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BACKGROUND: Small molecule phytocompounds can potentially ameliorate degenerative changes in cerebral tissues. Thus, the current study aimed to evaluate the neuroprotective efficacy of phytocompounds of methanolic shoots extract of Calligonum polygonoides L. (MSECP) in hypercholesterolemia-associated neurodegenerations. METHODS: Phytochemical screening of the extract was made by LCMS/MS and validated by a repository of the chemical library. The hypercholesterolemia was induced through the intraperitoneal administration of poloxamer-407 with a high-fat diet. The in-silico assessments were accomplished by following the molecular docking, ADME and molecular dynamics. MMPBSA and PCA (Principal Component Analysis) analyzed the molecular dynamics simulations. Consequently, in-vivo studies were examined by lipid metabolism, free radical scavenging capabilities and histopathology of brain tissues (cortex and hippocampus). RESULTS: 22 leading phytocompounds were exhibited in the test extract, as revealed by LCMS/ MS scrutiny. Molecular docking evaluated significant interactions of apigenin triacetate with target proteins (HMGCR (HMG-CoA reductase), (AChE-Acetylcholinesterase) and (BuChE- Butyrylcholinesterase). Molecular dynamics examined the interactions through assessments of the radius of gyration, RSMD, RSMF and SASA at 100 ns, which were further analyzed by MMPBSA (Molecular Mechanics Poisson-Boltzmann) and PCA (Principal Component Analysis). Accordingly, the treatment of test extract caused significant alterations in lipid profile, dyslipidemia indices, antioxidant levels and histopathology of brain tissues. CONCLUSION: It can be concluded that apigenin triacetate is a potent phytoconstituent of MSEPC and can interact with HMGCR, AChE, and BuChE, which resulted in improved hypercholesterolemia along with neuroprotective ameliorations in the cortex and hippocampus.
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In this paper, the natural chalcones: 2'-hydroxy-4,4',6'-trimethoxychalcone (HCH), cardamonin (CA), xanthohumol (XN), isobavachalcone (IBC) and licochalcone A (LIC) are studied using spectroscopic techniques such as UV-vis, fluorescence spectroscopy, scanning electron microscopy (SEM) and single-crystal X-ray diffraction (XRD). For the first time, the spectroscopic and structural features of naturally occurring chalcones with varying numbers and positions of hydroxyl groups in rings A and B were investigated to prove the presence of the aggregation-induced emission enhancement (AIEE) effect. The fluorescence studies were carried out in the aggregate form in a solution and in a solid state. As to the results of spectroscopic analyses conducted in the solvent media, the selected mixtures (CH3OH:H2O and CH3OH:ethylene glycol), as well as the fluorescence quantum yield (ÏF) and SEM, confirmed that two of the tested chalcones (CA and HCH) exhibited effective AIEE behaviour. On the other hand, LIC showed a large fluorescence quantum yield and Stokes shift in the polar solvents and in the solid state. Moreover, all studied compounds were tested for their promising antioxidant activities via the utilisation of 1,1- diphenyl-2-picrylhydrazyl as a free-radical scavenging reagent as well as potential anti-neurodegenerative agents via their ability to act as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. Finally, the results demonstrated that licochalcone A, with the most desirable emission properties, showed the most effective antioxidant (DPPH IC50 29%) and neuroprotective properties (AChE IC50 23.41 ± 0.02 µM, BuChE IC50 42.28 ± 0.06 µM). The substitution pattern and the biological assay findings establish some relation between photophysical properties and biological activity that might apply in designing AIEE molecules with the specified characteristics for biological application.
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Butirilcolinesterasa , Chalconas , Chalconas/farmacología , Chalconas/química , Acetilcolinesterasa/química , Antioxidantes/farmacología , Antioxidantes/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Solventes/químicaRESUMEN
A series of cyclic biguanidine derivatives (E01-E16) was designed, synthesized, characterized by FTIR, NMR, elemental analysis and evaluated as cholinesterase [acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)] inhibitory effects for the treatment of Alzheimer's disease (AD). The cyclic biguanidine derivatives (E01-E16) were obtained as hydrochloride salt from one-pot reaction of 2-cyanoguanidine, p-substitute aniline derivatives and cyclohexanone/4-ethylcyclohexanone in the acidic medium. The crystal structures of compounds E13 and E16 were determined by XRD studies. The in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory assessment of the compounds revealed that compounds showed considerable inhibitory activity. The substitute groups on the phenyl rings have an impact on the inhibitory activity of the compounds. Compound E08, containing an ester group on the phenyl ring, showed the highest inhibitory activity against BuChE (IC50: 97.97 ± 0.13 µM) compared to other compounds. According to the docking result, compound E08 exhibited higher binding affinity (-10.17 kcal/mol) against BuChE than the standard drug tacrine (-7.02 kcal/mol). Compound E08 was orientated towards the active site of the enzyme BuChE.Communicated by Ramaswamy H. Sarma.
