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1.
Future Med Chem ; 16(7): 623-645, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38470247

RESUMO

Background: In Alzheimer's disease, butyrylcholinesterase (BuChE) activity gradually increases, while acetylcholinesterase (AChE) activity decreases or remains unchanged. Dual inhibitors have important roles in regulation of synaptic acetylcholine levels and progression of Alzheimer's disease. Methods: 1-(Thiomorpholin-4-ylmethyl)/benzyl-5-trifluoromethoxy-2-indolinones (6-7) were synthesized. AChE and BuChE inhibitory effects were investigated with Ellman's method. Molecular docking studies were performed for analyzing the possible binding interactions at active sites. Results: Compound 6g was the strongest inhibitor against both AChE (Ki = 0.35 µM) and BuChE (Ki = 0.53 µM). It showed higher inhibitory effects than both donepezil and galantamine. Moreover, compound 7m had a higher inhibitory effect than galantamine and the effect was comparable to that of donepezil against both AChE (Ki = 0.69 µM) and BuChE (Ki = 0.95 µM). Conclusion: The benzyl substitution compared with 1-(thiomorpholin-4-ylmethyl) group significantly increased both AChE and BuChE inhibitory effects.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Humanos , Inibidores da Colinesterase/farmacologia , Donepezila , Galantamina , Simulação de Acoplamento Molecular , Butirilcolinesterase , Acetilcolinesterase , Doença de Alzheimer/tratamento farmacológico , Oxindóis
2.
Chem Biol Drug Des ; 103(3): e14506, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38480508

RESUMO

A series of new betulin, lupeol, erythrodiol, and oleanolic acid phosphoryloxy- and furoyloxy-derivatives has been synthesized and their structure was confirmed by NMR spectroscopy. Synthesized compounds were subjected to Ellman's assays to determine their ability to inhibit the enzymes AChE and BChE. Among them, diethoxyphosphoryloxy-oleanolic acid inhibited BChE with a value of 99%, thereby acting as a mixed-type inhibitor holding very low Ki values of Ki = 6.59 nM and Ki ' = 1.97 nM, respectively.


Assuntos
Ácido Oleanólico , Triterpenos , Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Acetilcolinesterase/metabolismo , Ácido Oleanólico/farmacologia , Triterpenos/farmacologia , Triterpenos/química , Relação Estrutura-Atividade
3.
Molecules ; 29(5)2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38474561

RESUMO

Berberis species have a long history of use in traditional Chinese medicine, Ayurvedic medicine, and Western herbal medicine. The aim of this study was the quantification of the main isoquinoline alkaloids in extracts obtained from various Berberis species by HPLC, in vitro and in silico determination of anti-cholinesterase activity, and in vitro and in vivo investigations of the cytotoxic activity of the investigated plant extracts and alkaloid standards. In particular, Berberis species whose activity had not been previously investigated were selected for the study. In the most investigated Berberis extracts, a high content of berberine and palmatine was determined. Alkaloid standards and most of the investigated plant extracts exhibit significant anti-cholinesterase activity. Molecular docking results confirmed that both alkaloids are more favourable for forming complexes with acetylcholinesterase compared to butyrylcholinesterase. The kinetic results obtained by HPLC-DAD indicated that berberine noncompetitively inhibited acetylcholinesterase, while butyrylcholinesterase was inhibited in a mixed mode. In turn, palmatine exhibited a mixed inhibition of acetylcholinesterase. The cytotoxic activity of berberine and palmatine standards and plant extracts were investigated against the human melanoma cell line (A375). The highest cytotoxicity was determined for extract obtained from Berberis pruinosa cortex. The cytotoxic properties of the extract were also determined in the in vivo investigations using the Danio rerio larvae xenograft model. The obtained results confirmed a significant effect of the Berberis pruinosa cortex extract on the number of cancer cells in a living organism. Our results showed that extracts obtained from Berberis species, especially the Berberis pruinosa cortex extract, can be recommended for further in vivo experiments in order to confirm the possibility of their application in the treatment of neurodegenerative diseases and human melanoma.


