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Targeting α -(1,4)-glucosidase in diabetes mellitus type 2: The role of new synthetic coumarins as potent inhibitors

dc.contributor.authorFigueroa-Benavides C.
dc.contributor.authorMatos M.J.
dc.contributor.authorPeñaloza-Amion M.
dc.contributor.authorVeas R.
dc.contributor.authorValenzuela-Barra G.
dc.contributor.authorZapata G.
dc.contributor.authorDelogu G.
dc.contributor.authorUriarte E.
dc.contributor.authorSantana L.
dc.contributor.authorOlea-Azar C.
dc.contributor.authorDelporte C.
dc.date.accessioned2020-09-02T22:18:16Z
dc.date.available2020-09-02T22:18:16Z
dc.date.issued2018
dc.identifier10.2174/1568026619666181130113033
dc.identifier.citation18, 27, 2327-2337
dc.identifier.issn15680266
dc.identifier.urihttps://hdl.handle.net/20.500.12728/4559
dc.descriptionDiabetes 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 (IC 50 = 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. © 2018 Bentham Science Publishers.
dc.language.isoen
dc.publisherBentham Science Publishers B.V.
dc.subjectCoumarins
dc.subjectDiabetes mellitus
dc.subjectDmt2
dc.subjectDocking studies
dc.subjectMedicinal chemistry
dc.subjectΑ-(1,4)-glucosidase inhibition
dc.subject3 (4 bromothiophen 2 yl) 6 hydroxycoumarin
dc.subject3 (4 bromothiophen 2 yl) coumarin
dc.subject4 chloro n (7 hydroxy 4 methoxycoumarin 8 yl)benzamide
dc.subjectacarbose
dc.subjectalpha (1,4) glucosidase
dc.subjectalpha glucosidase
dc.subjectalpha glucosidase inhibitor
dc.subjectantidiabetic agent
dc.subjectcoumarin derivative
dc.subjecthydrogen
dc.subjectn (4 hydroxycoumarin 3 yl) 4 methoxybenzamide
dc.subjectn (4 hydroxycoumarin 3 yl)acetamide
dc.subjectn (7 hydroxy 4 methylcoumarin 8 yl) 4 nitrobenzamide
dc.subjectn (7 hydroxy 4 methylcoumarin 8 yl) nicotinamide
dc.subjectn (7 hydroxy 4 methylcoumarin 8 yl)benzamide
dc.subjectphenylalanine
dc.subjectSaccharomyces cerevisiae protein
dc.subjectunclassified drug
dc.subjectcoumarin derivative
dc.subjectglucan 1,4 alpha glucosidase
dc.subjectglycosidase inhibitor
dc.subjectArticle
dc.subjectchemical interaction
dc.subjectcontrolled study
dc.subjectdrug potency
dc.subjectdrug structure
dc.subjectdrug synthesis
dc.subjectdrug targeting
dc.subjectenzyme active site
dc.subjectenzyme inhibition
dc.subjecthydrogen bond
dc.subjecthydrophobicity
dc.subjectin vitro study
dc.subjectmolecular docking
dc.subjectnon insulin dependent diabetes mellitus
dc.subjectSaccharomyces cerevisiae
dc.subjectantagonists and inhibitors
dc.subjectchemical structure
dc.subjectchemistry
dc.subjectdose response
dc.subjectenzymology
dc.subjecthuman
dc.subjectmetabolism
dc.subjectnon insulin dependent diabetes mellitus
dc.subjectstructure activity relation
dc.subjectCoumarins
dc.subjectDiabetes Mellitus, Type 2
dc.subjectDose-Response Relationship, Drug
dc.subjectGlucan 1,4-alpha-Glucosidase
dc.subjectGlycoside Hydrolase Inhibitors
dc.subjectHumans
dc.subjectMolecular Structure
dc.subjectStructure-Activity Relationship
dc.titleTargeting α -(1,4)-glucosidase in diabetes mellitus type 2: The role of new synthetic coumarins as potent inhibitors
dc.typeArticle


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