Design, synthesis, and biological evaluation of ring‐expanded thioacetal derivatives as potent and selective butyrylcholinesterase inhibitors

Abstract A novel series of thioacetal–amide derivatives ( 18 – 33 ) were developed as potent, selective butyrylcholinesterase (BuChE) inhibitors through a strategic ring‐expansion of the lipoic acid scaffold. Transitioning from a five‐membered 1,2‐dithiolane to a six‐membered 1,3‐dithiane moiety induced a striking reversal in selectivity, achieving up to a 671‐fold improvement over the lead compound A . Among the analogs, the meta ‐trifluoromethyl derivative 29 exhibited the highest BuChE potency (IC 50 = 0.031 μM; 300‐fold superior to galantamine), while the ortho ‐methoxy derivative 22 demonstrated exceptional selectivity (IC 50 = 28.99 μM for AChE, IC 50 = 0.080 μM for BuChE; SI = 362). Molecular docking simulations attributed this selectivity to the volumetric complementarity of the expansive BuChE active site, which accommodates the bulky thioacetal pharmacophore through robust π–π interactions, whereas the constricted AChE gorge induces severe steric clashes. These findings further support the thioacetal–amide scaffold as a promising lead for advanced‐stage Alzheimer's disease, with favorable in vitro cytocompatibility at concentrations well above the enzyme‐active range.