Assuntos
Alcaloides , Antineoplásicos , Berberina , Berberis , Melanoma , Humanos , Berberina/farmacologia , Acetilcolinesterase , Butirilcolinesterase , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento Molecular , Alcaloides/farmacologia , Extratos Vegetais/farmacologia
4.
Can J Anaesth ; 71(3): 378-389, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38429621

RESUMO

PURPOSE: There is evidence that cholinergic imbalance secondary to neuroinflammation plays a role in the pathophysiology of sepsis-associated encephalopathy (SAE). Blood acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities have been proposed as surrogate parameters for the cholinergic function of the central nervous system. Viral sepsis is associated with systemic inflammation and BChE has been reported to be of prognostic value in a small cohort of COVID-19 patients. Nevertheless, the prognostic value of AChE in patients with viral sepsis remains unclear. METHODS: We investigated the role of AChE and BChE activities as prognostic biomarkers of SAE and mortality in patients with viral vs nonviral sepsis enrolled in two prospective cohort studies. We quantified the AChE and BChE activities in whole blood of patients at two time points in the acute phase of viral sepsis (N = 108) and compared them with the activities in patients with nonviral sepsis (N = 117) and healthy volunteers (N = 81). Patients were observed until discharge from the intensive care unit (ICU). RESULTS: Three days after sepsis onset, the median [interquartile range] levels of AChE and BChE were reduced in both patients with viral sepsis (AChE, 5,105 [4,010-6,250] U·L-1; BChE, 1,943 [1,393-2,468] U·L-1) and nonviral sepsis (AChE, 4,424 [3,630-5,055] U·L-1; BChE, 1,095 [834-1,526] U·L-1) compared with healthy volunteers (AChE, 6,693 [5,401-8,020] U·L-1; BChE, 2,645 [2,198-3,478] U·L-1). Patients with viral sepsis with SAE during their ICU stay had lower AChE activity three days after sepsis onset than patients without SAE (4,249 [3,798-5,351] U·L-1 vs 5,544 [4,124-6,461] U·L-1). Butyrylcholinesterase activity seven days after sepsis onset was lower in patients with viral sepsis who died in the ICU than in surviving patients (1,427 [865-2,181] U·L-1 vs 2,122 [1,571-2,787] U·L-1). CONCLUSION: Cholinesterase activities may be relevant prognostic markers for the occurrence of SAE and mortality in the ICU in patients with viral sepsis. STUDY REGISTRATION: This study constitutes an analysis of data from the ongoing studies ICROS (NCT03620409, first submitted 15 May 2018) and ICROVID (DRKS00024162, first submitted 9 February 2021).


RéSUMé: OBJECTIF: Certaines données probantes soutiennent que le déséquilibre cholinergique secondaire à la neuroinflammation joue un rôle dans la physiopathologie de l'encéphalopathie associée au sepsis (EAS). Les activités de l'acétylcholinestérase (AChE) et de la butyrylcholinestérase (BChE) sanguines ont été proposées comme paramètres de substitution de la fonction cholinergique du système nerveux central. Le sepsis viral est associé à une inflammation systémique et il a été rapporté que la BChE possédait une valeur pronostique dans une petite cohorte atteinte de COVID-19. Néanmoins, la valeur pronostique de l'AChE chez les patient·es atteint·es de sepsis viral reste incertaine. MéTHODE: Nous avons étudié le rôle des activités de l'AChE et de la BChE en tant que biomarqueurs pronostiques de l'EAS et de la mortalité chez les patient·es atteint·es de sepsis viral vs non viral recruté·es dans deux études de cohorte prospectives. Nous avons quantifié les activités de l'AChE et de la BChE dans le sang total de patient·es à deux moments de la phase aiguë du sepsis viral (N = 108) et les avons comparées aux activités chez les patient·es atteint·es de sepsis non viral (N = 117) et chez des volontaires sain·es (N = 81). Les patient·es ont été observé·es jusqu'à leur sortie de l'unité de soins intensifs (USI). RéSULTATS: Trois jours après l'apparition du sepsis, les taux médians [écart interquartile] d'AChE et BChE étaient réduits tant chez la patientèle atteinte de sepsis viral (AChE, 5105 [4010­6250] U·L−1; BChE, 1943 [1393­2468] U·L−1) et de sepsis non viral (AChE, 4424 [3630­5055] U·L−1; BChE, 1095 [834­1526] U·L−1) par rapport aux volontaires sain·es (AChE, 6693 [5401­8020] U·L−1; BChE, 2645 [2198­3478] U·L−1). Les patient·es atteint·es de sepsis viral avec EAS pendant leur séjour aux soins intensifs avaient une activité AChE plus faible trois jours après l'apparition du sepsis que les personnes sans EAS (4249 [3798­5351] U·L−1 vs 5544 [4124­6461] U·L−1). L'activité de la butyrylcholinestérase sept jours après l'apparition du sepsis était plus faible chez les patient·es atteint·es de sepsis viral décédé·es à l'USI que chez les personnes ayant survécu (1427 [865­2181] U·L-1 vs 2122 [1571­2787] U·L-1). CONCLUSION: Les activités des cholinestérases pourraient constituer des marqueurs pronostiques pertinents pour la survenue d'EAS et la mortalité en soins intensifs chez la patientèle atteinte de sepsis viral. ENREGISTREMENT DE L'éTUDE: Cette étude constitue une analyse des données des études en cours ICROS (NCT03620409, première soumission le 15 mai 2018) et ICROVID (DRKS00024162, première soumission le 9 février 2021).


