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1.
Ann Afr Med ; 23(4): 704-709, 2024 Oct 01.
Artigo em Francês, Inglês | MEDLINE | ID: mdl-39279177

RESUMO

BACKGROUND: Poisoning is a significant health hazard and a leading cause of morbidity and mortality worldwide. India, being a predominantly agrarian country, routinely employs organophosphate (OP) pesticides in farming, and they are readily available "over the counter." OPs exert their toxicity by interfering with the normal function of acetylcholine, an essential neurotransmitter throughout the autonomic and central nervous systems. Due to the limited availability of facilities and resources in health-care systems, and economically restraining patients, it is necessary to rely more on clinical features to assess the severity of poisoning and manage the condition properly. METHODOLOGY: It was a hospital-based prospective observational study that included patients aged >13 years in a tertiary care hospital. All patients were clinically evaluated based on their history and examination. The diagnosis was made based on characteristic clinical manifestations or evidence of exposure to organophosphorus compounds (corroborative evidence such as empty containers and the odor of gastric aspirates). Clinical severity was assessed and categorized according to the Peradeniya Organophosphorus Poisoning Scale (POP scale). A score of 0-3 is considered mild poisoning, 4-7 as moderate poisoning, and 8-11 as severe poisoning. RESULTS: Out of the 50 patients enrolled in the study, 17 (34.00%) were aged <20 years, 19 (38%) were in the 20-30 years age group, and 14 (28%) were aged >30 years. Ingestion is the only mode of exposure to poisoning. None of the patients had history of contact or inhalational exposure. Of the 50 cases, 12 (24.0%) were in the mild category, 26 (52.0%) in the moderate category, and 12 (24%) in the severe category on the POP grading. A comparison of the mean serum pseudocholinesterase, troponin-T, and pro-BNP levels with severity was performed. In mild OP poisoning, the mean serum PChE level was 2766.58 ± 1120.44; in moderate, it was 1969.35 ± 1330.07, and in severe, it was 701.83 ± 961.17. Pseudocholinesterase levels decreased progressively with increasing clinical severity from mild-to-severe cases, and this association was statistically significant (P < 0.001). Two-dimensional echocardiography screening done in all patients did not show any significant abnormalities. CONCLUSION: This study shows that serum PCE is reduced in OP poisoning and correlates with the clinical severity grading done by the POP scale and is also associated with an increase in the duration of intensive care unit stay. No significant evidence of direct cardiac injury was observed in this study. A low Glasgow Coma Scale score and an increased respiratory rate at presentation are associated with poor outcomes.


Résumé Contexte:L'empoisonnement est un risque important pour la santé et une cause principale de morbidité et de mortalité dans le monde. L'Inde, étant principalement pays agraire, utilise régulièrement des pesticides organophosphotés (OP) dans l'agriculture, et ils sont facilement disponibles «en vente libre¼. OPS exerce leur toxicité en interférant avec la fonction normale de l'acétylcholine, un neurotransmetteur essentiel à travers l'autonomie et le centre systèmes nerveux. En raison de la disponibilité limitée des installations et des ressources dans les systèmes de soins de santé, et de la contention économique des patients, il est nécessaire pour s'appuyer davantage sur les caractéristiques cliniques pour évaluer la gravité de l'empoisonnement et gérer correctement la condition.Méthodologie:c'était un Étude d'observation prospective basée à l'hôpital qui comprenait des patients âgés de> 13 ans dans un hôpital de soins tertiaires. Tous les patients étaient cliniquement évalué en fonction de leur histoire et de leur examen. Le diagnostic a été posé sur la base de manifestations cliniques caractéristiques ou de preuves de Exposition aux composés organophosphores (preuves corroborantes telles que les conteneurs vides et l'odeur des aspirations gastriques). Gravité clinique a été évalué et classé selon l'échelle d'empoisonnement de Peradeniya organophosphorus (échelle pop). Un score de 0 à 3 est considéré comme doux Empoisonnement, 4­7 comme empoisonnement modéré et 8-11 comme empoisonnement sévère.Résultats:Sur les 50 patients inscrits à l'étude, 17 (34,00%) étaient âgés de <20 ans, 19 ans (38%) dans le groupe d'âge de 20 à 30 ans et 14 (28%) étaient âgés de> 30 ans. L'ingestion est le seul mode d'exposition à empoisonnement. Aucun des patients n'avait des antécédents de contact ou d'inhalation. Sur les 50 cas, 12 (24,0%) étaient dans la catégorie légère, 26 (52,0%) Dans la catégorie modérée, et 12 (24%) dans la catégorie sévère sur le classement POP. Une comparaison de la pseudocholinestérase sérique moyenne, Les niveaux de troponine - T et pro-BNP avec gravité ont été réalisés. Dans l'empoisonnement à l'op léger, le taux de PCHE sérique moyen était de 2766,58 ± 1120,44; dans Modéré, c'était 1969.35 ± 1330,07, et en sévère, il était de 701,83 ± 961,17. Les niveaux de pseudocholinestérase ont diminué progressivement avec l'augmentation Gravité clinique des cas légers à sévère, et cette association était statistiquement significative (P <0,001). Échocardiographie bidimensionnelle Le dépistage effectué chez tous les patients n'a montré aucune anomalie significative.Conclusion:cette étude montre que le PCE sérique est réduit en op empoisonnement et corréler avec le classement de gravité clinique effectué par l'échelle POP et est également associé à une augmentation de la durée de séjour de l'unité de soins intensifs. Aucune preuve significative de lésion cardiaque directe n'a été observée dans cette étude. Un score d'échelle de coma à faible Glasgow et un Une fréquence respiratoire accrue à la présentation est associée à de mauvais résultats.


