Novel PPAR-γ agonists as potential neuroprotective agents against Alzheimer's disease: rational design, synthesis, in silico evaluation, PPAR-γ binding assay and transactivation and expression studies.

Alzheimer's disease (AD) is a neurological disorder. It is caused by accumulation of amyloid beta (Aβ) plaques and tau tangles, which gradually leads to cognitive decline and memory loss. Peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor, plays a significant role in regulating genes responsible for metabolism and inflammation. Studies have shown that PPAR-γ activation has neuroprotective effects, can potentially reduce inflammation and oxidative stress, and stimulates mitochondrial biogenesis. Current study presents the design, synthesis and in vitro evaluation of PPAR-γ agonists for AD that are tailored to optimize binding with the PPAR-γ receptor. The compounds 4a, 4h and 4j exhibited notable binding affinities towards PPAR-γ LBD, with IC(50) values of 8.607, 9.242, and 5.974 μM, respectively, in TR-FRET binding assay. These compounds were cell proliferative and non-cytotoxic in a neuroblastoma cell line (SH-SY5Y). They also demonstrated dose-dependent PPAR-γ activation in transactivation assay. Their neuroprotective effect was studied based on their anti-inflammatory and anti-oxidant potential by reducing the levels of proinflammatory markers (TNF-α, IL-6 and IL-1β) and ROS in Aβ-induced SH-SY5Y neuroblastoma cells using a flow cytometry method. The synthesized compounds also showed interactions in molecular docking study with the PPAR-γ receptor and demonstrated good stability in MD simulation. Our results highlight that through activation of PPAR-γ, the compounds 4a, 4h and 4j offer neuroprotective effects by reducing neuroinflammation and oxidative stress, and hence, they may be considered lead molecules for treating AD.