Assuntos
Encefalopatia Associada a Sepse , Sepse , Humanos , Butirilcolinesterase , Acetilcolinesterase , Estudos Prospectivos , Sepse/complicações , Colinérgicos , Inibidores da Colinesterase
5.
ACS Chem Neurosci ; 15(6): 1135-1156, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38453668

RESUMO

For the potential therapy of Alzheimer's disease (AD), butyrylcholinesterase (BChE) has gradually gained worldwide interest in the progression of AD. This study used a pharmacophore-based virtual screening (VS) approach to identify Z32439948 as a new BChE inhibitor. Aiding by molecular docking and molecular dynamics, essential binding information was disclosed. Specifically, a subpocket was found and structure-guided design of a series of novel compounds was conducted. Derivatives were evaluated in vitro for cholinesterase inhibition and physicochemical properties (BBB, log P, and solubility). The investigation involved docking, molecular dynamics, enzyme kinetics, and surface plasmon resonance as well. The study highlighted compounds 27a (hBChE IC50 = 0.078 ± 0.03 µM) and (R)-37a (hBChE IC50 = 0.005 ± 0.001 µM) as the top-ranked BChE inhibitors. These compounds showed anti-inflammatory activity and no apparent cytotoxicity against the human neuroblastoma (SH-SY5Y) and mouse microglia (BV2) cell lines. The most active compounds exhibited the ability to improve cognition in both scopolamine- and Aß1-42 peptide-induced cognitive deficit models. They can be promising lead compounds with potential implications for treating the late stage of AD.


Assuntos
Doença de Alzheimer , Neuroblastoma , Humanos , Camundongos , Animais , Butirilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Estrutura Molecular , Simulação de Acoplamento Molecular , Inibidores da Colinesterase/química , Linhagem Celular Tumoral , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 268: 116289, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38452730

RESUMO

Most recently, worldwide interest in butyrylcholinesterase (BChE) as a potential target for treating Alzheimer's disease (AD) has increased. In this study, the previously obtained selective BChE inhibitors with benzimidazole-oxadiazole scaffold were further structurally modified to increase their aqueous solubility and pharmacokinetic (PK) characteristics. S16-1029 showed improved solubility (3280 µM, upgraded by 14 times) and PK parameters, including plasma exposure (AUC0-inf = 1729.95 ng/mL*h, upgraded by 2.6 times) and oral bioavailability (Fpo = 48.18%, upgraded by 2 times). S16-1029 also displayed weak or no inhibition against Cytochrome P450 (CYP450) and human ether a-go-go related gene (hERG) potassium channel. In vivo experiments on tissue distribution revealed that S16-1029 could cross the blood-brain barrier (BBB) and reach the central nervous system (CNS). In vivo cognitive improvement efficacy and good in vitro target inhibitory activity (eqBChE IC50 = 11.35 ± 4.84 nM, hBChE IC50 = 48.1 ± 11.4 nM) were also assured. The neuroprotective effects against several AD pathology characteristics allowed S16-1029 to successfully protect the CNS of progressed AD patients. According to the findings of this study, altering molecular planarity might be a viable strategy for improving the drug-like property of CNS-treating drugs.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Humanos , Butirilcolinesterase/metabolismo , Solubilidade , Inibidores da Colinesterase/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Cognição , Acetilcolinesterase/metabolismo , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Estrutura Molecular
7.
Arch Toxicol ; 98(4): 1135-1149, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38446233

RESUMO

A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 µM and HssBChE IC50 = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.


