Lv_2025_Bioorg.Med.Chem_127_118219

To address the multifactorial pathology of Alzheimer's disease (AD), eighteen butyrylcholinesterase (BChE) and histone deacetylase 6 (HDAC6) dual inhibitors were designed, synthesized, and biologically evaluated. Through structure-activity relationship studies, compound 17 emerged as the most potent candidate, with IC(50) value of 0.3 nM for human BChE and 56.7 nM for HDAC6. This compound demonstrated favorable safety profiles, drug-like properties, and significant neuroprotective effects in vitro. In a mouse model of scopolamine-induced cognitive impairment, 17 (10 mg/kg) exhibited excellent safety and markedly improved cognitive deficits. These findings highlight compound 17 as a promising BChE/HDAC6 dual inhibitor, supporting its further development as a potential therapeutic agent for AD.