Cholinesterase Inhibitors Research Articles

Brain targeting efficacy of novel drug delivery system in the treatment of Alzheimer's disease.

Alzheimer's disease (AD), a common degenerative disease of the central nervous system in the elderly, has become the third largest health killer after cardiovascular and cerebrovascular diseases and tumors. Based on the fact that Alzheimer's disease is a disease with multiple etiologies and complex pathology, a single target is bound to have a limited curative effect, and the synergy of multiple links and multiple targets is expected to achieve a better curative effect. The aim of this study is to investigate the brain targeting of a drug modified by chitosan, based on the new nanodrug delivery system for treating Alzheimer's disease developed by the research group. Chitosan with good biocompatibility, biosorption, and degradation products that can protect and promote the regeneration of nerve cells was selected to combine with galantamine, a natural representative cholinesterase inhibitor, to develop a new nano drug delivery system for nasal delivery of anti-Alzheimer's disease with a multi-target synergistic effect. Synchronous analysis was conducted on the blood and brain tissue drug concentrations after intravenous and nasal administration of the original drug solution and system solution. The brain targeting index (DTI) is used to evaluate the brain targeting effect of the nano-drug delivery system after intranasal administration. The blood concentration of galantamine original drug solution and galantamine system solution after intravenous injection and nasal show that in the two administration methods of intravenous injection and nasal administration, under the same administration method, the time point of the system reaching the highest blood drug concentration is much higher than that of the original drug. The content of galantamine in plasma samples and tissue samples indicate that after intravenous administration and intranasal administration of the galantamine system, at the same time point, the drug concentration in brain tissue was far greater than that of the original drug of galantamine, and the duration was also longer. The concentration of drugs in brain tissue decreased gradually in the order of olfactory bulb, olfactory tract, brain, and cerebellum. In the brain tissues of the olfactory bulb, olfactory tract, cerebrum, and cerebellum, the drug concentration of the galantamine system after intravenous injection is lower than that after nasal administration. This study concludes that compared with the original drug solution, the nano drug delivery system has significant brain targeting for nasal administration, and intravenous injection also has brain targeting. In the olfactory bulb, olfactory tract, brain, and cerebellum, the brain targeting index at the olfactory bulb is the highest, and the targeting is the best.

Neurogenetics: Precision Medicine-Based Approaches to Neurological Disorders with an Emphasis on Addressing Alzheimer’s Disease and Schizophrenia

There exist over 600 neurological conditions, each characterized by unique pathologies tailored to individual patients. Over the past two decades, advances in biotechnology have propelled the field of neurogenetics forward. This progress has illuminated therapeutic targets and methodologies tailored to the specific needs of each patient. Current treatment options primarily encompass therapies and conventional medications like cholinesterase inhibitors for Alzheimer’s disease and antipsychotics for schizophrenia. However, these treatments often address symptoms or general targets rather than the precise underlying causes. Precision medicine has emerged as a promising approach in both animal and human clinical trials. Examples include the identification of specific genetic variations linked to Alzheimer's risk and progression, as well as the application of multigenic pharmacogenomics-guided therapies for schizophrenia patients. This review paper delves into the role of precision medicine in neurogenetics, focusing on neural stem cells, induced pluripotent stem cells (iPSCs), genetic profiling, and pharmacogenetics within the contexts of Alzheimer’s disease and schizophrenia. By evaluating current achievements alongside existing challenges, this paper underscores precision medicine as a pivotal strategy for effectively targeting neurological disorders.

Vegan and Vegetarian Soups Are Excellent Sources of Cholinesterase Inhibitors.

