Design of N-salicyltryptamines-based highly selective BChE inhibitors to elevate brain acetylcholine, improve learning, and reduce amyloid-β in Alzheimer's disease

Neurodegenerative diseases (NDDs) merges conserved mechanisms with disease-specific pathology. A dual-targeting approach, featuring a core scaffold for conserved pathological pathways and modular disease-specific pharmacophores could provide a systematic therapeutic framework for NDDs. Herein, we synthesized a series of N-salicyltryptamines-carbamate derivatives by appending AD specific BChE-targeted carbamate pharmacophores to anti-inflammatory carrier scaffolds M11/18 with NMe₂ substituent on N-salicyloyl tryptamine derivatives. Among them, compound 17 exhibits picomolar BChE inhibition and exceptional selectivity (eqBChE IC₅₀ = 7.44 × 10^-5 ± 1.55 × 10^-6 μM; SI = 270,000; hBChE IC₅₀ = 1.48 × 10^-3 ± 1.3 × 10^-4 μM). In vitro and in vivo studies demonstrated 17 exhibited excellent COX-2 inhibitory activity (IC₅₀ = 0.11 ± 0.01 μM), excellent blood-brain barrier permeability (P_e = 7.18 × 10^-6 cm/s) and neuroprotective. Besides, ameliorated scopolamine-induced cognitive deficits superior to rivastigmine. Crucially, 17 demonstrated greater acetylcholine elevation than rivastigmine in mice brain, attributable to its highly selective BChE inhibition. This study identifies 17 as a promising AD therapeutic candidate and validates the potential of the N-Salicyltryptamines-based dual-targeting approach.