Dual‐Target Molecular Docking and ADMET Analysis of Chalcone Derivatives against Neurorelevant Macromolecules in Alzheimer's Disease and Anxiety Disorders

ABSTRACT

A series of n‐alkoxy chalcone derivatives ( N1–N3 ) was designed, synthesized, and structurally characterized using ¹ H‐NMR, ^{1 3} C‐NMR, and ESI–MS. Their neuroactive potential was investigated through a dual‐target molecular docking approach against two key central nervous system macromolecules: the human histamine H1 receptor (PDB: 3ZRE) and acetylcholinesterase (PDB: 4YE7), using doxepin and donepezil as reference ligands. Docking results demonstrated that all compounds were successfully accommodated within the active sites of both targets, with binding affinities influenced by alkoxy chain length and substituent effects. Among the studied derivatives, N1 exhibited the most favorable interaction with H1R (−5.5 kcal/mol), surpassing doxepin, while N2 showed the highest affinity toward AChE (−6.2 kcal/mol). Notably, N1 and N3 formed stable ligand–enzyme complexes through multiple short hydrogen bonds, suggesting enhanced binding stabilization despite the absence of π–π stacking interactions. In addition, in silico ADMET analysis revealed excellent intestinal absorption across all compounds, along with increased lipophilicity, variable blood–brain barrier permeability, and elevated toxicity risks relative to the reference drugs. The combined evaluation of dual‐target binding and pharmacokinetic profiling highlights the potential of n‐alkoxy chalcone derivatives as multifunctional neuroactive candidates. It provides a rational basis for further experimental validation.