A new entry into the portfolio of α-glucosidase inhibitors as potent therapeutics for type 2 diabetes: Design, bioevaluation and one-pot multi-component synthesis of diamine-bridged coumarinyl oxadiazole conjugates
| Autor: | Madiha Kazmi, Imtiaz Khan, Aliya Ibrar, Sumera Zaib, Jamshed Iqbal, Sayyeda Tayyeba Amjad, Saifullah Mehsud, Zainab Shafique, Aamer Saeed |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Oxadiazole Context (language use) Saccharomyces cerevisiae Diamines 01 natural sciences Biochemistry Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Coumarins Drug Discovery medicine Glucose homeostasis Glycoside Hydrolase Inhibitors Molecular Biology IC50 Acarbose chemistry.chemical_classification Oxadiazoles Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Organic Chemistry Active site alpha-Glucosidases Combinatorial chemistry 0104 chemical sciences Molecular Docking Simulation Kinetics 030104 developmental biology Enzyme Diabetes Mellitus Type 2 chemistry Drug Design biology.protein Glucosidases medicine.drug |
| Zdroj: | Bioorganic Chemistry. 77:190-202 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2017.12.022 |
| Popis: | Diabetes mellitus (DM), a chronic multifarious metabolic disorder resulting from impaired glucose homeostasis has become one of the most challenging diseases with severe life threat to public health. The inhibition of α-glucosidase, a key carbohydrate hydrolyzing enzyme, could serve as one of the effective methodology in both preventing and treating diabetes through controlling the postprandial glucose levels and suppressing postprandial hyperglycemia. In this context, three series of diamine-bridged bis-coumarinyl oxadiazole conjugates were designed and synthesized by one-pot multi-component methodology. The synthesized conjugates (4a–j, 5a–j, 6a–j) were evaluated as potential inhibitors of glucosidases. Compound 6f containing 4,4′-oxydianiline linker was identified as the lead and selective inhibitor of α-glucosidase enzyme with an IC50 value of 0.07 ± 0.001 μM (acarbose: IC50 = 38.2 ± 0.12 μM). This inhibition efficacy was ∼545-fold higher compared to the standard drug. Compound 6f was also emerged as the lead molecule against intestinal maltase-glucoamylase with good inhibition strength (IC50 = 0.04 ± 0.02 μM) compared to acarbose (IC50 = 0.06 ± 0.01 μM). Against β-glucosidase enzyme, compound 6 g was noted as the lead inhibitor with IC50 value of 0.08 ± 0.002 μM. Michaelis–Menten kinetic experiments were performed to explore the mechanism of inhibition. Molecular docking studies of the synthesized library of hybrid structures against glucosidase enzyme were performed to describe ligand-protein interactions at molecular level that provided an insight into the biological properties of the analyzed compounds. The results suggested that the inhibitors could be stabilized in the active site through the formation of multiple interactions with catalytic residues in a cooperative fashion. In addition, strong binding interactions of the compounds with the amino acid residues were effective for the successful identification of α-glucosidase inhibitors. |
| Databáze: | OpenAIRE |
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