Assuntos
Reativadores da Colinesterase , Compostos de Pralidoxima , Taurina/análogos & derivados , Ratos , Humanos , Animais , Reativadores da Colinesterase/farmacologia , Trimedoxima/farmacologia , Butirilcolinesterase , Acetilcolinesterase , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Antídotos/farmacologia , Inibidores da Colinesterase/toxicidade , Fósforo , Oxigênio
8.
Drug Dev Res ; 85(2): e22161, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38445811

RESUMO

In this study, a series of novel benzyloxybenzene substituted (S)-α-amino acid methyl esters and their amide derivatives were synthesized and evaluated for their inhibitory actions against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidase A (MAO-A), and monoamine oxidase B (MAO-B). The synthetic strategy was based on starting from benzyl bromide (5) and 4-hydroxybenzaldehyde (6). The reaction of 5 and 6 in the presence of K2 CO3 gave benzyloxybenzaldehyde 7. Benzyloxybenzene substituted (S)-α-amino acid methyl esters 11, 12, 13, (±)-19, and (±)-20 were obtained from the reaction of  L-amino acid methyl esters with benzyloxybenzaldehyde (7) followed by in situ reduction with NaBH4 . The reaction of (S)-11, (S)-12, 13, (±)-19, and (±)-20 with excess ammonia gave amides (S)-14, (S)-15, 16, (±)-21, and (±)-22. The in vitro inhibitory activities of compounds against MAO-A, MAO-B, AChE, and BChE were investigated. Within the α-amino acid methyl ester series, 13 (21.32 ± 0.338 µM) showed selectivity by inhibiting the MAO-B better than MAO-A. 13 emerged as the most active member of this series, exhibiting a 12-fold selectivity for MAO-B. 14 (4.501 ± 0.295 µM) demonstrated a pronounced selectivity for MAO-A over MAO-B, with a selectivity ratio of 110-fold. In addition, it was determined that compound 15 (95.65 ± 3.09 µM) had high selectivity for BChE inhibition. 21 was demonstrated the most potent inhibition (18.36 ± 1.36 µM) against AChE.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , Amidas/farmacologia , Aminoácidos/farmacologia , Ésteres , Monoaminoxidase
9.
Methods Appl Fluoresc ; 12(2)2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38428023

RESUMO

Forsythoside E is one secondary metabolite ofForsythia suspensa(Thunb.) Vahl. In the study, the interactions between forsythoside E and two types of cholinesterases, acetylcholinesterase and butyrylcholinesterase were investigated in the different conditions. Forsythoside E increased the fluorescence intensity of acetylcholinesterase but quenched the fluorescence of butyrylcholinesterase. Aß25-35used in the study may not form complexes with cholinesterases, and did not affect the interaction between forsythoside E and cholinesterases. The charged quaternary group of AsCh interacted with the 'anionic' subsite in acetylcholinesterase, which did not affect the interaction between forsythoside E and acetylcholinesterase. The enhancement rate of forsythoside E to acetylcholinesterase fluorescence from high to low was acid solution (pH 6.4), neutral solution (pH 7.4) and alkaline solution (pH 8.0), while the reduction rate of forsythoside E to butyrylcholinesterase fluorescence was in reverse order. Metal ions may interact with cholinesterases, and increased the effects of forsythoside E to cholinesterases fluorescence, in order that Fe3+was the highest, followed by Cu2+, and Mg2+. A forsythoside E-butyrylcholinesterase complex at stoichiometric ratio of 1:1 was spontaneously formed, and the static quenching was the main quenching mode in the process of forsythoside E binding with butyrylcholinesterase. TheKvalues of two complexes were pretty much the same, suggesting that the interaction between cholinesterases and forsythoside E was almost unaffected by acid-base environment and metal ions. Thennumbers of two cholinesterases approximately equaled to one, indicating that there was only one site on each cholinesterase applicable for forsythoside E to bind to.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Fluorescência , Íons
10.
BMC Neurol ; 24(1): 80, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38424490