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Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Humanos , Inhibidores de la Colinesterasa/química , Butirilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Enfermedad de Alzheimer/tratamiento farmacológicoRESUMEN
Optimization and re-optimization of bioactive molecules using in silico methods have found application in the design of more active ones. Herein, we applied a pharmacophore modeling approach to screen potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) aimed at Alzheimer's disease (AD) treatment. The investigation entails molecular dynamics simulation, docking, pharmacophore modeling, drug-like screening, and binding energy analysis. We prepared a pharmacophore model from approved inhibitors of AChE and BuChE to predict the crucial moieties required for optimum molecular interaction with these proteins. The obtained pharmacophore model, used for database screening via some critical criteria, showed 229 hit molecules. Further analyses showed 42 likely dual inhibitors of AChE/BuChE with drug-like and pharmacokinetics properties the same as the approved cholinesterase inhibitors. Finally, we identified 14 dual molecules with improved potentials over the existing inhibitors and simulated ZINC92385797 bound to human AChE and BuChE structure after noticing that these 14 molecules are similar. The selected compound maintained relative stability at the active sites of both proteins over 120 ns simulation. Our integrated protocols showed the pertinent recipes of anti-AD drug design through the in silico pipeline.
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Acetilcolinesterasa , Enfermedad de Alzheimer , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
Rational modification of known drug candidates to design more potent ones using computational methods has found application in drug design, development, and discovery. Herein, we integrate computational and theoretical methodologies to unveil rivastigmine derivatives as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) for Alzheimer's disease (AD) management. The investigation entails pharmacokinetics screening, density functional theory (DFT) mechanistic study, molecular docking, and molecular dynamics (MD) simulation. We designed over 20 rivastigmine substituents, subject them to some analyses, and identified RL2 with an appreciable blood-brain barrier score and no permeability glycoprotein binding. The compound shows higher acylation energy and a favored binding affinity to the cholinesterase enzymes. RL2 interacts with the AChE and BuChE active sites showing values of -41.1/-39.5â kcal mol-1 while rivastigmine binds with -32.7/-30.7â kcal mol-1 for these enzymes. The study revealed RL2 (4-fluorophenyl rivastigmine) as a potential dual inhibitor for AChE and BuChE towards Alzheimer's disorder management.
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Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Fármacos Neuroprotectores/farmacología , Rivastigmina/farmacología , Enfermedad de Alzheimer/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Teoría Funcional de la Densidad , Humanos , Modelos Moleculares , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Rivastigmina/síntesis química , Rivastigmina/químicaRESUMEN
The identification of dual inhibitors targeting the active sites of the cholinesterase enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), have lately surfaced as a multi-approach towards Alzheimer treatment. More recently, a novel series of 4-N-phenylaminoquinolines was synthesized and evaluated against AChE and BuChE in which one of the compounds displayed appreciable inhibition compared to the standard compound, galantamine. To provide a clearer picture of the inhibition mechanism of this potent compound at the molecular level, computational biomolecular modeling was carried out. The investigation was initiated with the exploration of the chemical properties of the identified compound 11 b and reference drug, galantamine. Density functional theory (DFT) calculations reveal some conceptual parameters that provide information on the stability and reactivity of the compounds as potential inhibitors. To unveil the binding mechanism, energetics and enzyme-ligand interactions, molecular dynamics (MD) simulations of six different systems were executed over a period. Calculated binding free energy values are in the same order with experimental IC50 data. Identification of the main residues driving optimum binding of the active compound 11 b to the binding region of both AChE and BuChE showed Trp81 and Trp110 as the most important, respectively. It was proposed that the studied compound could serve as a dual inhibitor for AChE and BuChE, therefore, would potentially be a promising moiety in a multi-target approach for the treatment of Alzheimer's disorder.Communicated by Ramaswamy H. Sarma.
