Design, Synthesis and Evaluation Donepezil-Based Dual BuChE/FAAH Inhibitors for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is multifactorial, prompting multi-target therapy. A series of donepezil-based derivatives were designed, synthesized, and evaluated as dual inhibitors of human butyrylcholinesterase (hBuChE) and fatty acid amide hydrolase (hFAAH). Among them, lead G15 displayed potent and balanced inhibition with IC50 values of 2.44 μM and 0.17 μM, respectively, and favorable selectivity over carboxylesterases CES1/2 (SI 14.4 and 8.4). G15 not only acted as a time-dependent, mixed-type hFAAH inhibitor and a pseudo-irreversible hBuChE inhibitor, but also exhibited good drug-like properties, including high BBB permeability and oral bioavailability (108%). Moreover, G15 chelated Zn2+, protected PC12 cells from oxidative stress, and promoted microglial M1 → M2 polarization. In an Aβ1-42-induced mouse model, G15 significantly reversed cognitive deficits, outperforming donepezil. Therefore, G15 is poised for further development as a promising multi-target candidate for AD therapy.