Cyclic amines-modified metformin derivatives with enhanced glucose uptake activity

Metformin is the first-line therapy for type 2 diabetes mellitus, but its limited oral bioavailability and side effects necessitate structural modifications to improve its pharmacological profile. In this study, we report the synthesis and biological evaluation of thirteen cyclic amine-modified metformin derivatives, structurally inspired by moroxydine. The compounds were synthesised in moderate to good yields and structurally characterised using 1 H NMR, 13 C NMR, FTIR, and LCMS. In-vitro cytotoxicity screening using HepG2 cells confirmed that all compounds were non-toxic within the tested concentration range (3.125–100 μg/mL). Glucose uptake assay using HepG2 cells revealed that two derivatives, 6 and 8 , exhibited significantly enhanced activity compared to metformin HCl at 25–100 μg/mL ( p < 0.05). Molecular docking studies further supported these findings, showing that compound 8 formed stable interactions with key residues in the GLUT1 transporter (binding energy: −7.9 kcal/mol), surpassing the docking score of metformin (−4.7 kcal/mol). Pharmacokinetic profiling indicated that these compounds meet Veber's criteria for oral bioavailability. These results highlight that compounds 6 and 8 are promising hits for further optimisation as antihyperglycemic agents. • Thirteen cyclic amine-modified metformin derivatives were synthesised and evaluated • Compounds 6 and 8 exhibited significantly enhanced glucose uptake activity relative to metformin • Compound 8 binds strongly to GLUT1 (binding energy: −7.9 kcal/mol) • Both compounds meet Veber's criteria for oral bioavailability