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Enfermedad de Alzheimer , Butirilcolinesterasa , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alzheimer's disease (AD), sertaconazole was identified through a combination of structure-based virtual screening followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may benefit the treatment of late stage AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Imidazoles/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Isoindoles/farmacología , Tiofenos/farmacología , Enfermedad de Alzheimer/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Imidazoles/síntesis química , Imidazoles/química , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Isoindoles/síntesis química , Isoindoles/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
Alzheimer disease (AD) is characterized by a low level of acetylcholine, beta-amyloid (Aβ) aggregation and oxidative stress. Donepezil is the core medicine used for the treatment of AD. Various structural modifications of donepezil have been carried out. Benzylpiperidine part of donepezil has been replaced with benzylpyridine, pyridyl methylpiperidine, benzylpiperazine, pyrimidyl piperazine. These derived molecules showed promising activities as anti-Alzheimer agents. Replacement of indanone part by other heterocyclic rings such as pyridine resulted in the formation of compounds which exhibited monoamine oxidase (MAO) as well as acetylcholinesterase (AChE) inhibition. Propargylamine containing derivatives displayed AChE as well as MAO inhibition properties. Attachment of donepezil with natural compounds like ferulic acid, flavonoids, and curcumin showed antioxidant activities in addition to inhibition of the AChE. Benzylpiperidine and benzylpiperazine have also been combined with condensed heterocyclic rings and these compounds displayed promising anti-Alzheimer properties. This review highlights the important structural modifications of donepezil and their influence on biological activities as anti-Alzheimer agents.
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BACKGROUND: Insulin resistance causes decreased uptake of glucose which promotes the susceptibility of type 2 associated neurological impairments. METHODS: The study was aimed to evaluate the inhibition potential of the ethanolic extract of Prosopis cineraria (EPC) pods against DPP-4 and cholinesterase enzymes by in-vitro, in-vivo and in-silico assessments. The present study consists of in vivo studies on a diabetes-induced rat model by HOMA (Homeostasis model assessment) and related parameters, in vitro studies through the DPP-4 enzyme assay and cholinesterase assays using Ellman's reaction. The in-silico studies were conducted by the molecular docking of Cinerin C with targeted enzymes. The phytochemical characterization of the extract was demonstrated through LCMS studies. The antioxidant studies on the extract were performed by FRAP and TEAC assays. RESULTS: The extract showed 64.8% maximum inhibition of DPP-4, 34.91% inhibition of AChE and 74.35% inhibition of BuChE. The antioxidant capacity of the extract was observed to be 847.81±16.25µM Fe2+ equivalent in the FRAP assay and 0.40 ± 0.08 mmol/l of Trolox equivalent in the TEAC assay. The in vivo study showed competent glycaemic control against significant HOMA IR (1.5), HOMA % ß (26.5) and HOMA % S (68.8) as well as pancreatic cell mass proliferation. The insilico analysis also revealed positive interactions of Cinerin C with targeted enzymes (DPP4 and cholinesterase). CONCLUSION: It can be concluded that the phytoconstituents of Prosopis cineraria pod extract can be significantly considered in neuropharmacology to resolve insulin resistance-induced neurological complications as it showed inhibition against DPP-4, AChE and BuChE target enzymes.
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Inhibidores de la Colinesterasa/farmacología , Diabetes Mellitus Experimental/complicaciones , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Extractos Vegetales/farmacología , Prosopis , Animales , Antioxidantes/química , Antioxidantes/farmacología , Inhibidores de la Colinesterasa/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/patología , Etanol/química , Simulación del Acoplamiento Molecular , Enfermedades del Sistema Nervioso/enzimología , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/patología , Páncreas/efectos de los fármacos , Páncreas/patología , Fitoquímicos/química , Fitoquímicos/farmacología , Extractos Vegetales/química , RatasRESUMEN
Chalcones and chalcone epoxides are important synthetic intermediates in organic and medicinal chemistry. Chalcones possess a broad spectrum of biological activities; however, 1,3-diphenyl-2-propenone or chalcone has not been given the attention it deserve as its substituted derivatives. In this study, the inhibition effects of chalcone and its epoxidated derivative chalcone epoxide against human carbonic anhydrase isozymes I and II (hCA I and hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were evaluated. The results obtained showed that both compounds exhibited potent inhibitory activity, with IC50 values less than 10 µM. IC 50 values in the submicromolar (hCA I and hCA II) to low micromolar range (AChE and BuChE) were observed for both compounds. The mechanism of inhibition and the inhibitory constants ( K i values) for each compound were also determined. Furthermore, chalcone epoxide was docked within the active sites of hCA I, hCA II, AChE, and BuChE to explore its binding mode with the enzymes.
