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Novel Coumarin Containing Dithiocarbamate Derivatives As Potent Α-Glucosidase Inhibitors for Management of Type 2 Diabetes Publisher Pubmed



Mollazadeh M1 ; Mohammadikhanaposhtani M2 ; Valizadeh Y3 ; Zonouzi A4 ; Faramarzi MA4 ; Kiani M4 ; Biglar M3 ; Larijani B3 ; Hamedifar H5 ; Mahdavi M3 ; Hajimiri MH6
Authors
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Authors Affiliations
  1. 1. School of Chemistry, College of Science, University of Tehran, Tehran, Iran
  2. 2. Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
  3. 3. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran
  6. 6. Nano Alvand Company, Avicenna Tech Park, Tehran University of Medical Sciences, Tehran, Iran

Source: Medicinal Chemistry Published:2021


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 car-bohydrate 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 inhibi-tory 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 inter-acted 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. © 2021 Bentham Science Publishers.
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