Title:Novel Coumarin Containing Dithiocarbamate Derivatives as Potent α-Glucosidase Inhibitors for Management of Type 2 Diabetes
Volume: 17
Issue: 3
Author(s): Marjan Mollazadeh, Maryam Mohammadi-Khanaposhtani, Yousef Valizadeh, Afsaneh Zonouzi, Mohammad A. Faramarzi, Mitra Kiani, Mahmood Biglar, Bagher Larijani, Haleh Hamedifar , Mohammad Mahdavi *Mir Hamed Hajimiri*
Affiliation:
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran,Iran
- Nano Alvand Company, Avicenna Tech Park, Tehran University of Medical Sciences, Tehran,Iran
Keywords:
Anti-diabetic activity, α-glucosidase, molecular docking, coumarin, dithiocarbamate, in vitro evaluation.
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.