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Acetilcolinesterasa , Butirilcolinesterasa/química , Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/química , Calcógenos/química , Inhibidores de la Colinesterasa/química , Acetilcolinesterasa/química , Compuestos Epoxi/química , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/química , HumanosRESUMEN
There is a dire need for new treatments for Alzheimer's disease (AD). Principal drugs have reached maturity, and the number of people affected by AD is growing at a rapid rate. After years of research and many clinical trials, only symptomatic treatments are available. An effective disease-modifying drug for AD needs to be discovered. The research presented in this paper aims to facilitate in the discovery of new potential targets that could help in the ongoing AD research. Aryl methanesulfonate derivatives were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. IC50 values between 0.660 and 3.397 µM against AChE and 0.885 and 2.596 µM against BuChE were obtained.
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Inhibidores de la Colinesterasa/farmacología , Descubrimiento de Drogas , Mesilatos/farmacología , Nootrópicos/farmacología , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Animales , Butirilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Ácido Ditionitrobenzoico/química , Electrophorus , Proteínas de Peces/antagonistas & inhibidores , Proteínas de Peces/metabolismo , Caballos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Concentración Osmolar , Espectrofotometría , Reactivos de Sulfhidrilo/químicaRESUMEN
Organophosphate compounds (OPCs) are commonly used as pesticides and were developed as nerve agents for chemical warfare. Exposure to OPCs results in toxicity due to their covalent binding and inhibition of acetylcholinesterase (AChE). Treatment for toxicity due to OPC exposure has been largely focused on the reactivation of AChE by oxime-based compounds via direct nucleophilic attack on the phosphorous center. However, due to the disadvantages to existing oxime-based reactivators for treatment of OPC poisoning, we considered non-oxime mechanisms of reactivation. A high throughput screen of compound libraries was performed to discover previously unidentified reactivation compounds, followed by studies on their analogs. In the process, we discovered multiple non-oxime classes of compounds, the most robust of which we have already reported [1]. Herein, we report other classes of compounds we identified in our screen that are efficient at reactivation. During biochemical characterization, we also found some compounds with other activities that may inspire novel therapeutic approaches to OPC toxicity. Specifically, we found compounds that [1] increase the rate of substrate hydrolysis by AChE and, [2] protect the enzyme from inhibition by OPC. Further, we discovered that a subset of reactivator compounds recover activity from both AChE and the related enzyme butyrylcholinesterase (BuChE). We now report these compounds, their activities and discuss how each relates to therapeutic approaches that would provide alternatives to traditional oxime-based reactivation.
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Reactivadores de la Colinesterasa/uso terapéutico , Intoxicación por Organofosfatos/tratamiento farmacológico , Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/toxicidad , Donepezilo , Ensayos Analíticos de Alto Rendimiento , Humanos , Hidrólisis , Imidazoles/farmacología , Indanos/química , Indanos/farmacología , Cinética , Oximas/uso terapéutico , Piperazinas/farmacología , Piperidinas/química , Piperidinas/farmacología , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
In our endeavor towards the development of potent multi-target ligands for the treatment of Alzheimer's disease, miconazole was identified to show BuChE-IDO1 dual-target inhibitory effects. Morris water maze test indicated that miconazole obviously ameliorated the cognitive function impaired by scopolamine. Furthermore, it showed good safety in primary hepatotoxicity evaluation. Based on these results, we designed, synthesized, and evaluated a series of miconazole derivatives as BuChE-IDO1 dual-target inhibitors. Out of the 12 compounds, 5i and 5j exhibited the best potency in enzymatic evaluation, thus were selected for subsequent behavioral study, in which the two compounds exerted much improved effect than tacrine. Meanwhile, 5i and 5j displayed no apparent hepatotoxicity. The results suggest that miconazole analogue offers an attractive starting point for further development of new BuChE-IDO1 dual-target inhibitors against Alzheimer's disease.
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Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Miconazol/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Relación Dosis-Respuesta a Droga , Electrophorus , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Caballos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Ligandos , Miconazol/síntesis química , Miconazol/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC50 values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC50, 6c, 3.3 µM; 6f, 0.97 µM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds 6c and 6f exhibited negligible toxicity, which made them suitable for the further study of AD in vivo.