Assuntos
Butirilcolinesterase , Intoxicação por Organofosfatos , Índice de Gravidade de Doença , Humanos , Intoxicação por Organofosfatos/sangue , Feminino , Masculino , Adulto , Estudos Prospectivos , Pessoa de Meia-Idade , Índia/epidemiologia , Adulto Jovem , Butirilcolinesterase/sangue , Adolescente , Praguicidas/intoxicação , Compostos Organofosforados , Biomarcadores/sangue , Idoso
2.
Bioorg Med Chem Lett ; 112: 129938, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39222891

RESUMO

Alzheimer's disease is associated with a progressive loss of neurons and synaptic connections in the cholinergic system. Oxidative stress contributes to neuronal damages and to the development of amyloid plaques and neurofibrillary tangles. Therefore, antioxidants have been widely studied to mitigate the progression of Alzheimer's disease, and among these, lipoic acid has demonstrated a neuroprotective effect. Here, we present the synthesis, the molecular modelling, and the evaluation of lipoic acid-donepezil hybrids based on O-desmethyldonepezil. As compounds 5 and 6 display a high inhibition of acetylcholinesterase (IC50 = 7.6 nM and 9.1 nM, respectively), selective against butyrylcholinesterase, and a notable neuroprotective effect, slightly better than that of lipoic acid, the present study suggests that O-desmethyldonepezil could serve as a platform for the straightforward design of donepezil hybrids.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Butirilcolinesterase , Inibidores da Colinesterase , Donepezila , Indanos , Fármacos Neuroprotetores , Piperidinas , Ácido Tióctico , Ácido Tióctico/química , Ácido Tióctico/farmacologia , Ácido Tióctico/síntese química , Donepezila/farmacologia , Donepezila/química , Donepezila/síntese química , Doença de Alzheimer/tratamento farmacológico , Piperidinas/química , Piperidinas/farmacologia , Piperidinas/síntese química , Indanos/química , Indanos/farmacologia , Indanos/síntese química , Humanos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Acetilcolinesterase/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Butirilcolinesterase/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Modelos Moleculares
3.
Biosens Bioelectron ; 266: 116747, 2024 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-39243742