The cholinesterase theory stands as the most popular worldwide therapy for Alzheimer's disease (AD). Given the absence of a cure for AD, a plant-based diet has been repeatedly shown as positive in the prevention of AD, including exploring ready-made products in stores and the development of new functional foods. This study compared the anti-acetyl- and butyrylcholinesterase activity of thirty-two Polish market soups and five newly formulated soups intended to be functional. Additionally, the research aimed to assess the significance of animal content, distinguishing between vegan and vegetarian options, in cholinesterase inhibition. The anticholinesterase activity was investigated using a spectrophotometric method, and the inhibitory activity was expressed as % inhibition of the enzyme. The study categorized soups into three groups based on ingredients: those containing animal-derived components, vegetarian soups and vegan soups. Soups exhibited varying levels of activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), indicating differences in their compositions. Composition appeared to be the primary factor influencing anticholinesterase activity, as soups within each group showed significant variability in activity levels. While some commercial soups demonstrated notable anticholinesterase activity, they did not surpass the effectiveness of the optimized soups developed in the laboratory. Certain ingredients were associated with higher anticholinesterase activity, such as coconut, potato, onion, garlic, parsley and various spices and herbs. Vegetarian and vegan soups exhibited comparable or even superior anticholinesterase activity compared to animal-derived soups, highlighting the importance of plant-based ingredients. The study underscores the need for further research to explore the mechanisms underlying the anticholinesterase activity of soups, including the impact of ingredient combinations and processing methods.

Relationship between donepezil and fracture risk in patients with dementia with Lewy bodies.

Patients with dementia with Lewy bodies (DLB) are at a high risk for falls and fractures. Although cholinesterase inhibitors reportedly are effective in suppressing the progression of cognitive symptoms in DLB patients, their effects on fracture risk remain unclarified. This study aimed to evaluate the association between donepezil use and hip fracture risk in older patients with DLB. Using the Japanese insurance claim database, we collected the data of patients aged ≥65 years with DLB from April 2012 to March 2019. After propensity score matching, we compared the fracture rate over 3 years between DLB patients receiving donepezil and those not receiving antidementia drugs. Altogether, 24 022 239 individuals aged ≥65 years were newly registered from April 2012 to March 2016 and had verifiable information from 6 months before to 3 years after the registration. We identified 6634 pure-DLB patients and analyzed the data of 1182 propensity score-matched pairs. The characteristics, including age, sex, fracture history, osteoporosis, and bone mineral density test rate, of the two groups were well balanced by propensity score matching. The incidence rate of hip fracture was significantly lower in DLB patients receiving donepezil than in those not receiving antidementia drugs (0.60 vs. 1.44/100 person-years, P < 0.001), whereas that of vertebral fractures was the same. Donepezil administration in Japanese people aged ≥65 years with DLB was significantly associated with a decreased risk of hip fracture. Donepezil may provide new benefits to DLB patients. Geriatr Gerontol Int 2024; 24: 782-788.

Novel quinolone-grafted chitosan derivatives with potential therapeutic properties: synthesis, characterization, in silico investigations, cholinesterase inhibitory potential, and antioxidant activity

Cholinesterase inhibitors are employed for treating different neuromuscular disorders that arise due to decreased levels of ACh in the cortical and hippocampal, such as Alzheimer’s disease. There is a need to synthesize novel drug candidates to improve therapeutic efficacy and reduce side effects due to toxicity and emerging drug resistance. Chitosan was grafted with quinolone derivatives using EDC and NHS as coupling agents. The newly synthesized quinolone-grafted chitosan derivatives were characterized by elemental analysis, UV–Vis, FTIR, SEM and TGA. The determination of substitution degree was carried out through elemental analysis, utilizing C/N ratios. The in vitro acetylcholinesterase and butyrylcholinesterase activities and antioxidant capacity of the compounds were investigated. Additionally, in silico investigations, including quantum chemistry calculations and docking studies, were conducted to gain insights into the molecular geometry, electronic properties, and interaction modes of the quinolone units. As a result, the synthesized derivatives CsMOC and CsMON exhibited a moderate inhibitory effect on AChE when compared to Donepezil with IC50 values of 0.22 ± 0.04 and 0.88 ± 0.05 µM, respectively. In contrast, CsMON displayed noteworthy activity against BChE with an IC50 values of 1.39 ± 0.22 µM. Furthermore, both derivatives showed potent antioxidant capacity.

