butyrylcholinesterase

Overview

Butyrylcholinesterase (BChE; also known as pseudocholinesterase, plasma cholinesterase, or non-specific cholinesterase) is a serine hydrolase enzyme encoded by the BCHE gene in humans. It belongs to the cholinesterase family and preferentially hydrolyzes butyrylcholine, though it can also act on acetylcholine and a broad range of choline esters. Unlike its close paralog acetylcholinesterase (AChE), which is concentrated at neuromuscular junctions and synapses, BChE is expressed widely across tissues including the liver, plasma, intestine, and brain. Structurally, BChE possesses a catalytic triad (Ser-His-Glu) within a deep, gorge-shaped active site, flanked by a peripheral anionic site and a choline-binding pocket—features that are exploited extensively in drug design efforts.

BChE plays a complex and context-dependent role in cholinergic neurotransmission. Under normal physiological conditions, it contributes modestly to the hydrolysis of acetylcholine; however, in advanced Alzheimer's disease (AD), AChE activity declines markedly while BChE activity progressively compensates, making BChE an increasingly important therapeutic target as neurodegeneration advances. Beyond neurological disease, BChE is implicated in lipid metabolism, glucose homeostasis linked to insulin resistance, and detoxification of xenobiotics. Its expression has also been identified in certain tumor microenvironments, extending its relevance beyond neuropharmacology into oncology. These diverse roles have made BChE the subject of intense multidisciplinary research, spanning synthetic medicinal chemistry, natural product pharmacology, parasitology, and cancer biology.

Focus of Latest Publications

Recent publications have continued to position butyrylcholinesterase as an important target in Alzheimer’s disease research, particularly in studies seeking dual cholinesterase inhibition alongside acetylcholinesterase. Several synthetic series were designed and evaluated specifically for BChE activity, including flavonoid-fused aminoquinolines, chiral anthranilic diamide derivatives, thieno[3,2-d]pyrimidine hybrids, benzothiazole-linked oxadiazoles, coumarin-based derivatives, and benzimidazole analogs. Across these reports, BChE inhibition was commonly assessed in vitro and supported by molecular docking, with some studies also incorporating molecular dynamics, MM-GBSA calculations, and ADMET or ADME profiling to prioritize lead compounds.

Among the most potent BChE-directed findings, the chromeno[4,3-b]quinoline derivative (±)-7-amino-6-phenyl-6H-chromeno[4,3-b]quinoline showed strong human BChE inhibition with an IC50 of 0.096 μM, outperforming its AChE activity. Chiral anthranilic diamide derivatives also showed significant BChE inhibition, with compounds 7a and 7b displaying nanomolar potency and enzyme-specific stereoselectivity; docking and simulation studies supported 7a as the stronger BChE binder. Thieno[3,2-d]pyrimidine-phenolic Mannich base hybrids were reported as dual cholinesterase inhibitors with low-nanomolar Ki values, and compounds 5 and 9 were highlighted for strong BChE inhibition. In the benzothiazole-oxadiazole series, K11 and K7 showed notable BChE inhibitory activity comparable to the reference drug, while coumarin derivative 10f demonstrated significant BuChE inhibition at 303 nM.

Other studies extended BChE-focused work into broader multifunctional anti-Alzheimer strategies. The benzimidazole analog IMS48 inhibited BChE with an IC50 of 1.85 μM and, in an in vivo rat model, improved behavioral outcomes while reducing markers associated with neurodegeneration and inflammation. Hydrazide-hydrazone indole congeners were also screened against BChE as part of a multi-target program that included AChE, BACE-1, MAO-A, MAO-B, and COX-2; compounds 3c, 3f, and 3k were advanced based on their overall biological profiles. In parallel, plant-derived extracts from fruit tree leaves and Epimedium pubigerum were reported to inhibit BChE alongside other enzymes, with molecular docking suggesting that identified phytochemicals may contribute to cholinergic system modulation.

