title: Synthesis and mechanism of hypoglycemic activity of benzothiazole derivatives.
abstract: 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.
authors.affiliation: Division of Medicinal Chemistry, Department of Chemistry, Faculty of Exact Sciences, Bar Ilan University , Ramat Gan, 5290002, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Meltzer-Mats
authors.forename: Gali
authors.initials: G
authors.lastname: Babai-Shani
authors.forename: Lily
authors.initials: L
authors.lastname: Pasternak
authors.forename: Neta
authors.initials: N
authors.lastname: Uritsky
authors.forename: Tamar
authors.initials: T
authors.lastname: Getter
authors.forename: Olga
authors.initials: O
authors.lastname: Viskind
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eckel
authors.forename: Erol
authors.initials: E
authors.lastname: Cerasi
authors.forename: Hanoch
authors.initials: H
authors.lastname: Senderowitz
authors.forename: Shlomo
authors.initials: S
authors.lastname: Sasson
authors.forename: Arie
authors.initials: A
authors.lastname: Gruzman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D051381:Rats
chemical_list: D052160:Benzothiazoles; D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; C005465:benzothiazole; D005947:Glucose