Piperazine Derivatives Attenuate Scopolamine‐Induced Memory Deficits by Modulating Neuroinflammation and Oxidative Stress via the NF‐κB/TNF‐α/COX‐2 Pathway

Abstract Oxidative stress‐induced neuro‐inflammatory events are common in neurodegenerative illnesses, addressing neuro‐inflammation and oxidative distress could be an effective approach for ameliorating the typical effects associated with scopolamine‐induced neurodegeneration. Elevated levels of tumor necrosis factor‐alpha (TNF‐α), nuclear factor‐B (p‐NF‐B), and pyrin domain‐containing protein 3 were associated with changes in antioxidant enzyme levels NLRP3 (NOD‐, LRR–and pyrin domain‐containing protein 3). The present study aimed to synthesize a series of piperazine derivatives and evaluate their neuroprotective effects in mice with scopolamine‐induced learning and memory impairments. The synthesized derivatives 2(a–i) were characterized spectroscopically using proton NMR (¹H‐NMR) and carbon‐13 NMR which were then tested for their antioxidant potential. Based on the strong antioxidant activity of compounds 2b , 2f and 2h were selected for further investigation of their neuroprotective potential. The result of the study indicated the neuroprotective role of 2b , 2f , and 2h which reduced neuro‐inflammation, oxidative stress, and memory impairment. Among these three derivatives 2h significantly reduced the elevated level of cyclooxygenase‐2 (COX‐2, p‐NF‐B, and TNF‐α). Molecular docking analysis supported our hypothesis by showing strong binding affinity of all synthesized compounds with selected targets (COX‐2 and TNF‐α). Overall, our findings suggest that these derivatives could serve as lead compounds for further drug development aimed at controlling neuro‐inflammation and neurodegeneration.