Synthesis of diarylpentane derivatives as novel α-glucosidase inhibitors: Their inhibitory mechanism and hypoglycemic effects

Abstract

Diabetes mellitus (DM) characterized by hyperglycemia is due to insulin deficiency, insulin dysfunction, or both. α-Glucosidase is a well-established therapeutic target for DM, and its inhibitors can effectively mitigate postprandial hyperglycemia, particularly in T2DM. In this study, a series of diarylpentane derivatives were designed and synthesized as potential α-glucosidase inhibitors. In vitro enzymatic assays showed that the para-substituted derivatives exhibited superior inhibitory activity against α-glucosidase, with inhibition rates ranging from 23.3 % to 75.7 % at 100 μM. Notably, compound 5c demonstrated the most potent inhibition with an IC₅₀ value of 18.1 μM, approximately 17-fold more potent than acarbose (IC₅₀ = 312.0 μM). The inhibitory activity of 5c is highly affected by macromolecular crowding effects, especially polyethylene glycol (PEG) inducing a molecular weight-dependent efficacy reduction. Mechanism study through enzyme kinetics, molecular docking and spectroscopic analyses indicated that 5c binds with α-glucosidase via hydrogen bonds, electrostatic interactions and hydrophobic effects, which induces significant conformational alterations in the secondary structure of α-glucosidase. These changes includes transition between α-helix and β-sheet, and decrease of the surface hydrophobicity to enhance structural rigidity and stabilize secondary structure of the enzyme, ultimately leading to reversible inhibition of α-glucosidase. In vivo pharmacological evaluation demonstrated that 5c dose-dependently attenuated postprandial hyperglycemia in starch/sucrose-challenged mice, achieving 29.4 % and 21.7 % reductions in glycemic AUC at a dose of 40 mg/kg. Computational ADME profiling confirmed that 5c complied with Lipinski's rules, suggesting favorable oral bioavailability. These results collectively identify 5c as a promising oral inhibitor of α-glucosidase for the treatment of T2DM.