Design, synthesis, and structure-activity relationships of novel 4,7,12,12a-tetrahydro-5 H -thieno[3′,2′:3,4]pyrido[1,2- b ]isoquinoline and 5,8,12,12a-tetrahydro-6 H -thieno[2′,3′:4,5]pyrido[2,1- a ]isoquinoline derivatives as cellular activators of adenosine 5′-monophosphate-activated protein kinase (AMPK)

Abstract To discover more derivatives with better glucose-lowering efficacy compared with berberine, twenty-three novel compounds with 4,7,12,12a-tetrahydro-5 H -thieno[3′,2′:3,4]pyrido[1,2- b ]isoquinoline or 5,8,12,12a-tetrahydro-6 H -thieno[2′,3′:4,5]pyrido[2,1- a ]isoquinoline cores were designed, synthesized, and biologically evaluated in vitro in continuation of our previous work on indirect activators of adenosine 5′-monophosphate-activated protein kinase (AMPK). Nine compounds effectively stimulated glucose consumption (>2.3-fold at 10 μM) in L6 myotube cells, and two compounds ( 4d and 4s ) exhibited superior inhibitory activity (