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

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

Volume: 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*

Affiliation:

• Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela,Spain

• Departamento de Quimica Farmacologica y Toxicologica, Laboratorio de Productos Naturales, Facultad de Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago,Chile

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

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.

Cite this article as:

Figueroa-Benavides Catalina , Matos João Maria*, Peñaloza-Amion Montserrat , Veas Rubén , Valenzuela-Barra Gabriela , Zapata Gerald , Delogu Giovanna , Uriarte Eugenio , Santana Lourdes , Olea-Azar Claudio and Delporte Carla *, Targeting α -(1,4)-Glucosidase in Diabetes Mellitus Type 2: The Role of New Synthetic Coumarins as Potent Inhibitors, Current Topics in Medicinal Chemistry 2018; 18 (27) . https://dx.doi.org/10.2174/1568026619666181130113033