Discovery of a highly selective BChE inhibitor with concomitant anti-neuroinflammatory activity for treating Alzheimer's disease.

Recently, butyrylcholinesterase (BChE) has emerged as a potential therapeutic target for advanced Alzheimer's disease (AD). Herein, 20 novel carbamate-based N-benzoyl tryptamine derivatives were designed and synthesized by integrating a BChE-targeting fragment with the original carrier scaffold, which possesses good anti-neuroinflammatory activity. Among them, N14 was proved to be the most potent and highly selective BChE inhibitor [eqBChE IC50 = 18.00 ± 0.485 pM, selectivity index (SI) = 84,7252, hBChE IC50 = 1.50 ± 0.155 nM], which is 388 times greater than the BChE inhibitor previously identified by our research group. Additionally, N14 showed superior neuroprotective effects against Aβ1-42-induced injury model and inhibitory effects on Aβ1-42 self-aggregation compared to rivastigmine. Moreover, N14 could significantly ameliorate scopolamine-induced cognition impairment. Notably, N14 exhibited a superior capacity in the regulation of BChE and acetylcholine levels in the mouse hippocampus compared to rivastigmine, indicating that a highly selective BChE inhibitor possesses more pronounced efficacy to rectify cholinergic system dysfunction. Furthermore, N14 demonstrated a high safety profile, good pharmacokinetic properties and favorable BBB permeability in vivo. Especially, N14 had a 3-fold longer half-life T1/2 than the BChE inhibitor developed by our group. Therefore, the highly selective BChE inhibitor N14 is a promising multifunctional lead compound for treating AD.