Synthesis, characterization, and α-glucosidase inhibitory activity of methyl proline derivatives of phenylpropanoid

Abstract

To discover novel α-glucosidase inhibitors for diabetes management, a series of six proline methyl ester phenylpropanoid derivatives were synthesized through a seven-step synthetic route involving bromination and nucleophilic substitution. The structures of the target compounds (2f–7f) were confirmed by ¹H NMR, ¹³C NMR, and HRMS. Using the PNPG method, we evaluated their inhibitory activity against α-glucosidase and found that some compounds acted as effective inhibitors. Among them, compound 6f demonstrated the strongest activity, with an IC₅₀ value of 91 µM. Molecular docking elucidated that 6f exploits its specific substitution pattern to form a robust complex, stabilized by a near-parallel π–π stacking with Trp59 and a dense hydrogen-bonding network. The proline ring further enhances stability through deep complementary burial within a hydrophobic cleft, resulting in a highly stable binding pose. Further insights were provided by DFT calculations and wavefunction analyses (including IRI, RDG, and ESP), which revealed that favorable electrostatic complementarity and intramolecular non-covalent interactions contribute to its binding affinity. Preliminary ADME predictions indicated promising drug-like properties for this series. In conclusion, compound 6f shows strong potential as an α-glucosidase inhibitor and merits further investigation for the treatment of diabetes.