RESUMO

BACKGROUND AND OBJECTIVES: Postoperative delirium is a frequent and severe complication after cardiac surgery. Activity of butyrylcholinesterase (BChE) has been discussed controversially regarding a possible role in its development. This study aimed to investigate the relevance of BChE activity as a biomarker for postoperative delirium after cardiac surgery or percutaneous valve replacement. METHODS: A total of 237 patients who received elective cardiothoracic surgery or percutaneous valve replacement at a tertiary care centre were admitted preoperatively. These patients were tested with the Montreal Cognitive Assessment investigating cognitive deficits, and assessed for postoperative delirium twice daily for three days via the 3D-CAM or the CAM-ICU, depending on their level of consciousness. BChE activity was measured at three defined time points before and after surgery. RESULTS: Postoperative delirium occurred in 39.7% of patients (n = 94). Univariate analysis showed an association of pre- and postoperative BChE activity with its occurrence (p = 0.037, p = 0.001). There was no association of postoperative delirium and the decline in BChE activity (pre- to postoperative, p = 0.327). Multivariable analysis including either preoperative or postoperative BChE activity as well as age, MoCA, type 2 diabetes mellitus, coronary heart disease, type of surgery and intraoperative administration of red-cell concentrates was performed. Neither preoperative nor postoperative BChE activity was independently associated with the occurrence of postoperative delirium (p = 0.086, p = 0.484). Preoperative BChE activity was lower in older patients (B = -12.38 (95% CI: -21.94 to -2.83), p = 0.011), and in those with a history of stroke (B = -516.173 (95% CI: -893.927 to -138.420), p = 0.008) or alcohol abuse (B = -451.47 (95% CI: -868.38 to -34.55), p = 0.034). Lower postoperative BChE activity was independently associated with longer procedures (B = -461.90 (95% CI: -166.34 to -757.46), p = 0.002), use of cardiopulmonary bypass (B = -262.04 (95% CI: -485.68 to -38.39), p = 0.022), the number of administered red cell-concentrates (B = -40.99 (95% CI: -67.86 to -14.12), p = 0.003) and older age (B = -9.35 (95% CI: -16.04 to -2.66), p = 0.006). CONCLUSION: BChE activity is not independently associated with the occurrence of postoperative delirium. Preoperative BChE values are related to patients' morbidity and vulnerability, while postoperative activities reflect the severity, length and complications of surgery.


Assuntos
Delírio , Diabetes Mellitus Tipo 2 , Delírio do Despertar , Idoso , Humanos , Butirilcolinesterase , Estudos de Coortes , Delírio/epidemiologia , Delírio/etiologia , Diabetes Mellitus Tipo 2/complicações , Delírio do Despertar/complicações , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Fatores de Risco
11.
Aquat Toxicol ; 268: 106868, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38387248

RESUMO

Worldwide production of alkyl phenols and ethoxylated alkyl phenols is high due to their broad industrial uses. It has been widely documented that they are endocrine disruptors, and it has been suggested that they could exert neurotoxic effects. However, a lack of information about the neurotoxic effects of APs and APEs prevails. In this study, the bisphenol A (BPA), 4-nonylphenol (NP), and 3­tert-butylphenol (tertBP) effects on brain and spinal cord of Nile tilapia exposed to environmental concentrations were evaluated by assessing acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and carboxylesterases (CES) activities, and γ-aminobutyric acid (GABA) levels and their effects were evaluated by molecular docking. BPA and NP, tertBP behave as agonists and antagonists of AChE, BuChE, CES, and GABA, with notable differences among organs. However, none of these compounds or their metabolites interact with the enzymes' catalytic triad, suggesting an indirect alteration of enzymatic activities. While inhibiting these enzymes stand out hydrophobic interactions with the peripheral anion site, contacts with the inner face of the active site and blocking the mouth of the gorge of the active site, and steric hindrance in the enzyme pocket of glutamate decarboxylase (GAD). In contrast, inductions probably are by homotropic pseudo-cooperative phenomenon, where APEs behave as anchors favoring the active site to remain open and interactions that confer a conservative stabilization of the regulatory domain. Although the results of this study are complex, with notable differences between organs and toxicants, they are some of the first evidence of the neurotoxicity of alkylphenols and their ethoxylated derivatives.


