Semisynthetic p‐Coumaric Acid Derivatives as Lead Dual Inhibitors Against DPP‐IV and GSK‐3β for Antidiabetic Therapy

ABSTRACT Type 2 diabetes mellitus is a dramatically increasing global public health challenge. The prevalence is projected almost double, from 194 million in 2003 to 333 million in 2025 with type 2 diabetes mellitus representing approximately 90%–95% of cases. Dual inhibitors for antidiabetic targets is still novel and promising strategy for discovery of more effective therapies. Ester and triazole derivatives of p ‐coumaric acid were obtained from Williamson synthesis and Microwave‐assisted click reaction, respectively. Chemical structures were finely characterized through IR, 1H, and 13C NMR and HRMS. They were tested for their dual inhibitory activity against GSK‐3β kinase and DPP‐IV. The complexes resulting from docking were used for all‐atom molecular dynamics simulations, including the enzymes in the apo form, using the GROMACS 2022.3. Two inhibitors 2 and 5 demonstrated promising inhibition at low and submicromolar against both proteins. Molecular Dynamic simulations revealed that the binding pattern of the control inhibitors were reproduced by p‐coumaric acid derivatives 2 and 5 with crucial interactions involving the same residues. The p‐coumaric skeleton can be considered as a promising core for GSK‐3β kinase and DPP‐IV dual inhibitors.