Design, synthesis and evaluation of tetrahydrocarbazole derivatives as potential hypoglycemic agents

[Display omitted] •Two series of tetrahydrocarbazole derivatives were designed and synthesized.•12b showed 1.2-fold higher hypoglycemic activity than the positive compounds.•The synthesized derivatives exhibit activity via the activation of the AMPK.•The in vivo hypoglycemic effect of 12b was assessed via an OGTT assay.•The pharmacokinetic profiles of 12b have also been investigated is SD rats. Two series of tetrahydrocarbazole derivatives have been designed and synthesized based on ZG02, a promising candidate developed in our previous studies. The newly prepared compounds were screened for glucose consumption activity in HepG2 cell lines. Aza-tetrahydrocarbazole compound 12b showed the most potent hypoglycemic activity with a 45% increase in glucose consumption when compared to the solvent control, which had approximately 1.2-fold higher activity than the positive control compounds (metformin and ZG02). An investigation of the potential mechanism indicated that 12b may exhibit hypoglycemic activity via activation of the AMPK pathway. Metabolic stability assays revealed that 12b showed good stability profiles in both artificial gastrointestinal fluids and blood plasma from SD rats. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 12b was a potent hypoglycemic agent.