Dual-target inhibitors based on BuChE: A review from medicinal chemistry perspective

Butyrylcholinesterase (BuChE) plays a crucial role in maintaining neurotransmission homeostasis as a key complementary hydrolase to acetylcholinesterase (AChE), making it an essential target for addressing neurodegenerative diseases, neuroinflammation, and chemical toxin metabolism. A variety of selective BuChE inhibitors have been developed; however, their clinical translation remains constrained by insufficient efficacy, off-target effects, and poor blood-brain barrier (BBB) permeability. Recently, dual-target inhibitors have emerged as a promising strategy to circumvent these limitations. By integrating BuChE inhibition with complementary targets, researchers have designed multifunctional ligands through rational structural fusion and hybridization strategies and combinatorial library screening. These inhibitors exhibit enhanced neuroprotective efficacy, improved selectivity, and reduced side effects. This review highlights recent advances in the rational design, structure-activity relationship (SAR), and preclinical efficacy of novel BuChE dual-target inhibitors, focusing on their therapeutic potential for Alzheimer's disease (AD).