RESUMO

Expanding target pesticide species and intelligent pesticide recognition were formidable challenges for existing cholinesterase inhibition methods. To improve this status, multi-active Mel-Cu nanozyme with mimetic Cu-N sites was prepared for the first time. It exhibited excellent laccase-like and peroxidase-like activities, and can respond to some pesticides beyond the detected range of enzyme inhibition methods, such as glyphosate, carbendazim, fumonisulfuron, etc., through coordination and hydrogen bonding. Inspired by the signal complementarity of Mel-Cu and cholinesterase, an integrated sensor array based on the Mel-Cu laccase-like activity, Mel-Cu peroxidase-like activity, acetylcholinesterase, and butyrylcholinesterase was creatively constructed. And it could successfully discriminate 12 pesticides at 0.5-50 µg/mL, which was significantly superior to traditional enzyme inhibition methods. Moreover, on the basis of above array, a unified stepwise prediction model was built using classification and regression algorithms in machine learning, which enabled concentration-independent qualitative identification as well as precise quantitative determination of multiple pesticide targets, simultaneously. The sensing accuracy was verified by blind sample analysis, in which the species was correctly identified and the concentration was predicted within 10% error, suggesting great intelligent recognition ability. Further, the proposed method also demonstrated significant immunity to interference and practical application feasibility, providing powerful means for pesticide residue analysis.


Assuntos
Acetilcolinesterase , Técnicas Biossensoriais , Butirilcolinesterase , Cobre , Aprendizado de Máquina , Praguicidas , Triazinas , Triazinas/química , Triazinas/análise , Praguicidas/análise , Técnicas Biossensoriais/métodos , Cobre/química , Acetilcolinesterase/química , Butirilcolinesterase/química , Butirilcolinesterase/análise , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/química , Limite de Detecção
4.
Sci Rep ; 14(1): 21115, 2024 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-39256495

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects the elderly population globally and there is an urgent demand for developing novel anti-AD agents. In this study, a new series of indole-isoxazole carbohydrazides were designed and synthesized. The structure of all compounds was elucidated using spectroscopic methods including FTIR, 1H NMR, and 13C NMR as well as mass spectrometry and elemental analysis. All derivatives were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Out of all synthesized compounds, compound 5d exhibited the highest potency as AChE inhibitor with an IC50 value of 29.46 ± 0.31 µM. It showed significant selectivity towards AChE, with no notable inhibition against BuChE. A kinetic study on AChE for compound 5d indicated a competitive inhibition pattern. Also, 5d exhibited promising BACE1 inhibitory potential with an IC50 value of 2.85 ± 0.09 µM and in vitro metal chelating ability against Fe3+. The molecular dynamic studies of 5d against both AChE and BACE1 were executed to evaluate the behavior of this derivative in the binding site. The results showed that the new compounds deserve further chemical optimization to be considered potential anti-AD agents.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Butirilcolinesterase , Inibidores da Colinesterase , Indóis , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Humanos , Simulação de Acoplamento Molecular , Isoxazóis/química , Isoxazóis/farmacologia , Isoxazóis/síntese química , Relação Estrutura-Atividade , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Modelos Moleculares , Sítios de Ligação , Simulação de Dinâmica Molecular , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Cinética , Hidrazinas
5.
Bioorg Med Chem Lett ; 112: 129928, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39151660

RESUMO

Alzheimer's disease is age-related multifactorial neurodegenerative disease manifested by gradual loss of memory, cognitive decline and changes in personality. Due to rapid and continuous growth of its prevalence, the treatment of Alzheimer's disease calls for development of new and efficacies drugs, especially those that could be able to simultaneously act on more than one of possible targets of action. Aminoquinolines have proven to be a highly promising structural scaffold in the design of such a drug as cholinesterases and ß-secretase 1 inhibitors. In this study, we synthesised twenty-two new 4-aminoquinolines with different halogen atom and its position in the terminal N-benzyl group or with a trifluoromethyl or a chlorine as C(7)-substituents on the quinoline moiety. All compounds were evaluated as multi-target-directedligands by determining their inhibition potency towards human acetylcholinesterase, butyrylcholinesterase and ß-secretase 1. All of the tested derivatives were very potent inhibitors of human acetylcholinesterase and butyrylcholinesterase with inhibition constants (Ki) in the nM to low µM range. Most were estimated to be able to cross the blood-brain barrier by passive transport and were nontoxic toward cells that represented the main models of individual organs.


