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Targeting α -(1,4)-Glucosidase in Diabetes Mellitus Type 2: The Role of New Synthetic Coumarins as Potent Inhibitors

[ Vol. 18 , Issue. 27 ]

Author(s):

Catalina Figueroa-Benavides, Maria João Matos*, Montserrat Peñaloza-Amion, Rubén Veas, Gabriela Valenzuela-Barra, Gerald Zapata, Giovanna Delogu, Eugenio Uriarte, Lourdes Santana, Claudio Olea-Azar and Carla Delporte*   Pages 2327 - 2337 ( 11 )

Abstract:


Diabetes mellitus type 2 (DMT2) is a metabolic disease characterized by a chronic increase in glycemia that promotes several long-term complications and high mortality. Some enzymes involved in glycaemic control, such as α -(1,4)-glucosidase, have now been established as novel pharmacological targets. Coumarins have shown benefits in attenuating signs and complications of DMT2, including inhibition of this enzyme. In this work, new synthetic coumarins (bearing different amide and aryl substituents) were studied in vitro as inhibitors of α-(1,4)-glucosidase. Among them, five molecules proved to be excellent α-(1,4)-glucosidase inhibitors, being compound 7 (IC50 = 2.19 µM) about 200 times more potent than acarbose, a drug currently used for the treatment of DMT2. In addition, most of the coumarins presented uncompetitive inhibition for the α-(1,4)-glucosidase. Molecular docking studies revealed that coumarins bind to the active site of the enzyme in a more external area comparing to the substrate, without interfering with it, and displaying aromatic and hydrophobic interactions, as well as some hydrogen bonds. According to the results, aromatic interactions with two phenylalanine residues, 157 and 177, were the most common among the studied coumarins. This study is a step forward for the understanding of coumarins as potential anti-diabetic compounds displaying α-(1,4)-glucosidase inhibition.

Keywords:

Coumarins, Diabetes mellitus, α-(1, 4)-glucosidase inhibition, Docking studies, Medicinal chemistry, DMT2.

Affiliation:

Departamento de Quimica Farmacologica y Toxicologica, Laboratorio de Productos Naturales, Facultad de Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Inorganic and Analytical Chemistry Department, Laboratory, Department, Molecular Graphic Unit, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Sergio Livingstone 1007, Independencia, Santiago, Departamento de Quimica Farmacologica y Toxicologica, Laboratorio de Productos Naturales, Facultad de Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago, Departamento de Quimica Farmacologica y Toxicologica, Laboratorio de Productos Naturales, Facultad de Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago, Inorganic and Analytical Chemistry Department, Laboratory, Department, Molecular Graphic Unit, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Sergio Livingstone 1007, Independencia, Santiago, Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Free Radical and Antioxidants Laboratory, Inorganic and Analytical Department, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Sergio Livingstone 1007, Independencia, Santiago, Departamento de Quimica Farmacologica y Toxicologica, Laboratorio de Productos Naturales, Facultad de Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago

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