Therapeutic Potential of Multifunctional Tacrine Analogues. Tacrine is a potent inhibitor of cholinesterases (acetylcholinesterase and butyrylcholinesterase) that shows limiting clinical application by liver toxicity. In spite of this, analogues of tacrine are considered as a model inhibitor of cholinesterases in the therapy of Alzheimer's disease. The interest in these compounds is mainly related to a high variety of their structure and biological properties. In the present review, we have described the role of cholinergic transmission and treatment strategies in Alzheimer's disease as well as the synthesis and biological activity of several recently developed classes of multifunctional tacrine analogues and hybrids, which consist of a new paradigm to treat Alzheimer's disease. We have
Tacrine(10)-Hupyridone Prevents Post-operative Cognitive Dysfunction via the Activation of BDNF Pathway and the Inhibition of AChE in Aged Mice Post-operative cognitive dysfunction (POCD) could cause short-term or long-term cognitive disruption lasting weeks or months after anesthesia and surgery in elderly. However, no effective treatment of POCD is currently available. Previous studies indicated that the enhancement of brain-derived neurotrophic factor (BDNF) expression, and the elevation the cholinergic system, might be effective to prevent POCD. In this study, we have discovered that tacrine(10)-hupyridone (A10E), a novel acetylcholinesterase (AChE) inhibitor derived from tacrine and huperzine A, could prevent surgery-induced short-term and long-term impairments of recognition
Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors A marine natural product, pulmonarin B (), and a series of related tacrine hybrid analogues were synthesized and evaluated as cholinesterase (ChE) inhibitors. The in vitro ChE assay results revealed that showed moderate dual acetylcholinesterase (AChE)/ butyrylcholinesterase (BChE) inhibitory activity, while the hybrid proved to be the most potent dual inhibitor among the designed derivatives, being almost as active as tacrine. Molecular modeling studies together with kinetic analysis suggested that interacted with both the catalytic active site and peripheral anionic site of AChE. Compounds and could also
Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering
Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease The cholinergic hypothesis has long been a "polar star" in drug discovery for Alzheimer's disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal
The Liver-Gut Microbiota Axis Modulates Hepatotoxicity of Tacrine in the Rat. The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses is poorly understood. In this study, we investigated the role of the liver-gut microbiota axis in underpinning the hepatotoxicity of tacrine. We employed an integrated strategy combining pharmacokinetics, toxicology, metabonomics, genomics, and metagenomics to elucidate and validate the mechanism of tacrine-induced hepatotoxicity in Lister hooded rats. Pharmacokinetic studies in rats demonstrated 3.3-fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealing enhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup
Design, synthesis and biological evaluation of tacrine-1,2,3-triazole derivatives as potent cholinesterase inhibitors †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7md00457e We report herein the design and synthesis of a series of 11 novel tacrine-1,2,3-triazole derivatives a Cu(i)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction. The newly modeling studies may provide valuable insights into the design of better tacrine-triazole analogues with potential therapeutic applications for AD.
Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer's agents was assessed. Their inhibitory activity towards human acetylcholinesterase (AChE) and human butyrylcholinesterase (BChE), antioxidant
Novel multitarget-directed tacrine derivatives as potential candidates for the treatment of Alzheimer’s disease Alzheimer's disease (AD) is a neurodegenerative disorder, which is complex and progressive; it has not only threatened the health of elderly people, but also burdened the whole social medical and health system. The available therapy for AD is limited and the efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the design and development of efficacious and safe anti-AD agents has become a hotspot in the field of pharmaceutical research. Due to the multifactorial etiology of AD, the multitarget-directed ligands (MTDLs) approach is promising in search for new drugs for AD. Tacrine, which is the first acetylcholinesterase (AChE
