New insights into butyrylcholinesterase: Pharmaceutical applications, selective inhibitors and multitarget-directed ligands.

Butyrylcholinesterase (BChE), also known as pseudocholinesterase and serum cholinesterase, is an isoenzyme of acetylcholinesterase (AChE). It mediates the degradation of acetylcholine, especially under pathological conditions. Proverbial pharmacological applications of BChE, its mutants and modulators consist of combating Alzheimer's disease (AD), influencing multiple sclerosis (MS), addressing cocaine addiction, detoxifying organophosphorus poisoning and reflecting the progression or prognosis of some diseases. Of interest, recent reports have shed light on the relationship between BChE and lipid metabolism. It has also been proved that BChE is going to increase abnormally as a compensator for AChE in the middle and late stages of AD, and BChE inhibitors can alleviate cognitive disorders and positively influence some pathological features in AD model animals, foreboding favorable prospects and potential applications. Herein, the selective BChE inhibitors and BChE-related multitarget-directed ligands published in the last three years were briefly summarized, along with the currently known pharmacological applications of BChE, aiming to grasp the latest research directions. Thereinto, some emerging strategies for designing BChE inhibitors are intriguing, and the modulators based on target combination of histone deacetylase and BChE against AD is unprecedented. Furthermore, the involvement of BChE in the hydrolysis of ghrelin, the inhibition of low-density lipoprotein (LDL) uptake, and the down-regulation of LDL receptor (LDLR) expression suggests its potential to influence lipid metabolism disorders. This compelling prospect likely stimulates further exploration in this promising research direction.

Design, Synthesis, and Proof of Concept of Balanced Dual Inhibitors of Butyrylcholinesterase (BChE) and Histone Deacetylase 6 (HDAC6) for the Treatment of Alzheimer's Disease.

Concomitant inhibition of butyrylcholinesterase (BChE) and histone deacetylase 6 (HDAC6) is supposed to be effective in the treatment of Alzheimer's disease (AD). Inspired by our previous efforts in designing BChE inhibitors, herein, selective BChE and HDAC6 dual inhibitors were successfully identified through the fusion of the core pharmacophoric moiety of BChE and HDAC6 inhibitors. After the structure-activity relationship (SAR) studies, two compounds (24g and 29a) were confirmed to have superior inhibitory activity against BChE (the IC50 against hBChE are 4.0 and 1.8 nM, respectively) and HDAC6 (the IC50 against HDAC6 are 8.9 and 71.0 nM, respectively). These two compounds showed prominently neuroprotective effects in vitro, potent reactive oxygen species (ROS) scavenging effects, and effective metal ion (Fe2+ and Cu2+) chelation. In addition, they exhibited pronounced inhibition of phosphorylated tau and a moderate immunomodulatory effect, with a lack of neurotoxicity at the cellular level. In vivo studies showed that both 24g and 29a ameliorated the cognitive impairment in an Aß1-42-induced mouse model at a low dosage (2.5 mg/kg). Our data demonstrated that BChE/HDAC6 dual inhibitors could establish the basis for a potential new symptomatic and disease-modifying strategy to treat AD.