Synthesis and mechanism of hypoglycemic activity of benzothiazole derivatives
| Autor: | Neta Uritsky, Olga Viskind, Hanoch Senderowitz, Shlomo Sasson, Ella Meltzer-Mats, Lily Pasternak, Gali Babai-Shani, Arie Gruzman, Jürgen Eckel, Erol Cerasi, Tamar Getter |
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| Rok vydání: | 2013 |
| Předmět: |
Blood Glucose
Male Glucose uptake Muscle Fibers Skeletal AMP-Activated Protein Kinases Cell Line chemistry.chemical_compound Mice Adenosine Triphosphate Drug Discovery medicine Animals Hypoglycemic Agents Benzothiazoles Thiazole Protein kinase A chemistry.chemical_classification Glucose Transporter Type 4 biology Molecular Structure Chemistry Cell Membrane AMPK Adenosine Rats Enzyme Activation Enzyme Glucose Biochemistry Benzothiazole Models Chemical Hyperglycemia biology.protein Molecular Medicine GLUT4 medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 56(13) |
| ISSN: | 1520-4804 |
| Popis: | Adenosine 5'-monophosphate activated protein kinase (AMPK) has emerged as a major potential target for novel antidiabetic drugs. We studied the structure of 2-chloro-5-((Z)-((E)-5-((5-(4,5-dimethyl-2-nitrophenyl)furan-2-yl)methylene)-4-oxothiazolidin-2-ylidene)amino)benzoic acid (PT-1), which attenuates the autoinhibition of the enzyme AMPK, for the design and synthesis of different benzothiazoles with potential antidiabetic activity. We synthesized several structurally related benzothiazole derivatives that increased the rate of glucose uptake in L6 myotubes in an AMPK-dependent manner. One compound, 2-(benzo[d]thiazol-2-ylmethylthio)-6-ethoxybenzo[d]thiazole (34), augmented the rate of glucose uptake up to 2.5-fold compared with vehicle-treated cells and up to 1.1-fold compared to PT-1. Concomitantly, it elevated the abundance of GLUT4 in the plasma membrane of the myotubes and activated AMPK. Subcutaneous administration of 34 to hyperglycemic Kuo Kondo rats carrying the Ay-yellow obese gene (KKAy) mice lowered blood glucose levels toward the normoglycemic range. In accord with its activity, compound 34 showed a high fit value to a pharmacophore model derived from the PT-1. |
| Databáze: | OpenAIRE |
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