Wang_2024_Bioorg.Chem_153_107845

Photopharmacology is an emerging method in medicinal chemistry to achieve light-controlled drug activity. Azobenzene-based photoswitchable ligands have found widespread application as chemical tools in photopharmacological studies. This study pioneers the design and synthesis of a novel series of photoswitchabled butyrylcholinesterase (BChE) inhibitors, achieved by strategically integrating an azo moiety into an N-benzyl benzamide scaffold. Through a meticulous investigation of the structure-activity relationship (SAR), we discovered that the lead compound, Azo-9, exhibits dynamic cis/trans conformational shifts, dynamically modulating its BChE-binding efficacy. This unique property translates into potential therapeutic benefits, including neuroprotection and cognitive enhancement. Complementary molecular docking simulations underscored the preferential binding of the cis-isomer of Azo-9 to BChE, which was subsequently validated in a glutamate-mediated neuronal injury model. Collectively, Azo-9 emerges as a promising precision tool for Alzheimer's disease (AD) therapy, while also facilitating deeper insights into the disease's underlying mechanisms.