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Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Pirazolonas/farmacología , Pirimidinonas/farmacología , Rivastigmina/farmacología , Enfermedad de Alzheimer/enzimología , Péptidos beta-Amiloides/química , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Línea Celular Tumoral , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Ligandos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Estrés Oxidativo , Fragmentos de Péptidos/química , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Agregación Patológica de Proteínas/prevención & control , Conformación Proteica , Pirazolonas/síntesis química , Pirazolonas/química , Pirimidinonas/síntesis química , Pirimidinonas/química , Rivastigmina/síntesis química , Rivastigmina/químicaRESUMEN
BACKGROUND: Oxidative stress affects women fertility and influences on the sperm quality by alterating activities of cholinesterases, a molecular marker of stress-related infertility. The aim of the present study was to investigate the role of acetyl-cholinesterase (AChE), butyrylcholinesterase (BuChE) activities and phenotypes in patients with unexplained infertility (idiopathic). It's possible association with inflammation marker C-reactive protein (CRP) and other oxidative stress markers, i.e. before and after intra uterine insemination (IUI). METHODS: In this study, blood samples of 60 patients with unexplained infertility were collected the day before and 24 hr after IUI (between 8 AM and 9 AM after the overnight fasting) and activities of BuChE, AChE, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GpX) and serum levels of thiol proteins (TP), C-reactive protein (CRP), total antioxidant capacity (TAC) were measured. Statistical significance was assumed at p<0.05. RESULTS: Before IUI, there was a significant (p=0.048) positive correlation between BuChE activity and plasma TAC and a significant difference in the CAT activity between various BuChE (UU and non-UU) phenotypes. However, after IUI, a significant negative correlation between the AChE activity and BuChE activity was found (p=0.045) and the level of RBC AChE activity was significantly reduced (382.4± 163.19 vs. 586.7±384 IU/grHb, p=0.025). Meanwhile, after IUI, the activities of SOD (1568±847.5 IU/grHb vs. 1126±229.3, p=0.031) and CAT (310±53.4 IU/grHb vs. 338±73, p=0.025) were increased. CONCLUSION: This study suggests that decline in cholinesterases activities may be responsible for stimulation of oxidative stress and inflammation and reduction in fertility rates by IUI.
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In the present study, some 9-aminoacridine derivatives have been synthesized by condensation of 9-aminoacridine with substituted phenacyl, benzoyl, and benzyl halides (RM1-RM6). Compounds were investigated for acetylcholinesterase and butyrylcholinesterase inhibition potential, considering these enzymes playing a key role in Alzheimer's disease. All derivatives showed better inhibition of enzymes than the standard galantamine, whereas except RM4, all exhibit better results than tacrine, a well-known acridine derivative used for the treatment of Alzheimer's disease.
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Enfermedad de Alzheimer/enzimología , Aminacrina/síntesis química , Inhibidores de la Colinesterasa/síntesis química , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Técnicas In VitroRESUMEN
There is some evidence indicating lipid peroxidation can affect progression of atherosclerosis, cardiovascular diseases (CVDs) and glomerulonephritis in systemic lupus erythematosus (SLE) patients. Human butyrylcholinesterase (BuChE) and paraoxonase-1 (PON1) are two major bioscavenger enzymes that are associated with inflammation, oxidative stress and lipid metabolism. Hyperlipidemia, increase in lipid oxidation reactions and defects in antioxidant status may lead to increased oxidative stress and high frequency of CVDs in SLE. It has also been suggested that deficiency in the function of the antioxidant system and an increase in reactive oxygen release (ROS) may play an important role in the pathogenesis of SLE. This study is the first investigation to examine the association of BuChE phenotypes, PON1 (L55M; PON-55-M) polymorphism, the levels of malondialdehyde (MDA), neopterin, lipid-lipoprotein and activities of BuChE and arylesterase activity (ARE) of PON with severity of SLE. The present case-control study consisted of 109 SLE patients and 101 gender- and age-matched, unrelated healthy control subjects from the population of west Iran. We found that the PON-55-M allele and BuChE non-UU act synergistically to increase the risk of SLE by 2.5 times (1.03-6.7, p = 0.044). There was a significant negative correlation between severity of SLE with serum BuChE activity (R = -0.31, p < 0.001) and positive correlation with serum neopterin level. The SLE patients with the PON-55-M (M/L + M/M) allele or with BuChE non-UU phenotype had significantly lower serum ARE and BuChE activities than those with PON-55-L/L or BuChE-UU phenotypes, respectively. In addition, their serum levels of MDA, neopterin and LDL-C were significantly elevated, suggesting that these individuals are more susceptible to CVD. However, further studies are needed to shed more light on the contribution of the M allele of PON1 and non-UU phenotypes of BuChE in the development of SLE in different ethnicities.
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Arildialquilfosfatasa/genética , Butirilcolinesterasa/sangre , LDL-Colesterol/sangre , Peroxidación de Lípido , Lupus Eritematoso Sistémico/enzimología , Lupus Eritematoso Sistémico/genética , Estrés Oxidativo , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Irán , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/diagnóstico , Masculino , Malondialdehído/sangre , Persona de Mediana Edad , Neopterin/sangre , Fenotipo , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Given the fundamentally multifactorial character of Alzheimer's disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid ß fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC50=90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction.