Synthesis, Biological Evaluation, and QPLD Studies of Piperazine Derivatives as Potential DPP-IV Inhibitors

Background: Diabetes mellitus is a serious global health issue, currently affecting 425 million people and is set to affect over 690 million people by 2045. It is a chronic disease characterized by hyperglycemia due to relative or absolute insulin hormone deficiency. Dipeptidyl peptidase IV (DPP-IV) inhibitors are hypoglycemic agents augmenting the action of the incretin hormones that stimulate insulin secretion from the pancreatic beta cells. Objective: In this study, synthesis and biological evaluation of seven piperazine derivatives 3a-g was carried out. Methods: The synthesized molecules were characterized using proton-nuclear magnetic resonance, carbon-nuclear magnetic resonance, infrared spectroscopy and mass spectrometry. Results: In vitro biological evaluation study showed comparable DPP-IV inhibitory activity for the targeted compounds ranging from 19%-30% at 100 mu M concentration. Furthermore, the in vivo hypoglycemic activity of 3d was evaluated using streptozotocin-induced diabetic mice. It was found that compound 3d significantly decreased the blood glucose level when the diabetic group treated with 3d was compared to the control diabetic group. Quantum-Polarized Ligand Docking (QPLD) studies demonstrate that 3a-g fit the binding site of DPP-IV enzyme and form H-bonding with the backbones of R125, E205, E206, K554, W629, Y631, Y662, R669, and Y752. Conclusion: Piperazine derivatives were successfully found to be new scaffolds as potential DPP-IV inhibitors.

Automated summary

This study synthesized and evaluated seven piperazine derivatives for their hypoglycemic activity, with one compound showing significant reduction in blood glucose levels. In vitro studies demonstrated high DPP-IV inhibitory activity for these compounds, potentially serving as promising precursors for new DPP-IV inhibitors.