Catalina Figueroa-Benavides
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Maria João Matos
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Montserrat Peñaloza-Amion
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Rubén Veas
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Gabriela Valenzuela-Barra
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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.