Evaluation of acridine derivatives as acetylcholinesterase inhibitors: Cytotoxicity, molecular interactions, and neuroprotective potential in AD

Alzheimer's disease (AD) is characterized by progressive neurodegeneration, memory impairment, and neuroinflammation. Acetylcholinesterase (AChE) represents a critical therapeutic target due to its role in acetylcholine regulation and amyloid-beta aggregation. This study evaluated five synthesized acridine derivatives (AAM7, AAM5, AC8, AC6, AM1) as potential AChE inhibitors through molecular docking, dynamics simulations, ADMET profiling, and cytotoxicity assessment using SH-SY5Y neuroblastoma cells. Molecular docking revealed AAM7 exhibited the highest binding affinity (-10.6 kcal/mol) to AChE, followed by AAM5, AC6, and AC8 (each −10.2 kcal/mol), while AM1 showed the lowest affinity (-9.1 kcal/mol). Molecular dynamics simulations confirmed AAM7's stable protein-ligand interactions with consistent hydrogen bonding (>70 % trajectory occupancy) and π-π stacking with key residues Tyr124, Asp74, Ser125, and Trp86. ADMET analysis demonstrated favorable CNS penetration for all compounds, with AAM7 showing optimal drug-like properties (MW: 383.49 g/mol, LogP: 4.65, TPSA: 45.23 Ų) despite moderate solubility concerns. Cytotoxicity studies revealed AC6 as the most potent compound (IC₅₀: 135.56 μg/ml), followed by AM1 (IC₅₀: 202.36 μg/ml), while AAM7 demonstrated minimal cytotoxicity (IC₅₀: 394.02 μg/ml), indicating superior safety profile. Network analysis identified AChE as a central hub protein in neurodegeneration pathways. These findings establish AAM7 as a promising lead compound for AD therapy, combining strong AChE binding affinity with favorable safety characteristics, warranting further optimization for clinical development.