Design, synthesis, and inhibition of oxidative, amyloidogenic, and cholinergic dysfunction of Saxagliptin-derived Schiff bases against STZ-induced sporadic AD-like pathology.

Alzheimer's disease (AD) shares significant pathological convergence with diabetes, primarily through insulin resistance. This leads to oxidative stress, neuronal inflammation, plaque formation, cholinergic dysfunction, and impaired neuronal survival. Herein, we report 10 Saxagliptin (SXG, a potent DPP-IV inhibitor)-derived Schiff base derivatives that were virtually designed and screened. Five leads were prioritized using ADMET profiling and molecular docking, then synthesized via Schiff base condensation with selected aryl aldehydes to target AD progression associated with diabetes. Structural integrity, redox activity, and stability were confirmed by comprehensive characterization, including chromatographic and spectroscopic analyses, DFT calculations, and in vitro antioxidant assays. Neuroprotective potential was thus assessed in vivo by inducing AD-like pathology in rats with a single i.p. dose of STZ at 45 mg/kg, thereby reproducing brain insulin resistance, oxidative-nitrosative stress, and cholinergic dysfunction. Significant neurodegeneration in STZ-treated rats was evidenced by behavioral analyses, biochemical markers (AChE, Aβ42), oxidative stress indices (SOD, CAT, GSH, GPx, MDA, NO, MPO), and hippocampal histology. Treatment with SXG and derivatives at 0.5 mg/kg, orally, resulted in significant restoration of antioxidant defenses, inhibition of lipid peroxidation and NO overproduction, reduction of inflammatory oxidative bursts, and improved cognition in treated groups. Remarkably, derivatives 3c and 3e showed superior free-radical scavenging and greater regulation of redox biomarkers, which were associated with healthy, defined hippocampal cytoarchitecture and reduced neuronal pyknosis and necrosis compared with SXG. Additionally, 3e showed strong therapeutic efficacy by targeting oxidative stress, cholinergic, and amyloidogenic pathways synchronously.