Assuntos
Acetilcolinesterase , Aminoquinolinas , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Butirilcolinesterase , Inibidores da Colinesterase , Humanos , Secretases da Proteína Precursora do Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Aminoquinolinas/farmacologia , Aminoquinolinas/química , Aminoquinolinas/síntese química , Butirilcolinesterase/metabolismo , Relação Estrutura-Atividade , Acetilcolinesterase/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Estrutura Molecular , Halogênios/química , Relação Dose-Resposta a Droga
6.
Molecules ; 29(15)2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39124935

RESUMO

The derivatives of isoindoline-1,3-dione are interesting due to their biological activities, such as anti-inflammatory and antibacterial effects. Several series have been designed and evaluated for Alzheimer's therapy candidates. They showed promising activity. In this work, six new derivatives were first tested in in silico studies for their inhibitory ability against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Molecular docking and molecular dynamic simulation were applied. Next, these compounds were synthesized and characterized by 1H NMR, 13C NMR, FT-IR, and ESI-MS techniques. For all imides, the inhibitory activity against AChE and BuChE was tested using Ellaman's method. IC50 values were determined. The best results were obtained for the derivative I, with a phenyl substituent at position 4 of piperazine, IC50 = 1.12 µM (AChE) and for the derivative III, with a diphenylmethyl moiety, with IC50 = 21.24 µM (BuChE). The compounds tested in this work provide a solid basis for further structural modifications, leading to the effective design of potential inhibitors of both cholinesterases.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Relação Estrutura-Atividade , Simulação de Dinâmica Molecular , Humanos , Isoindóis/química , Isoindóis/farmacologia , Isoindóis/síntese química , Estrutura Molecular
7.
Molecules ; 29(15)2024 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-39124978

RESUMO

This study delves into the transformative effects of supercritical carbon dioxide (scCO2) cannabis extracts and prebiotic substances (dextran, inulin, trehalose) on gut bacteria, coupled with a focus on neuroprotection. Extracts derived from the Bialobrzeska variety of Cannabis sativa, utilising supercritical fluid extraction (SFE), resulted in notable cannabinoid concentrations (cannabidiol (CBD): 6.675 ± 0.166; tetrahydrocannabinol (THC): 0.180 ± 0.006; cannabigerol (CBG): 0.434 ± 0.014; cannabichromene (CBC): 0.490 ± 0.017; cannabinol (CBN): 1.696 ± 0.047 mg/gD). The assessment encompassed antioxidant activity via four in vitro assays and neuroprotective effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The extract boasting the highest cannabinoid content exhibited remarkable antioxidant potential and significant inhibitory activity against both enzymes. Further investigation into prebiotic deliveries revealed their proficiency in fostering the growth of beneficial gut bacteria while maintaining antioxidant and neuroprotective functionalities. This study sheds light on the active compounds present in the Bialobrzeska variety, showcasing their therapeutic potential within prebiotic systems. Notably, the antioxidant, neuroprotective, and prebiotic properties observed underscore the promising therapeutic applications of these extracts. The results offer valuable insights for potential interventions in antioxidant, neuroprotective, and prebiotic domains. In addition, subsequent analyses of cannabinoid concentrations post-cultivation revealed nuanced changes, emphasising the need for further exploration into the dynamic interactions between cannabinoids and the gut microbiota.


Assuntos
Antioxidantes , Cannabis , Fármacos Neuroprotetores , Extratos Vegetais , Prebióticos , Cannabis/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Antioxidantes/farmacologia , Antioxidantes/química , Canabinoides/química , Canabinoides/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-39147449

RESUMO

Brazil is one of the world's largest consumers of pesticides. This intense use impacts the environment and exposes a wide range of individuals to pesticides, including rural workers who are occupationally exposed and rural residents who are environmentally exposed. We aimed to evaluate the effects of occupational exposure to pesticides on the health of rural workers and rural residents. We conducted an epidemiological study with 104 farmers and 23 rural residents of Casimiro de Abreu (Rio de Janeiro, Brazil). A comparison group (urban residents) comprised 103 residents of the urban area of the same city. We determined the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using a modified version of Ellman's method to evaluate exposure. In addition, we performed genotoxic and mutagenic analyses with the comet assay and the cytokinesis-block micronucleus (CBMN) assay. There was a reduction in cholinesterase activity, mainly BChE, in rural workers and rural residents compared with urban residents (p = 0.002). There was an increase in genotoxic effects in rural workers compared with urban residents (comet assay, p < 0.001; CBMN assay, p < 0.001). In addition, there was a greater chance of genotoxic changes in rural workers exposed to pesticides based on the comet assay (odds ratio [OR] 7.6, 95 % confidence interval [CI] 6.6-15.9) and the CBMN assay (OR 22.7, 95 % CI 10.3-49.9). We found that individuals occupationally exposed to pesticides are more likely to have genotoxic effects. These findings are useful for the development of programs to monitor populations exposed to genotoxic substances and allow the development of strategies for the prevention, control, and surveillance of effects that result from occupational and environmental exposures to pesticides.


