Novel Pyrazoline Derivatives as Therapeutic Candidate for Alzheimer's Disease: An Integrated Network Pharmacology and...

Alzheimer's disease (AD) is a complex neurodegenerative condition marked by amyloid-β accumulation, tau pathology, and neuroinflammation, while current single-target therapies largely provide symptomatic relief without effectively halting disease progression. Therefore, the rational design and synthesis of novel small molecules capable of simultaneously modulating multiple AD-related targets represent a promising therapeutic strategy. Based on this rationale, novel pyrazoline derivatives were synthesized and their therapeutic potential was evaluated using an integrative computational framework. AD-related genes were retrieved from GeneCards, CTD, and DisGeNET databases, and hub genes were identified through topological and centrality analyses, followed by functional enrichment analyses to explore their biological relevance. Molecular docking was used to evaluate the binding affinities of the synthesized compounds toward the identified hub targets, while 3D-QSAR modeling was used to predict their inhibitory potential. A total of 63 common genes were identified across the three databases, with APOE, BACE1, and CSF1R emerging as key hub genes. Enrichment analysis revealed their involvement in PI3K-Akt, mTOR, NF-κB, TNF, AMPK, and FoxO signaling pathways associated with amyloid processing, tau pathology, and neuroinflammation. Among the evaluated compounds, compound 2a exhibited the strongest binding affinities toward the hub targets along with favorable drug-likeness, pharmacokinetics, toxicity, and promising IC₅₀ values (226-336 nM). The 3D-QSAR models showed high predictive reliability (R² = 0.93-0.96; Q² = 0.94-0.95). These findings highlight APOE, BACE1, and CSF1R as key therapeutic targets and identify compound 2a as a promising multi-target lead candidate for additional experimental validation in AD.