Wu_2025_Eur.J.Med.Chem_302_118273

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 NMe(2) substituent on N-salicyloyl tryptamine derivatives. Among them, compound 17 exhibits picomolar BChE inhibition and exceptional selectivity (eqBChE IC(50) = 7.44 x 10(-5) +/- 1.55 x 10(-6) microM; SI = 270,000; hBChE IC(50) = 1.48 x 10(-3) +/- 1.3 x 10(-4) microM). In vitro and in vivo studies demonstrated 17 exhibited excellent COX-2 inhibitory activity (IC(50) = 0.11 +/- 0.01 microM), excellent blood-brain barrier permeability (P(e) = 7.18 x 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.