Assuntos
Butirilcolinesterase , Ensaio Cometa , Dano ao DNA , Testes para Micronúcleos , Exposição Ocupacional , Praguicidas , População Rural , Humanos , Praguicidas/toxicidade , Brasil , Exposição Ocupacional/efeitos adversos , Adulto , Masculino , Pessoa de Meia-Idade , Butirilcolinesterase/genética , Feminino , Dano ao DNA/efeitos dos fármacos , Fazendeiros , Acetilcolinesterase , População Urbana
9.
Drug Dev Res ; 85(5): e22240, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39105636

RESUMO

In an effort to develop new and effective therapeutic agents for Alzheimer's disease, a series of hydrazone derivatives bearing piperidine rings have been designed and synthesized. The chemical structures of the compounds were characterized by various spectroscopic techniques. In vitro antioxidant and cholinesterase activities of the compounds were evaluated. Among the compounds, N12 exhibited the most antioxidant activity in all methods (CUPRAC, FRAP, DPPH, ABTS). In vitro acetylcholinesterase (AChE) activity results of the compounds showed good IC50 values between 14.124 ± 0.084 and 49.680 ± 0.110 µM were obtained (IC50 = 38.842 ± 0.053 µM for Donepezil). Among the compounds, N7 and N6 are much more effective derivatives than the standard compound donepezil with IC50 values of 14.124 ± 0.084 and 17.968 ± 0.072 µM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 ± 0.025 and 52.230 ± 0.027 µm. Among the compounds, N6 has the highest BChE inhibition with an IC50 value of 13.505 µm in the series. The cytotoxicity and AChE inhibitory activity of the compounds on SH-SY5Y cell lines were also evaluated. Kinetic studies were also performed to determine the behavior of the compounds as competitive or noncompetitive inhibitors. The binding modes of N6, which was determined to be highly effective according to in vitro analyses, with AChE and BChE were investigated using molecular docking studies, and the stability of the complexes was determined by molecular dynamics simulations. These findings indicated that AChE and BChE enzymes maintained their overall structural stability and compactness during interactions with compound N6.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , Inibidores da Colinesterase , Desenho de Fármacos , Hidrazonas , Simulação de Acoplamento Molecular , Piperidinas , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Hidrazonas/farmacologia , Hidrazonas/síntese química , Hidrazonas/química , Piperidinas/farmacologia , Piperidinas/química , Piperidinas/síntese química , Butirilcolinesterase/metabolismo , Acetilcolinesterase/metabolismo , Humanos , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Relação Estrutura-Atividade , Modelos Moleculares
10.
BMC Res Notes ; 17(1): 230, 2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39169443

RESUMO

INTRODUCTION: Gulf War illness (GWI) is an environmentally-triggered chronic multisymptom illness typified by protean symptoms, in which mitochondrial impairment is evident. It has been likened to accelerated aging. Nuclear genetics of detoxification have been linked to GWI. OBJECTIVE: To see whether mitochondrial (mt) haplogroup U - a heritable profile of mitochondrial DNA that has been tied to aging-related conditions - significantly predicts greater GWI severity; and to assess whether GWI severity is influenced by mitochondrial as well as nuclear genetics. 54 consenting Gulf War veterans gave information on GWI severity, of whom 52 had nuclear DNA assessment; and 45 had both nuclear and mitochondrial DNA assessments. Regression with robust standard errors assessed prediction of GWI severity as a function of nuclear genetics (butyrylcholinesterase variants), mitochondrial genetics (haplogroup U, previously tied to aging-related conditions); or both. RESULTS: BChE "adverse" variants significantly predicted GWI severity (ß(SE) = 23.4(11.4), p = 0.046), as did mt haplogroup U (ß(SE) = 36.4(13.6), p = 0.010). In a model including both, BChE was no longer significant, but mt haplogroup U retained significance (ß(SE) = 36.7(13.0), p = 0.007). This is the first study to show that mitochondrial genetics are tied to GWI severity in Gulf-deployed veterans. Other data affirm a tie to nuclear genetics, making GWI indeed a "tale of two genomes."


