-Glucosidase is a hydrolyzing enzyme that plays a crucial role in the degradation of carbohydrates and starch to glucose. Hence, α-glucosidase is an important target in 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 from the reaction between 4-(bromomethyl)-7- methoxy-2H-chromen-2-one 1, carbon disulfide 2, and primary or secondary amines 3a-n in the presence of potassium hydroxide and ethanol at room temperature. In vitro α-glucosidase inhibition and kinetic study of these compounds were performed. Furthermore, a 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 a standard inhibitor (IC50 = 750.0 ± 9.0 μM). Among them, the secondary amine derivative 4d with pendant indole group was the most potent inhibitor. Enzyme kinetic study of the compound 4d revealed that this compound competes with a substrate to connect to the active site of α-glucosidase and therefore is a competitive inhibitor. Moreover, a molecular docking study predicted that this compound interacted with the α-glucosidase active site pocket.

Conclusion: Our results suggest that the coumarin-dithiocarbamate scaffold can be a promising lead structure for designing potent α-glucosidase inhibitors for the treatment of type 2 diabetes.

Keywords: Anti-diabetic activity, α-glucosidase, molecular docking, coumarin, dithiocarbamate, in vitro evaluation.

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