Emodin derivatives as novel potent DPP-4 inhibitors: Design, synthesis, and in vitro evaluation

Dipeptidyl peptidase-4 (DPP-4) inhibitors have gained recognition as effective agents for lowering blood sugar levels, significantly improving glycemic control for individuals with type 2 diabetes mellitus (T2DM). Emodin, an anthraquinone derived from the traditional herbs rhubarb (Rheum officinale) and Polygonum cuspidatum, has been identified as an important component in the development of new treatments for diabetes. In the present work, we explored the DPP-4 inhibitory activity of emodin derivatives. This study focused on the design, synthesis, and evaluation of emodin derivatives for their in vitro DPP-4 inhibitory activity. Molecular docking studies indicated that 3-o-toluoyl emodin (OTEM) had the lowest docking score (−134.073) against the DPP-4 protein among the tested compounds. OTEM also achieved the highest drug-likeness score of 0.56 and demonstrated DPP-4 inhibitory activity, with an IC50 value of 0.77 μM. Furthermore, structure-activity relationship (SAR) analysis suggested that the addition of an ortho-toluoyl group at the C-3 position could enhance DPP-4 inhibition. Additionally, quantitative structure-activity relationship (QSAR) model assessments revealed that log P was the only descriptor significantly influencing DPP-4 inhibitory activity. Therefore, the current study indicates that OTEM could serve as a promising lead compound to address the demand for antidiabetic agents.