Ocular surface alterations in agricultural workers exposed to pesticides in Cundinamarca, Colombia

BackgroundThe cholinergic system regulates a variety of structures on the ocular surface and maintains homeostasis. Therefore, dysregulation of cholinergic activity could impact lacrimal and conjunctival function. Consequently, exposure of the ocular surface to chemical agents, including pesticides such as acetylcholinesterase inhibitors, which interact closely with the ocular surface and anterior segment, could affect ocular homeostasis. In this study, we assess alterations in the ocular surface in workers exposed to organophosphate pesticides. MethodsA cross-sectional study was conducted involving 39 participants (23 controls and 16 cases exposed to agrochemicals). The ocular surface of all subjects was assessed using the Schirmer test, TBUT, conjunctival impression cytology, and the Q16 neurotoxicity and ocular symptoms questionnaire by Donate. ResultsConjunctival hyperemia, impression cytology and Schirmer test were found to be altered in the workers exposed to cholinesterase inhibitor pesticides. ConclusionThese findings suggest that ocular surface alterations can be seen in organophosphate pesticide exposure, and that lacrimal hypersecretion could be an ocular biomarker for detecting pesticide effects before adverse clinical effects occur.

DESIGN, SYNTHESIS, AND BIOLOGICAL ASSESSMENT OF NOVEL N'-(BENZYLIDENE)PROPANEHYDRAZIDES AS MTDL FOR ALZHEIMER’S DISEASE

Objective: In this study, following the multi-target directed ligands (MTDLs) strategy and drawing inspiration from the neuroprotective structure of ferulic acid, eight novel N'-(benzylidene)propanehydrazide derivatives were designed, synthesized, and tested to evaluate their cholinesterase inhibitory and antioxidant capacities. Material and Method: To obtain the final compounds, first, corresponding key intermediates, 3-(substitutedamino)propanehydrazides, were prepared by the hydrolysis with hydrazine hydrate of methyl 3-(substitutedamino)propanoate intermediates. These intermediates had been prepared from the Michael addition of methyl acrylate and commercially available tertiary amine derivatives. Subsequently, the final compounds were synthesized from the reaction of the starting compounds 4-hydroxybenzaldehyde or 4-methoxybenzaldehyde and the corresponding key intermediates. Structural analysis of the synthesized and purified compounds was carried out using 1H-NMR, 13C-NMR, and HRMS. Then, all the final compounds were examined for their cholinesterase inhibitory effect using the modified Ellman method, their antioxidant effect using the DPPH and ORAC methods, and their metal chelator effect using UV-spectroscopy analysis. Moreover, physicochemical parameters were calculated using QikProp Schrödinger Suite 2023 to predict the druggability of all compounds. Result and Discussion: Seven of the eight final compounds exhibited moderate cholinesterase inhibition at varying rates. Compounds 2a (IC50 = 12.83 µM) and 2d (IC50 = 16.02 µM) were identified as the most potent inhibitors for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively. Moreover, all the final compounds exhibited antioxidant activity in the ORAC assay. Chelator effects of all compounds were also observed for Cu(II), Fe(II), and Zn(II) ions at varying rates. Additionally, the final compounds demonstrated acceptable lead-like properties according to in-silico predictions.

Synthesis, insecticidal Activity, and molecular docking analysis of some benzo[h]quinoline derivatives against Culex pipiens L. Larvae

Some heterocycles bearing a benzo[h]quinoline moiety were synthesized through treating a 3-((2-chlorobenzo[h]quinolin-3-yl)methylene)-5-(p-tolyl)furan-2(3H)-one with four nitrogen nucleophiles comprising ammonium acetate, benzylamine, dodecan-1-amine, and 1,2-diaminoethane. Also, thiation reactions of furanone and pyrrolinone derivatives were investigated. The insecticidal activity of these compounds against mosquito larvae (Culex pipiens L.) was evaluated. All tested compounds exhibited significant larvicidal activity, surpassing that of the conventional insecticide chlorpyrifos. In silico docking analysis revealed that these compounds may act as acetyl cholinesterase (AChE) inhibitors, potentially explaining their larvicidal effect. Additionally, interactions with other neuroreceptors, such as nicotinic acetylcholine receptor and sodium channel voltage-gated alpha subunit were also predicted. The results obtained from this study reflected the potential of benzo[h]quinoline derivatives as promising candidates for developing more effective and sustainable mosquito control strategies. The ADME (absorption, distribution, metabolism, and excretion) analyses displayed their desirable drug-likeness and oral bioavailability properties.

Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer's Disease.

ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aβ) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments. The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) ≥ 22, Clinical Dementia Rating-Global (CDR-G) 0.5 or 1], apolipoprotein E4 (APOE4) genotypes including APOE4/4 and APOE3/4 genotypes, and positive cerebrospinal fluid (CSF) AD biomarkers or prior amyloid scans. The primary outcome was plasma p-tau181, HV evaluated by magnetic resonance imaging (MRI) was the key secondary outcome, and plasma Aβ42 and Aβ40 were the secondary biomarker outcomes. The cognitive outcomes were the Rey Auditory Verbal Learning Test and the Digit Symbol Substitution Test. Safety and tolerability evaluations included treatment-emergent adverse events and amyloid-related imaging abnormalities (ARIA). The study was designed and powered to detect 15% reduction from baseline in plasma p-tau181 at the 104-week endpoint. A sample size of 80 subjects provided adequate power to detect this difference at a significance level of 0.05 using a two-sided paired t-test. The enrolled population of 84 subjects (31 homozygotes and 53 heterozygotes) was 52% females, mean age 69 years, MMSE 25.7 [70% mild cognitive impairment (MCI), 30% mild AD] with 55% on cholinesterase inhibitors. Plasma p-tau181 reduction from baseline was significant (31%, p = 0.045) at 104 weeks and all prior visits; HV atrophy was significantly reduced (p = 0.0014) compared with matched external controls from an observational Early AD study. Memory scores showed minimal decline from baseline over 104 weeks and correlated significantly with decreased HV atrophy (Spearman's 0.44, p = 0.002). Common adverse events were COVID infection and mild nausea, and no drug-related serious adverse events were reported. Of 14 early terminations, 6 were due to nonserious treatment-emergent adverse events and 1 death due to COVID. There was no vasogenic brain edema observed on MRI over 104 weeks. The effect of ALZ-801 on reducing plasma p-tau181 over 2 years demonstrates target engagement and supports its anti-Aβ oligomer action that leads to a robust decrease in amyloid-induced brain neurodegeneration. The significant correlation between reduced HV atrophy and cognitive stability over 2 years suggests a disease-modifying effect of ALZ-801 treatment in patients with early AD. Together with the favorable safety profile with no events of vasogenic brain edema, these results support further evaluation of ALZ-801 in a broader population of APOE4 carriers, who represent two-thirds of patients with AD. https://clinicaltrials.gov/study/NCT04693520 .

New and emerging drug therapies for Alzheimer disease.

Established drug therapies for Alzheimer disease (cholinesterase inhibitors and memantine) do not modify the disease course and provide only modest clinical benefit. Biomarker measures of amyloid, tau and neurodegeneration have been integral to Alzheimer disease clinical trials for biologic drugs, for patient selection and efficacy monitoring. At the time of writing, two monoclonal antibodies targeting the amyloid-beta protein (aducanumab and lecanemab) have been approved in the USA, and two agents (lecanemab and donanemab) are under evaluation by the Therapeutic Goods Administration in Australia. Clinical trials have demonstrated that monoclonal antibodies are effective at removing amyloid from the brain in people with early Alzheimer disease. Cognitive benefits are statistically significant, but do not achieve the minimal clinically important difference. Amyloid-related imaging abnormalities of vasogenic oedema and microhaemorrhages occur more frequently on treatment; although these are usually asymptomatic or transient, in some people they are serious or fatal. Targeting amyloid as a unimodal strategy is unlikely to be sufficient and future therapies may need to be multimodal, targeting multiple pathogenic pathways. The burden of dementia is greatest in the older population where mixed dementia pathology dominates; the relationship between biomarkers, clinical phenotype and pathology attenuates; and frailty and comorbidity impact cognition. This creates challenges in identifying effective therapies for the group where dementia is most prevalent.

