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Biological Evaluation of 9-(1H-Indol-3-Yl) Xanthen-4-(9H)-Ones Derivatives As Noncompetitive Α-Glucosidase Inhibitors: Kinetics and Molecular Mechanisms Publisher



Nourisefat M1 ; Salehi N1 ; Yousefinejad S2 ; Panahi F3 ; Bagherzadeh K4 ; Amanlou M5 ; Khalafinezhad A6 ; Karimijafari MH1 ; Sheibani N7 ; Moosavimovahedi AA1, 8
Authors
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Authors Affiliations
  1. 1. Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
  2. 2. Research Center for Health Sciences, Institute of Health, Department of Occupational Health Engineering, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran
  3. 3. Department of Polymer Engineering and Color Technology, Amirkabir University of Technology, Tehran, Iran
  4. 4. Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
  5. 5. Department of Medicinal Chemistry, Faculty of Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71454, Iran
  7. 7. Departments of Ophthalmology and Visual Sciences, Cell and Regenerative Biology, and Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
  8. 8. UNESCO Chair on Interdisciplinary Research in Diabetes, University of Tehran, Tehran, Iran

Source: Structural Chemistry Published:2019


Abstract

The α-Glucosidase plays a key role in attenuation of postprandial hyperglycemia in diabetic patients. In this study, a class of 9-(1H-Indol-3-yl) xanthen-4-(9H)-ones derivatives (M1-M20) were evaluated for their α-Glucosidase inhibitory activity. The inhibitory activities of these compounds were evaluated via inhibition kinetics, molecular dynamic (MD) simulations, ensemble docking, and linear quantitative structure–activity relationship (QSAR) models. The results from the serial kinetic studies demonstrated that most of the ligands could directly inactivate enzyme activity in a dose-dependent manner. A typical non-competitive type of inhibition was observed, with compound M15 showing the highest inhibitory activity among the ligands tested. Also, MD simulations and ensemble docking studies on α-glucosidase homology model confirmed the non-competitive inhibition mechanism. The best binding mode for these inhibitors and efficacy of hydrogen bonds and hydrophobic interactions on inhibitory activities of synthetic ligands were also disclosed. The QSAR studies showed that the electronegative and oxygen-containing functional groups of indolyl-xanthone structures play a significant role in low-to-moderate inhibitory properties of these potentially anti-diabetic drugs against α-Glucosidase enzyme. Thus, our studies provide important molecular mechanisms delineating α-Glucosidase inhibition, which could aid in development of new drugs for type 2 diabetes mellitus treatment. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.
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