Design, synthesis and biological evaluation of 4,7,12,12a-tetrahydro-5H-thieno[3′,2':3,4]pyrido[1,2-b]isoquinolines as novel adenosine 5′-monophosphate-activated protein kinase (AMPK) indirect activators for the treatment of type 2 diabetes

A series of novel berberine derivatives, as AMPK indirect activators, was designed, synthesized, and biologically evaluated for their anti-diabetic activity. Optimized compound 4bq stimulated glucose consumption (2.2-fold) in L6 myotubes, reduced hepatocytes gluconeogenesis (by 85%) and improved pharmacokinetic profiles (bioavailability 45%) compared to berberine. In a db/db mice model compound 4bq lowered fasting blood glucose at a dose of 120 mg/kg/day, and compound 4bq exhibited no obvious hERG inhibition (IC50 > 10 μM).159