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Herein, we rationally designed and developed two novel glitazones (G1 and G2) to target peroxisome proliferatoractivated receptor-gamma coactivator 1-alpha (PGC-1α) signaling through peroxisome proliferator-activated receptors (PPAR)-γ agonism as a therapeutic for Parkinson's disease (PD). The synthesized molecules were analyzed by mass spectrometry and NMR spectroscopy. The neuroprotective functionality of the synthesized molecules was assessed by a cell viability assay in lipopolysaccharide-intoxicated SHSY5Y neuroblastoma cell lines. The ability of these new glitazones to scavenge free radicals was further ascertained via a lipid peroxide assay, and pharmacokinetic properties were verified using in silico absorption, distribution, metabolism, excretion, and toxicity analyses. The molecular docking reports recognized the mode of interaction of the glitazones with PPAR-γ. The G1 and G2 exhibited a noticeable neuroprotective effect in lipopolysaccharide-intoxicated SHSY5Y neuroblastoma cells with the half-maximal inhibitory concentration value of 2.247 and 4.509 μM, respectively. Both test compounds prevented 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced motor impairment in mice, as demonstrated by the beam walk test. Further, treating the diseased mice with G1 and G2 resulted in significant restoration of antioxidant enzymes glutathione and superoxide and reduced the intensity of lipid peroxidation inside the brain tissues. Histopathological analysis of the glitazones-treated mice brain revealed a reduced apoptotic region and a rise in the number of viable pyramidal neurons and oligodendrocytes. The study concluded that G1 and G2 showed promising results in treating PD by activating PGC-1α signaling in brain via PPAR-γ agonism. However, more extensive research is necessary for a better understanding of functional targets and signaling pathways.

The main objective of this research was to develop novel compounds from readily accessed natural products especially eugenol with potential biological activity. Eugenol, the principal chemical constituent of clove (Eugenia caryophyllata) from the family Myrtaceae is renowned for its pharmacological properties, which include analgesic, antidiabetic, antioxidant, anticancer, and anti-inflammatory effects. According to reports, PPARγ regulates inflammatory reactions. The synthesized compounds were structurally analyzed using FT-IR, 1HNMR, 13CNMR, and mass spectroscopy techniques. Molecular docking was performed to analyze binding free energy and important amino acids involved in the interaction between synthesized derivatives and the target protein. The development of the structure–activity relationship is based on computational studies. Additionally, the stability of the best-docked protein–ligand complexes was assessed using molecular dynamic modeling. The in-vitro PPARγ competitive binding Lanthascreen TR-FRET assay was used to confirm the affinity of compounds to the target protein. All the synthesized derivatives were evaluated for an in vitro anti-inflammatory activity using an albumin denaturation assay and HRBC membrane stabilization at varying concentrations from 6.25 to 400 µM. In this background, with the aid of computational research, we were able to design six novel derivatives of eugenol synthesized, analyzed, and utilized TR-FRET competitive binding assay to screen them for their ability to bind PPARγ. Anti-inflammatory activity evaluation through in vitro albumin denaturation and HRBC method revealed that 1f exhibits maximum inhibition of heat-induced albumin denaturation at 50% and 85% protection against HRBC lysis at 200 and 400 µM, respectively. Overall, we found novel derivatives of eugenol that could potentially reduce inflammation by PPARγ agonism.