Raza_2026_Chem.Biodivers_23_e03327

Alzheimer's disease is a neurodegenerative disease with limited therapeutic options and is most prevalent in the elderly. According to the cholinergic hypothesis, disease progression can be mitigated by inhibiting acetylcholinesterase (AChE). Herein, a series of substituted indole amines 19-42 was designed, synthesized via a Chiron-guided approach to generate structurally diverse 2,3-diphenyl-substituted indole derivatives, and characterized by UV-vis, FT-IR, NMR, and MS. In silico studies, such as molecular docking, molecular dynamics simulations, and ADMET analyses, were performed to evaluate binding interactions, stability, and drug-likeness, followed by in vitro cholinesterase inhibition assays. The compounds exhibited moderate inhibitory activity, with IC(50) values ranging from 4.28 to 12.70 microM. Among them, compound 25 showed the highest activity (IC(50) = 4.28 microM), comparable to galantamine (IC(50) = 4.71 microM). Docking studies revealed strong binding affinities for halogenated derivatives, particularly compound 27 (-11.93 kcal/mol), while MD simulations confirmed a stable protein-ligand complex. Structure-activity relationships indicated that phenyl and halogen substitution patterns influence binding and activity; however, biological potency did not strictly correlate with docking scores. ADMET analysis indicated several limitations, including poor solubility and limited BBB permeability, suggesting that these compounds should be considered preliminary lead scaffolds for further optimization.