Novel neuroprotective 5,6-dihydropyrido[2′,1':2,3]imidazo[4,5-c]quinoline derivatives acting through cholinesterase inhibition and CB2 signaling modulation

A novel group of 5,6-dihydropyrido [2′,1':2,3]imidazo [4,5-c]quinolines was prepared via a microwave assisted one-pot telescopic approach. The synthetic sequence involves the formation of an amine precursor of imidazo [1,2-a]pyridine via condensation and reduction under microwave irradiation. Subsequently, the Pictet-Spengler cyclisation reaction occurs with ketones (cyclic or acyclic) to obtain substituted 5,6-dihydropyrido [2′,1':2,3]imidazo [4,5-c]quinolines in excellent yields. The compounds were tested as neuroprotective agents. Observed protection of neuron-like cells, SH-SY5Y differentiated with ATRA, in Parkinson's and Huntington's disease models inspired further mechanistic studies of protective activity against damage induced by 1-methyl-4-phenylpyridinium (MPP+), a compound causing Parkinson's disease. The novel compounds exhibit similar or higher potency than ebselen, an established drug with antioxidant activity, in the cells against MPP + -induced total cellular superoxide production and cell death. However, they exhibit a significantly higher capacity to reduce mitochondrial superoxide and preserve mitochondrial membrane potential. We also observed marked differences between a selected derivative and ebselen in terms of normalizing MPP + -induced phosphorylation of Akt and ERK1/2. The cytoprotective activity was abrogated when signaling through cannabinoid receptor CB2 was blocked. The compounds also inhibit both acetylcholine and butyrylcholine esterases. Overall the data show that novel 5,6-dihydropyrido [2′,1':2,3]imidazo [4,5-c]quinoline have a broad cytoprotective activity which is mediated by several mechanisms including mitoprotection.

Alkylation of morpholine and prolidine by phthalimide substituted Ru(II)–NHC catalysts

In this study, a series of benzimidazolium salts and silver-benimidazol-2-ylidene complexes were synthesized. The obtained silver complexes were converted into Ru(II)- benimidazol-2-ylidene complex using the transmetallation method. After elucidating the structures of these Ru(II)–NHC compounds, the synthesized ruthenium complexes were used in the alkylation reaction of cyclic amines to synthesize valuable derivatives such as pyrrolidine and morpholine. Pyrrolidine derivatives are extensively studied for their antimicrobial, antiviral, antifungal, anticancer, anti-inflammatory, anticonvulsant, cholinesterase inhibition, and carbonic anhydrase inhibition properties. Morpholine derivatives are particularly studied in the context of central nervous system (CNS) diseases. The yield of the catalytic products obtained was determined by GC. High selectivity and yield were achieved in the alkylation reactions of heterocyclic structures.

Review on Study of Nanoparticles in Brain Targeting for Treatment Of Alzheimer’s

Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder, in which there is a progressive deterioration of intellectual and social functions, memory loss, personality changes and inability for self-care, and has become the fourth leading cause of death in developed countries. Pathogenesis of AD, there is a progressive deposition of β-amyloid (Aβ)- peptide in the hippocampal and cerebral cortical regions. This deposition is associated with the presence of neurofibrillary tangles (NFTs) and senile plaques. The senile plaques deposited between the neurons consist mainly protein β amyloid. Neurofibrillary tangles deposited inside the neurons fabricated from Tau protein. Diagnosing Alzheimer's requires careful medical evaluation thorough medical history, mental status testing, physical and neurological examination tests (such as blood tests and brain imaging), two classes of medications approved to treat AD. Cholinesterase inhibitors: Donepezil, Rivastigmine, Galantamine, NMDA receptor antagonists: Memantine. The major goal in designing nanoparticles as a delivery system are to control particle size, surface property and release of pharmacologically active agents in order to achieve the site-specific action of the drug at the therapeutic optimum rate and dose regimen of the agent to the CNS, but also the ability of the agent to access the relevant target site within the CNS. Many strategies have been developed to deliver the drug into brain by crossing the BBB: chemical delivery systems, magnetic drug targeting or drug carrier systems such as antibodies, liposomes or nanoparticles. Among those, nanoparticles have got a great concentration as the potential targeted drug delivery systems in the brain recently. Keywords: Alzheimer’s disease, β-amyloid, cholinesterase inhibitors, Curcumin nanoparticles.

