Herein, we rationally designed and developed two novel
glitazones (G1 and G2) to target
peroxisome proliferator-activated 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.