Assuntos
Ciclídeos , Hominidae , Poluentes Químicos da Água , Animais , Butirilcolinesterase/metabolismo , Ciclídeos/metabolismo , Fenol , Acetilcolinesterase/metabolismo , Simulação de Acoplamento Molecular , Poluentes Químicos da Água/toxicidade , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Hominidae/metabolismo , Ácido gama-Aminobutírico
12.
Drug Dev Res ; 85(1): e22146, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38349270

RESUMO

Sialic acid (SA) serves a critical role in neuronal repair and cognitive functions. SA is a nine-carbon carboxylated sugar with a glycoconjugate cap that acts as a ligand and surface decoration with SA facilitates delivery to the target site. The present research aimed to develop SA surface modified AA nanostructured lipid carrier (NLCs) with carbodiimide conjugation method. Sterylamine, poloxamer 188 and tween 80 were used as surfactants and several characterization studies including, differential scanning calorimetry, fourier transform infrared spectroscopy and x-ray photon spectroscopy were analyzed. Further, in vitro, neuroprotective efficiency was evaluated in SH-SY5Y cells and hCMEC/D3 cells and found significant potential effects with the treatments of developed NLCs. Pharmacodynamics studies were also assessed in beta-amyloid-injected rats following quantification of Alzheimer's disease (AD) hallmarks like, Aß(1-42), tau-protein, glycogen synthase kinase-3ß levels, interleukin-6 and tumor necrosis factor-α for neuroinflammatory responses. Characterization studies revealed the conjugation on developed NLCs. The in vitro and in vivo results showed significant effects of SA decorated NLCs in reversing the damage by toxicant which was further characterized by the levels of neurotransmitters like acetylcholinesterase, butyrylcholinesterase. The results revealed significant (p < .05) refurbishment of cholinergic functions after 28 days of treatment of developed NLCs. These preclinical findings support the use of SA as a ligand to deliver the AA at targeted site as well as to mitigate the cognitive deficits in AD.


Assuntos
Doença de Alzheimer , Neuroblastoma , Triterpenos Pentacíclicos , Humanos , Animais , Ratos , Ácido N-Acetilneuramínico , Doença de Alzheimer/tratamento farmacológico , Acetilcolinesterase , Butirilcolinesterase , Ligantes , Cognição
13.
ACS Chem Neurosci ; 15(5): 955-971, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38372253

RESUMO

Alzheimer's disease (AD) is a neurodegenerative form of dementia characterized by the loss of synapses and a progressive decline in cognitive abilities. Among current treatments for AD, acetylcholinesterase (AChE) inhibitors have efficacy limited to symptom relief, with significant side effects and poor compliance. Pharmacological agents that modulate the activity of type-2 cannabinoid receptors (CB2R) of the endocannabinoid system by activating or blocking them have also been shown to be effective against neuroinflammation. Herein, we describe the design, synthesis, and pharmacological effects in vitro and in vivo of dual-acting compounds that inhibit AChE and butyrylcholinesterase (BChE) and target CB2R. Within the investigated series, compound 4g proved to be the most promising. It achieved IC50 values in the low micromolar to submicromolar range against both human cholinesterase isoforms while antagonizing CB2R with Ki of 31 nM. Interestingly, 4g showed neuroprotective effects on the SH-SY5Y cell line thanks to its ability to prevent oxidative stress-induced cell toxicity and reverse scopolamine-induced amnesia in the Y-maze forced alternation test in vivo.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Neuroblastoma , Fármacos Neuroprotetores , Humanos , Butirilcolinesterase/metabolismo , Acetilcolinesterase/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Receptores de Canabinoides , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Doença de Alzheimer/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
14.
Bioorg Med Chem ; 101: 117649, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38401458

RESUMO

Simple and scalable synthetic approach was used for the preparation of thirteen novel tacrine derivatives consisting of tacrine and N-aryl-piperidine-4-carboxamide moiety connected by a five-methylene group linker. An anti-Alzheimer disease (AD) potential of newly designed tacrine derivatives was evaluated against two important AD targets, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro pharmacological evaluation showed strong ChE inhibitory activity of all compounds, with IC50 values ranging from 117.5 to 455 nM for AChE and 34 to 324 nM for BuChE. As a representative of the series with the best cytotoxicity / ChE inhibitory activity ratio, expressed as the selectivity index (SI), 2-chlorobenzoyl derivative demonstrated mixed-type inhibition on AChE and BuChE, suggesting binding to both CAS and PAS of the enzymes. It also exhibited antioxidant capacity and neuroprotective potential against amyloid-ß (Aß) toxicity in the culture of neuron-like cells. In-depth computational analysis corroborated well with in vitro ChE inhibition, illuminating that all compounds exhibit significant potential in targeting both enzymes. Molecular dynamics (MD) simulations revealed that 2-chlorobenzoyl derivative, created complexes with AChE and BuChE that demonstrated sufficient stability throughout the observed MD simulation. Computationally predicted ADME properties indicated that these compounds should have good blood-brain barrier (BBB) permeability, an important factor for CNS-targeting drugs. Overall, all tested compounds showed promising pharmacological behavior, highlighting the multi-target potential of 2-chlorobenzoyl derivative which should be further investigated as a new lead in the drug development process.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Humanos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Tacrina/química , Butirilcolinesterase/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
15.
Org Biomol Chem ; 22(8): 1634-1638, 2024 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-38323382