Chemical composition, anticholinesterase activity, and molecular docking studies of Piper crassipes Korth. ex Miq. essential oil

The purpose of this study was to investigate the chemical composition and anticholinesterase inhibitory activity of the essential oil obtained from Piper crassipes leaves collected from Malaysia. Twenty-two components were identified using gas chromatography-flame ionisation detection (GC-FID) and gas chromatography/mass spectrometry (GC-MS), which represent 97.8% of the essential oil. The identified major components included chavibetol (59.8%), chavibetol acetate (10.4%), γ-muurolene (5.4%), and germacrene D (4.6%). Anticholinesterase activity was assessed using Ellman’s method. A moderate inhibitory effect was observed for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes with IC50 values of 77.2 ± 0.2 and 89.2 ± 0.2 µg/mL, respectively. The molecular docking studies revealed that chavibetol acetate showed potent interactions with the cholinesterase target, while other compounds exhibited varied binding patterns, providing crucial insights into their potential as cholinesterase inhibitors.

Investigation of 3-Phenylcoumarin Derivatives as Potential Multi-target Inhibitors for Human Cholinesterases and Monoamine oxidases: A Computational Approach.

Alzheimer's disease (AD) is the predominant etiology of dementia, impacting a global population of approximately 50 million individuals. In the field of medicinal chemistry, there have been notable advancements in the utilization of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors for the purpose of addressing the neurotransmitter shortage associated with Alzheimer's disease (AD). A selection of previously synthesized 3-Phenylcoumarin derivatives (5a-m) were selected for examination in the pursuit of potential multi-targeting inhibitors of MAO-A, MAO-B, AChE, and BChE. The stability and reactivity of the compounds were investigated through the utilization of density functional theory (DFT) simulations. Subsequently, a CoMFA technique, grounded in 3D-QSAR principles, was employed to construct a model and predict the inhibitory properties of analogues belonging to the class of 3-phenylcoumarin derivatives. Through the application of molecular docking methodologies, we have employed predictive analyses to determine the potential binding interactions and stability of the drugs under investigation. The results obtained from the present investigation indicate that the 3-phenylcoumarin derivatives possess a reactive electronic characteristic that is crucial for their anti-cholinesterase activity. Compound 5a demonstrated a noteworthy binding score with AChE, BChE, MAO-A and MAO-B, respectively, indicating a robust binding affinity.

The ric-8b protein (resistance to inhibitors of cholinesterase 8b) is key to preserving contractile function in the adult heart

Resistance to inhibitors of cholinesterases (ric-8 proteins) are involved in modulating G-protein function, but little is known of their potential physiological importance in the heart. In the present study, we assessed the role of resistance to inhibitors of cholinesterase 8b (Ric-8b) in determining cardiac contractile function. We developed a murine model in which it was possible to conditionally delete ric-8b in cardiac tissue in the adult animal after the addition of tamoxifen. Deletion of ric-8b led to severely reduced contractility as measured using echocardiography days after administration of tamoxifen. Histological analysis of the ventricular tissue showed highly variable myocyte size, prominent fibrosis, and an increase in cellular apoptosis. RNA sequencing revealed transcriptional remodeling in response to cardiac ric-8b deletion involving the extracellular matrix and inflammation. Phosphoproteomic analysis revealed substantial downregulation of phosphopeptides related to myosin light chain 2. At the cellular level, the deletion of ric-8b led to loss of activation of the L-type calcium channel through the β-adrenergic pathways. Using fluorescence resonance energy transfer-based assays, we showed ric-8b protein selectively interacts with the stimulatory G-protein, Gαs. We explored if deletion of Gnas (the gene encoding Gαs) in cardiac tissue using a similar approach in the mouse led to an equivalent phenotype. The conditional deletion of the Gαs gene in the ventricle led to comparable effects on contractile function and cardiac histology. We conclude that ric-8b is essential to preserve cardiac contractile function likely through an interaction with the stimulatory G-protein and downstream phosphorylation of myosin light chain2.

