Synthesis, Biological Evaluation, and In Silico Studies of Naphtalene‐Hydrazide Derivatives as Dual‐Action Agents for Alzheimer's Disease: Targeting BChE and Oxidative Stress

ABSTRACT

In this study, the ChE inhibitory effects and antioxidant capacities of newly synthesized naphthohydrazide derivatives ( 4a–9a ) are reported, along with molecular docking and molecular dynamics (MD) simulation results. In enzyme inhibition studies, the synthesized compounds displayed distinct selectivity toward BChE; derivatives 6a, 7a, and 8a (IC ₅₀ : 21.50–22.63 µM) showed strong BChE inhibition, which was closely comparable to that of the reference drug galantamine. In antioxidant assays, compound 7a exhibited exceptional potency in the ABTS radical scavenging assay (IC ₅₀ = 0.04 µM), significantly outperforming the standard reference. SAR analysis indicated that 7a offered an excellent steric fit for the expanded BChE active site, while the bromine atom in 8a established van der Waals interactions within the hydrophobic region, yielding a 5‐fold selectivity for BChE over AChE. Molecular docking further revealed that 7a achieved the lowest binding energies against both AChE (−11.3 kcal/mol) and BChE (−9.4 kcal/mol), forming key interactions with peripheral site residues (Ser125 and Tyr337 of AChE; Ile69 and Thr120 of BChE) and the catalytic triad residue His438 of BChE. Notably, compounds 7a and 8a exhibited five‐fold higher selectivity for BChE than AChE, suggesting their potential relevance for further exploration in the context of Alzheimer's disease therapeutics.