Tacrine, Trolox and Tryptoline as Lead Compounds for the Design and Synthesis of Multi-target Agents for Alzheimer’s Disease Therapy The versatile biological activities of tacrine, trolox and β-carboline derivatives make them promising lead structures for the development of multifunctional Alzheimer's disease (AD) agents. Based on the topology of the active site of cholinesterases and other target proteins involved in the pathogenesis of AD, we have designed and synthesized tacrine-trolox and tacrine-tryptoline hybrids with various linker chain lengths. The hybrids containing the trolox moiety () showed moderate to high AChE inhibition (IC: 17.37 - 2200 nM), eqBuChE inhibition (IC: 3.16 - 128.82 nM) and free radical scavenging activities (IC: 11.48 - 49.23 µM). The hybrids with longer
Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease. Alzheimer's disease is a multifactorial and fatal neurodegenerative disorder characterized by decline of cholinergic function, deregulation of other neurotransmitter systems, β-amyloid fibril deposition, and β-amyloid oligomers formation. Based disease have also been considered in the last years for producing multitarget compounds such as β-secretase, monoamino oxidases, serotonin receptors and sigma 1 receptors. The purpose of this review will be to highlight recent reports on the development of multitarget compounds for Alzheimer's disease published within the last years focusing on multifunctional ligands characterized by tacrine-like
Electroacupuncture at PC6 or ST36 Influences the Effect of Tacrine on the Motility of Esophagus. Aim. To investigate the mechanisms of gastrointestinal side effects of tacrine, and find treatment methods with electroacupuncture (EA). Methods. Twenty-five healthy cats were randomly divided into 5 groups: gastric-distention group (model group), tacrine group (cholinesterase inhibitor), tacrine + sham acupoint group (control group), tacrine + PC6 (neiguan) group, and tacrine + ST36 (zusanli) group, with 5 cats in each group. Saline 2 mL i.p. was given 30 min before gastric distention in model group. Tacrine 5.6 mg/kg i.p. was given 30 minutes before gastric distention in the other groups. Tacrine + sham acupoint group (control group), tacrine + PC6 group, and tacrine + ST36 group received EA
Highly selective inhibition of butyrylcholinesterase by a novel melatonin-tacrine heterodimers. Novel inhibitors of cholinesterases, especially butyrylcholinesterase (BuChE), were obtained by coupling melatonin-tacrine heterodimers via the carbamate bond. Compounds 14a-i possessed potent cholinesterase inhibitory activity (with IC50 values as low as 1.18 nM for acetylcholinesterase (AChE ) and 0.24 nM for butyrylcholinesterase (BuChE)). These heterodimers exhibit selectivity toward BuChE, being from 4- to 256-fold more active toward BuChE than AChE, but still acting as better AChE inhibitors than tacrine 4.
oxidation and glucuronidation). Ropinirole (Requip) • ↓ Cmax (30%) and AUC (38%) in study with patients with restless legs syndrome. • Smokers may need ↑ dosage Tacrine (Cognex) • ↓ Metabolism (induction of CYP1A2); ↓ half-life
A computational approach to identify phytochemicals as potential inhibitor of acetylcholinesterase: Molecular docking, ADME profiling and molecular dynamics simulations. Inhibition of acetylcholinesterase (AChE) is a crucial target in the treatment of Alzheimer's disease (AD). Common anti-acetylcholinesterase drugs such as Galantamine, Rivastigmine, Donepezil, and Tacrine have significant using Pyrx software, resulting in 638 molecules showing higher binding affinities compared to positive controls Tacrine (-9.0 kcal/mol), Donepezil (-7.3 kcal/mol), Galantamine (-8.3 kcal/mol), and Rivastigmine (-6.4 kcal/mol). Subsequently, ADME properties were assessed, including blood-brain barrier permeability and Lipinski's rule of five violations, leading to 88 compounds passing the ADME analysis
analysis. Based on the maximum molecular docking binding affinities and molecular dynamic simulation (100 ns) results, the ALB and GAD2 were found as prominent drug target proteins when tacrine and donepezil were identified as potential drug candidates for delirium and AD. The study outlined the common key biomolecules and biological pathways shared by delirium and AD. The computationally reported
A single-center, randomized, open-label, dose-escalation study to evaluate the pharmacokinetics of tacrine analogue octahydrogenacridine succinate tablets in healthy Chinese subjects. The objectives of the present study were to investigate the pharmacokinetics (PK) of tacrine analogue octahydrogenacridine (OHA) succinate tablets in healthy Chinese subjects. A single-center, randomized, open-label
Therapeutic Potential of Multifunctional Derivatives of Cholinesterase Inhibitors. The aim of this work is to review tacrine analogues from the last three years, which were not included in the latest review work, donepezil and galantamine hybrids from 2015 and rivastigmine derivatives from 2014. In this account, we summarize the efforts toward the development and characterization of non-toxic