RESUMO

Alzheimer's disease (AD) is characterized by cognitive decline, often attributed to the deficiency of acetylcholine, which can undergo hydrolysis by acetylcholinesterase (AChE) within the biological milieu. Here, we report a supramolecular strategy that takes advantage of confinement effects to inhibit such a hydrolysis process, shedding some light on AD therapy. A water-soluble and bowl-shaped molecule, hexacarboxylated tribenzotriquinacene (TBTQ-C6), was employed to shield acetylcholine (G1) from enzymatic degradation through host-guest binding interactions. Our study revealed highly efficient host-guest interactions with a binding ratio of 1 : 3, resulting in a significant reduction in acetylcholine hydrolysis from 91.1% to 7.4% in the presence of AChE under otherwise identical conditions. Furthermore, TBTQ-C6 showed potential for attenuating the degradation of butyrylcholine (G2) by butyrylcholinesterase (BChE). The broader implications of this study extend to the potential use of molecular containers in various biochemical and pharmacological applications, opening new avenues for research in the field of neurodegenerative diseases.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Humanos , Butirilcolinesterase/metabolismo , Acetilcolina/metabolismo , Acetilcolina/uso terapêutico , Acetilcolinesterase/metabolismo , Hidrólise , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Simulação de Acoplamento Molecular
16.
J Enzyme Inhib Med Chem ; 39(1): 2313682, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38362862

RESUMO

Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer's disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC50 = 4.68 nM; huBuChE IC50 = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 µM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound 7p was a mix-type BuChE inhibitor. Additionally, compound 7p displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound 7p had good safety in vivo as verified by an acute toxicity assay (LD50 > 1000 mg/kg). Most importantly, compound 7p effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound 7p could serve as a promising lead compound for treating AD.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Carbamatos/farmacologia , Doenças Neuroinflamatórias , Peptídeos beta-Amiloides , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Estrutura Molecular
17.
Molecules ; 29(3)2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38338420

RESUMO

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are enzymes that break down and reduce the level of the neurotransmitter acetylcholine (ACh). This can cause a variety of cognitive and neurological problems, including Alzheimer's disease. Taxifolin is a natural phytochemical generally found in yew tree bark and has significant pharmacological properties, such as being anti-cancer, anti-inflammatory, and antioxidant. The binding affinity and inhibitory potency of taxifolin to these enzymes were evaluated through molecular docking and molecular dynamics simulations followed by the MMPBSA approach, and the results were significant. Taxifolin's affinity for binding to the AChE-taxifolin complex was -8.85 kcal/mol, with an inhibition constant of 326.70 nM. It was observed to interact through hydrogen bonds. In contrast, the BChE-taxifolin complex binding energy was observed to be -7.42 kcal/mol, and it was significantly nearly equal to the standard inhibitor donepezil. The molecular dynamics and simulation signified the observed interactions of taxifolin with the studied enzymes. The MMPBSA total free energy of binding for AChE-taxifolin was -24.34 kcal/mol, while BChE-taxifolin was -16.14 kcal/mol. The present research suggests that taxifolin has a strong ability to bind and inhibit AChE and BChE and could be used to manage neuron-associated problems; however, further research is required to explore taxifolin's neurological therapeutic potential using animal models of Alzheimer's disease.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Quercetina/análogos & derivados , Animais , Acetilcolinesterase/metabolismo , Butirilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Inibidores da Colinesterase/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
18.
Molecules ; 29(3)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38338474