Assuntos
DNA Mitocondrial , Síndrome do Golfo Pérsico , Veteranos , Humanos , Síndrome do Golfo Pérsico/genética , Pessoa de Meia-Idade , Masculino , DNA Mitocondrial/genética , Feminino , Haplótipos , Butirilcolinesterase/genética , Adulto , Idoso , Índice de Gravidade de Doença
11.
Molecules ; 29(16)2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39202830

RESUMO

In this study, heterocyclic compounds containing a benzothiophene scaffold were designed and synthetized, and their inhibitory activity against cholinesterases (ChE) and the viability of SH-SY5Y cells have been evaluated. Benzothiophenes 4a-4i and benzothiophene-chalcone hybrids 5a-5i were tested against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing interesting structure-activity relationships. In general, benzothiophene-chalcone hybrids from series 5 proved to be better inhibitors of both enzymes, with compound 5f being the best AChE inhibitor (IC50 = 62.10 µM) and compound 5h being the best BChE inhibitor (IC50 = 24.35 µM), the last one having an IC50 similar to that of galantamine (IC50 = 28.08 µM), the reference compound. The in silico ADME profile of the compounds was also studied. Molecular docking calculations were carried out to analyze the best binding scores and to elucidate enzyme-inhibitors' interactions.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , Chalconas , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Tiofenos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Humanos , Tiofenos/química , Tiofenos/farmacologia , Tiofenos/síntese química , Chalconas/química , Chalconas/síntese química , Chalconas/farmacologia , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Relação Estrutura-Atividade , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Estrutura Molecular , Linhagem Celular Tumoral
12.
Int J Mol Sci ; 25(16)2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39201735

RESUMO

Cholinesterase (ChE) inhibitors are crucial therapeutic agents for the symptomatic treatment of certain chronic neurodegenerative diseases linked to functional disorders of the cholinergic system. Significant research efforts have been made to develop novel derivatives of classical ChE inhibitors and ChE inhibitors with novel scaffolds. Over the past decade, ruthenium complexes have emerged as promising novel therapeutic alternatives for the treatment of neurodegenerative diseases. Our research group has investigated a number of newly synthesized organoruthenium(II) complexes for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Three complexes (C1a, C1-C, and C1) inhibit ChE in a pharmacologically relevant range. C1a reversibly inhibits AChE and BChE without undesirable peripheral effects, making it a promising candidate for the treatment of Alzheimer's disease. C1-Cl complex reversibly and competitively inhibits ChEs, particularly AChE. It inhibits nerve-evoked skeletal muscle twitch and tetanic contraction in a concentration-dependent manner with no effect on directly elicited twitch and tetanic contraction and is promising for further preclinical studies as a competitive neuromuscular blocking agent. C1 is a selective, competitive, and reversible inhibitor of BChE that inhibits horse serum BChE (hsBChE) without significant effect on the peripheral neuromuscular system and is a highly species-specific inhibitor of hsBChE that could serve as a species-specific drug target. This research contributes to the expanding knowledge of ChE inhibitors based on ruthenium complexes and highlights their potential as promising therapeutic candidates for chronic neurodegenerative diseases.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , Inibidores da Colinesterase , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Animais , Humanos , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Rutênio/química , Rutênio/farmacologia , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Cavalos , Avaliação Pré-Clínica de Medicamentos
13.
Sci Rep ; 14(1): 19637, 2024 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-39179586

