1 research outputs found
Synthesis and Mechanism of Hypoglycemic Activity of Benzothiazole Derivatives
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-((<i>Z</i>)-((<i>E</i>)-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[<i>d</i>]thiazol-2-ylmethylthio)-6-ethoxybenzo[<i>d</i>]thiazole (<b>34</b>), 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 <b>34</b> 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 <b>34</b> showed a high fit value to a pharmacophore
model derived from the PT-1