Discovery and In Silico Evaluation of Novel Triazole–Naphthalene Derivatives Targeting Phosphorylated Tau for Alzheimer’s Disease: Molecular Docking and ADMET Profiling.

Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and neuronal death. A defining pathological hallmark of AD is the formation of intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Inhibiting the aggregation of this abnormal form of tau has emerged as a promising strategy for disease-modifying therapy. In this study, we designed a novel molecular scaffold combining 1,2,4-triazole and naphthalene moieties (TND), and developed ten structurally diverse derivatives (TND-1 to TND-10) by functionalizing various positions with electron-withdrawing and electron-donating substituents. These compounds were evaluated for their binding affinity against phosphorylated tau protein (PDB ID: 6HRF) using AutoDock Vina and further assessed for pharmacokinetic profiles using SwissADME. Docking scores ranged from −7.8 to −9.1 kcal/mol, indicating good binding potential. The top three compounds, TND-4, TND-6, and TND-9, demonstrated strong hydrogen bonding and π–π interactions with key active-site residues of the tau protein. ADMET predictions showed that most derivatives had favorable CNS penetration, high gastrointestinal absorption, and satisfied Lipinski’s rule of five, suggesting drug-likeness. These findings highlight the therapeutic promise of triazole–naphthalene derivatives in targeting tau pathology in AD. This study lays the groundwork for further lead optimization and experimental validation of these virtual candidates in future anti-Alzheimer’s drug discovery efforts.