RESUMO

Even though legumes are valuable medicinal plants with edible seeds that are extensively consumed worldwide, there is little information available on the metabolic variations between different dietary beans and their influence as potential anti-cholinesterase agents. High-resolution liquid chromatography coupled with mass spectrometry in positive and negative ionization modes combined with multivariate analysis were used to explore differences in the metabolic profiles of five commonly edible seeds, fava bean, black-eyed pea, kidney bean, red lentil, and chickpea. A total of 139 metabolites from various classes were identified including saponins, alkaloids, phenolic acids, iridoids, and terpenes. Chickpea showed the highest antioxidant and anti-cholinesterase effects, followed by kidney beans. Supervised and unsupervised chemometric analysis determined that species could be distinguished by their different discriminatory metabolites. The major metabolic pathways in legumes were also studied. Glycerophospholipid metabolism was the most significantly enriched KEGG pathway. Pearson's correlation analysis pinpointed 18 metabolites that were positively correlated with the anti-cholinesterase activity. Molecular docking of the biomarkers to the active sites of acetyl- and butyryl-cholinesterase enzymes revealed promising binding scores, validating the correlation results. The present study will add to the metabolomic analysis of legumes and their nutritional value and advocate their inclusion in anti-Alzheimer's formulations.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Fabaceae , Simulação de Acoplamento Molecular , Sementes , Doença de Alzheimer/metabolismo , Sementes/metabolismo , Sementes/química , Fabaceae/metabolismo , Fabaceae/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/metabolismo , Humanos , Acetilcolinesterase/metabolismo , Metabolômica/métodos , Antioxidantes/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Metaboloma , Butirilcolinesterase/metabolismo
14.
Future Med Chem ; 16(16): 1615-1631, 2024 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-39011621

RESUMO

Aim: Design and synthesis of a series of 5-benzylidene(thio)barbiturates 3a-r.Methodology: Evaluation of the inhibitory activity of the new chemical entities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Donepezil as the standard reference.Results & Conclusion: Compound 3r emerged as the most potent AChE inhibitor (IC50 = 9.12 µM), while compound 3q exhibited the highest inhibitory activity against BChE (IC50 = 19.43 µM). Toxicological bioassays confirmed the absence of cytotoxicity for the most potent compounds at the tested doses. Molecular docking analysis demonstrated that the tested derivatives effectively bind to the active sites of both enzymes. Overall, this study sheds light on the potential of barbiturate-sulfonate conjugates as promising drug candidates.


[Box: see text].


Assuntos
Acetilcolinesterase , Barbitúricos , Butirilcolinesterase , Inibidores da Colinesterase , Desenho de Fármacos , Simulação de Acoplamento Molecular , Ácidos Sulfônicos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Butirilcolinesterase/metabolismo , Acetilcolinesterase/metabolismo , Barbitúricos/química , Barbitúricos/farmacologia , Barbitúricos/síntese química , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacologia , Ácidos Sulfônicos/antagonistas & inibidores , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Animais , Modelos Moleculares
15.
Int J Biol Macromol ; 277(Pt 4): 134179, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39084425

RESUMO

The butyrylcholinesterase (BChE) is an attractive target for treating Alzheimer's disease. In this study, we report the discovery of five new monoterpene indole alkaloids (MIAs) along with three known analogues from Uncaria sessilifructus Roxb. as BChE inhibitors using affinity ultrafiltration based metabolomic profiling directed isolation strategy. Their structures were well identified through comprehensive spectroscopic and chiroptical analyses. Compounds 1-2 featured unique glycosidic linkages with 1,3-dioxane structure. All the compounds exhibited BChE inhibitory bioactivity without any cytotoxic effects. Enzymatic kinetic and molecular docking analyses of compounds 1 and 6 demonstrated their inhibiting mechanisms and binding patterns to BChE. These findings provide a valuable workflow for efficiently screening ligands that bind to proteins, and scientific recognition in the discovery of BChE inhibitors for treating neurodegenerative disorders.