RESUMO

Biological activities of six under-utilized medicinal leafy vegetable plants indigenous to Africa, i.e., Basella alba, Crassocephalum rubens, Gnetum africanum, Launaea taraxacifolia, Solanecio biafrae, and Solanum macrocarpon, were investigated via two independent techniques. The total phenolic content (TPC) was determined, and six microtiter plate assays were applied after extraction and fractionation. Three were antioxidant in vitro assays, i.e., ferric reducing antioxidant power (FRAP), cupric reduction antioxidant capacity (CUPRAC), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging, and the others were enzyme (acetylcholinesterase, butyrylcholinesterase, and tyrosinase) inhibition assays. The highest TPC and antioxidant activity from all the methods were obtained from polar and medium polar fractions of C. rubens, S. biafrae, and S. macrocarpon. The highest acetyl- and butyrylcholinesterase inhibition was exhibited by polar fractions of S. biafrae, C. rubens, and L. taraxacifolia, the latter comparable to galantamine. The highest tyrosinase inhibition was observed in the n-butanol fraction of C. rubens and ethyl acetate fraction of S. biafrae. In vitro assay results of the different extracts and fractions were mostly in agreement with the bioactivity profiling via high-performance thin-layer chromatography-multi-imaging-effect-directed analysis, exploiting nine different planar assays. Several separated compounds of the plant extracts showed antioxidant, α-glucosidase, α-amylase, acetyl- and butyrylcholinesterase-inhibiting, Gram-positive/-negative antimicrobial, cytotoxic, and genotoxic activities. A prominent apolar bioactive compound zone was tentatively assigned to fatty acids, in particular linolenic acid, via electrospray ionization high-resolution mass spectrometry. The detected antioxidant, antimicrobial, antidiabetic, anticholinesterase, cytotoxic, and genotoxic potentials of these vegetable plants, in particular C. rubens, S. biafrae, and S. macrocarpon, may validate some of their ethnomedicinal uses.


Assuntos
Anti-Infecciosos , Plantas Medicinais , Antioxidantes/química , Butirilcolinesterase , Verduras , Cromatografia em Camada Delgada , Acetilcolinesterase , Monofenol Mono-Oxigenase , Plantas Medicinais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Anti-Infecciosos/análise
19.
Fitoterapia ; 174: 105867, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38382891

RESUMO

The concept of multi-target-directed ligands offers fresh perspectives for the creation of brand-new Alzheimer's disease medications. To explore their potential as multi-targeted anti-Alzheimer's drugs, eighteen new bakuchiol derivatives were designed, synthesized, and evaluated. The structures of the new compounds were elucidated by IR, NMR, and HRMS. Eighteen compounds were assayed for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in vitro using Ellman's method. It was shown that most of the compounds inhibited AChE and BuChE to varying degrees, but the inhibitory effect on AChE was relatively strong, with fourteen compounds showing inhibition of >50% at the concentration of 200 µM. Among them, compound 3g (IC50 = 32.07 ± 2.00 µM) and compound 3n (IC50 = 34.78 ± 0.34 µM) showed potent AChE inhibitory activities. Molecular docking studies and molecular dynamics simulation showed that compound 3g interacts with key amino acids at the catalytically active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase and binds stably to acetylcholinesterase. On the other hand, compounds 3n and 3q significantly reduced the pro-inflammatory cytokines TNF-α and IL-6 released from LPS-induced RAW 264.7 macrophages. Compound 3n possessed both anti-acetylcholinesterase activity and anti-inflammatory properties. Therefore, an in-depth study of compound 3n is expected to be a multi-targeted anti-AD drug.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Fenóis , Humanos , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Desenho de Fármacos
20.
Mikrochim Acta ; 191(2): 119, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38300297

RESUMO

A ratiometric fluorescence platform was developed based on the cobalt oxyhydroxide (CoOOH) nanosheet-modulated fluorescence response of blue emissive copper nanoclusters (Cu NCs) and yellow emissive o-phenylenediamine (OPD). CoOOH nanosheets showed dual function of strong absorption and oxidation ability, which can effectively quench the blue fluorescence of Cu NCs, with an excitation and emission peak maximum at 390 and 450 nm, respectively , and transfer the OPD into yellow fluorescence products, with an excitation and emission peak maximum at 390 and 560 nm, respectively. Upon introducing butyrylcholinesterase (BChE) and its substrates, CoOOH nanosheets were decomposed into Co2+, and malachite green (MG) showed strong inhibition ability to this  process. This resulted in the obvious difference on the ratio of blue and yellow fluorescence recorded on the system in the presence and absence of MG, which was utilized for the quantitative detection of MG, with a limit of detection of 0.140 µM and a coefficient of variation of 3.5%. The fluorescence ratiometric assay showed excellent detection performances in practical sample analysis.


Assuntos
Butirilcolinesterase , Cobalto , Cobre , Óxidos , Fenilenodiaminas , Animais , Corantes de Rosanilina , Peixes
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