Exploring 2-Pyrazoline derivatives as potent antidiabetic agents and cholinesterase inhibitors: Their synthesis and molecular docking studies

Herein, unique pyrazoline derivatives were synthesized, and their structures were elucidated by various spectroscopic techniques. Moreover, potential in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-glucosidase, and α-amylase inhibition effects of the compounds were also investigated. Molecular docking studies were performed to further elucidate the enzyme inhibitory activities. The compound 2c (IC50 = 1.64±0.04 and 4.18±0.22 µM, respectively) exhibited the strongest inhibitory activity against AChE and BChE, while compounds 2 m (IC50 = 4.29±0.20 µM) and 2i (IC50 = 4.31±0.08 µM) showed promising AChE inhibitory activity. On the other hand, compounds 2a (IC50= 5.01±0.13 µM) and 2i (IC50 = 5.06±0.72 µM) significantly inhibited BChE. In addition, all compounds except 2c and 2f showed great inhibitory activity against α-amylase at lower concentrations compared to acarbose (IC50 = 72.57 ± 3.16 µM). Similarly, all compounds except 2k exhibited higher inhibitory activity than acarbose (IC50 = 207.08±12.20 µM) against α-glucosidase. Among the compounds, 2a (IC50 = 15.05±5.64 µM), 2b (IC50 = 14.34±5.05 µM), and 2e (IC50 = 11.72±0.46 µM) had excellent inhibitory activity at certain concentrations. The data obtained from the molecular docking studies supported inhibitory activity results. This study presents potential leads for the development of antidiabetic and Alzheimer's therapeutics.

Discovery of Novel Cholinesterase Inhibitors Easily Crossing the Blood-Brain Barrier via Structure-Property Relationship Investigation: Methylenedioxy-Cinnamicamide Containing Tertiary Amine Side Chain.

In the present investigation, a series of dimethoxy or methylenedioxy substituted-cinnamamide derivatives containing tertiary amine moiety (N. N-Dimethyl, N, N-diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood-brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC50: 1.52±0.19 μmol/L) and good blood-brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography-mass/mass spectrometry (UPLC-MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72±93.56 ng/g) after dosing 30 min. Its half-life in the serum is 331 min (5.52 h), and the CBrain/CSerum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24 hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs.

Discovering cholinesterase inhibitors from Chinese herbal medicine with deep learning models

Discovering cholinesterase inhibitors from Chinese herbal medicine with deep learning models

Evaluation of Anticholinesterase Activity of the Fungicides Mefentrifluconazole and Pyraclostrobin.

Triazoles are compounds with various biological activities, including fungicidal action. They became popular through cholinesterase studies after the successful synthesis of the dual binding femtomolar triazole inhibitor of acetylcholinesterase (AChE, EC 3.1.1.7) by Sharpless et al. via in situ click chemistry. Here, we evaluate the anticholinesterase effect of the first isopropanol triazole fungicide mefentrifluconazole (Ravystar®), developed to overcome fungus resistance in plant disease management. Mefentrifluconazole is commercially available individually or in a binary fungicidal mixture, i.e., with pyraclostrobin (Ravycare®). Pyraclostrobin is a carbamate that contains a pyrazole ring. Carbamates are known inhibitors of cholinesterases and the carbamate rivastigmine is already in use for the treatment of Alzheimer's disease. We tested the type and potency of anticholinesterase activity of mefentrifluconazole and pyraclostrobin. Mefentrifluconazole reversibly inhibited human AChE and BChE with a seven-fold higher potency toward AChE (Ki = 101 ± 19 μM). Pyraclostrobin (50 μM) inhibited AChE and BChE progressively with rate constants of (t1/2 = 2.1 min; ki = 6.6 × 103 M-1 min-1) and (t1/2 = 1.5 min; ki = 9.2 × 103 M-1 min-1), respectively. A molecular docking study indicated key interactions between the tested fungicides and residues of the lipophilic active site of AChE and BChE. Additionally, the physicochemical properties of the tested fungicides were compared to values for CNS-active drugs to estimate the blood-brain barrier permeability. Our results can be applied in the design of new molecules with a lesser impact on humans and the environment.