Novel derivatives of eugenol as potent anti-inflammatory agents via PPAR gamma agonism: rational design, synthesis, analysis, PPAR gamma protein binding assay and computational studies

Eugenol is a natural product abundantly found in clove buds known for its pharmacological activities such as anti-inflammatory, antidiabetic, antioxidant, and anticancer activities. It is well known from the literature that peroxisome proliferator-activated receptors (PPAR gamma) have been reported to regulate inflammatory responses. In this backdrop, we rationally designed semi-synthetic derivatives of eugenol with the aid of computational studies, and synthesized, purified, and analyzed four eugenol derivatives as PPAR gamma agonists. Compounds were screened for PPAR gamma protein binding by time-resolved fluorescence (TR-FRET) assay. The biochemical assay results were favorable for 1C which exhibited significant binding affinity with an IC50 value of 10.65 mu M as compared to the standard pioglitazone with an IC50 value of 1.052 mu M. In addition to the protein binding studies, as a functional assay, the synthesized eugenol derivatives were screened for in vitro anti-inflammatory activity at concentrations ranging from 6.25 mu M to 400 mu M. Among the four compounds tested 1C shows reasonably good anti-inflammatory activity with an IC50 value of 133.8 mu M compared to a standard diclofenac sodium IC50 value of 54.32 mu M. Structure-activity relationships are derived based on computational studies. Additionally, molecular dynamics simulations were performed to examine the stability of the protein-ligand complex, the dynamic behavior, and the binding affinity of newly synthesized molecules. Altogether, we identified novel eugenol derivatives as potential anti-inflammatory agents via PPAR gamma agonism.