Beyond Alzheimer’s disease, butyrylcholinesterase appeared in a bioinformatics study of cervical cancer, where BCHE was among the genes proposed as potential therapeutic targets linked to calcium signaling, cAMP, and inflammation-related pathways. Although this work did not test BChE enzymatic inhibition directly, it reinforced the enzyme’s broader relevance in disease-associated target discovery. Overall, the recent literature emphasizes BChE as a recurring target in dual cholinesterase inhibitor design, with several new scaffolds showing promising potency, selectivity, and computational support for further development.

Key Publications

• May Promising Flavonoid-Fused Aminoquinolines as Synthetic Alzheimer's Disease Models: Design, Synthesis, Anticholinesterase Activity, ADMET and Molecular Docking. (Chembiochem : a European journal of chemical biology, 2026, PMID 42179001): "...were evaluated for their AChE and BChE inhibitory activity and subjected to molecular docking studies."
• May The evaluation of HI-6 encapsulated in reconstituted lipid nanoparticles for central delivery and reactivation in soman-poisoned mice. (Neuroscience letters, 2026, PMID 42105850): "Prompt reactivation of inhibited cholinesterase is imperative; however, the blood-brain barrier (BBB) impedes the delivery of cholinesterase reactivators to the central nervous system (CNS)."
• May Design, Synthesis, and Enantioselective Cholinesterase Inhibition of Novel Chiral Anthranilic Diamide Derivatives: In Vitro and In Silico Studies. (Chirality, 2026, PMID 42050895): "Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes are responsible for the hydrolysis of acetylcholine and play a vital role in Alzheimer's disease (AD) pathology."
• Mar Targeting cholinergic dysfunction and neuroinflammation through rationally designed Thieno[3,2-d]pyrimidine hybrids. (Bioorganic chemistry, 2026, PMID 41871474): "The synthesized compounds exhibited potent inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with inhibition constants in the low nanomolar range."
• Mar In vitro, in vivo, and in silico profiling of optimized hydrazide-hydrazone indole congeners as multi-faceted AChE, BACE1, and MAO-B inhibitors for Alzheimer's disease therapy. (Bioorganic chemistry, 2026, PMID 41865568): "Preliminary in vitro screening against AChE and BChE highlighted compounds 3c, 3f, and 3k, each exhibiting >80% inhibition of AChE."
• May Comprehensive profiling of chlorophylls, carotenoids extracts and their derivatives in leaves of fruit tree species and assessment of antioxidant and enzyme inhibitory activities. (Food chemistry, 2026, PMID 41861736): "The extracts showed antioxidant activity (ABTS, ORAC), and inhibited key enzymes associated with antidiabetic (α-amylase, α-glucosidase, pancreatic lipase), neurodegenerative diseases (AChE, BChE), and inflammation (COX-1, COX-2, 15-LOX)."
• May Comparative HPLC profiling, antioxidant, enzyme inhibitory activities, and in silico molecular analysis of the aerial parts of Epimedium pubigerum. (Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 2026, PMID 41806791): "Molecular docking analyses revealed that the main compounds identified from E. pubigerum exerted inhibitory effects on the cholinergic system through acetylcholinesterase and butyrylcholinesterase targets and exhibited potential inhibitory activity against carbohydrate metabolism via α-amylase and α-glucosidase enzymes."
• Mar Synthesis, spectral characterization, and cholinesterase inhibitory evaluation of benzothiazole-linked oxadiazole derivatives as potential anti-Alzheimer's agents. (Bioorganic chemistry, 2026, PMID 41797133): "All derivatives were evaluated for their cholinesterase inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with donepezil used as the reference drug."
• Jun Development of coumarin-based acetylcholinesterase inhibitors: Synthesis, biological assessment and computational simulations. (Bioorganic chemistry, 2026, PMID 41691754): "...as multimodal anti-Alzheimer agents targeting acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and glycogen synthase kinase-3β (GSK-3β)."
• May Discovery of a novel IMS48 as a dual inhibitor of acetylcholinesterase and butyrylcholinesterase: In vitro and in vivo study for Alzheimer therapy. (Neuropharmacology, 2026, PMID 41628818): "In vitro screening identified 1-benzyl-3-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1H-benzo[d]imidazole-3-ium chloride (IMS48) as a potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC50 values of 0.31±0.04μM and 1.85±0.05μM, respectively, outperforming the standard drug donepezil."