Assuntos
Butirilcolinesterase , Inibidores da Colinesterase , Uncaria , Humanos , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Cinética , Metabolômica/métodos , Simulação de Acoplamento Molecular , Ultrafiltração , Uncaria/química
16.
Sci Rep ; 14(1): 15577, 2024 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-38971857

RESUMO

Alzheimer's disease is the most prevalent neurodegenerative disorder characterized by significant memory loss and cognitive impairments. Studies have shown that the expression level and activity of the butyrylcholinesterase enzyme increases significantly in the late stages of Alzheimer's disease, so butyrylcholinesterase can be considered as a promising therapeutic target for potential Alzheimer's treatments. In the present study, a novel series of 2,4-disubstituted quinazoline derivatives (6a-j) were synthesized and evaluated for their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes, as well as for their antioxidant activities. The biological evaluation revealed that compounds 6f, 6h, and 6j showed potent inhibitory activities against eqBuChE, with IC50 values of 0.52, 6.74, and 3.65 µM, respectively. These potent compounds showed high selectivity for eqBuChE over eelAChE. The kinetic study demonstrated a mixed-type inhibition pattern for both enzymes, which revealed that the potent compounds might be able to bind to both the catalytic active site and peripheral anionic site of eelAChE and eqBuChE. In addition, molecular docking studies and molecular dynamic simulations indicated that potent compounds have favorable interactions with the active sites of BuChE. The antioxidant screening showed that compounds 6b, 6c, and 6j displayed superior scavenging capabilities compared to the other compounds. The obtained results suggest that compounds 6f, 6h, and 6j are promising lead compounds for the further development of new potent and selective BuChE inhibitors.


Assuntos
Antioxidantes , Butirilcolinesterase , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Quinazolinas , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/síntese química , Quinazolinas/farmacologia , Quinazolinas/química , Quinazolinas/síntese química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Humanos , Relação Estrutura-Atividade , Domínio Catalítico , Animais , Cinética , Electrophorus
17.
Fitoterapia ; 177: 106141, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39053739

RESUMO

A series of C-3 arylated huperzine A (HPA) derivatives (1-30) were designed and synthesized in good yields via palladium-catalyzed Suzuki cross-coupling reaction. Cholinesterase inhibitory and neuroprotective activities of all 30 derivatives were evaluated. Cholinesterase inhibition results revealed that derivatives 2 and 15 exhibited dual inhibitory activity against both acetylcholinesterase (AChE inhibition: 2, IC50 = 1.205 ± 0.395 µM; 15, IC50 = 0.225 ± 0.062 µM) and butyrylcholinesterase (BChE inhibition: 2, IC50 = 8.598 ± 3.605 µM; 15, IC50 = 4.013 ± 0.068 µM), a feature not observed in huperzine A. Molecular docking results indicated that the introduction of aryl groups enhanced the affinity of the derivatives for the acyl-binding pocket of BChE, thereby limiting the hydrolysis of acetyl choline. However, these derivatives exhibited poor performance in cytotoxicity and neuroprotection assays.


Assuntos
Alcaloides , Doença de Alzheimer , Butirilcolinesterase , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores , Sesquiterpenos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Sesquiterpenos/farmacologia , Sesquiterpenos/síntese química , Sesquiterpenos/química , Alcaloides/farmacologia , Alcaloides/síntese química , Alcaloides/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Butirilcolinesterase/metabolismo , Estrutura Molecular , Doença de Alzheimer/tratamento farmacológico , Acetilcolinesterase/metabolismo , Animais , Humanos , Relação Estrutura-Atividade , Desenho de Fármacos
18.
Artigo em Inglês | MEDLINE | ID: mdl-38959705

RESUMO

This study established a method to prepare and detect OPs adducts on butyrylcholinesterase (BChE) and human serum albumin (HSA). OPs (methyl paraoxon, ethyl paraoxon, methyl parathion, parathion) were incubated with BChE or HSA in vitro, and the adducts of OPs-BChE or OPs-HSA were prepared and qualitatively analyzed by ultra-performance liquid chromatography data-dependent high-resolution tandem mass spectrometry (UPLC-ddHRMS/MS). The amounts of BChE and HSA in the incubating systems were varied and the resulting amounts of the adducts were determined using linear regression. OPs-BChE in the blood were isolated by immunomagnetic separation (IMS), and then digested into the OPs-nonapeptide adduct by pepsin. The proteins in the remaining blood plasma were precipitated and digested by pronase to OPs-tyrosines(OPs-Tyr), which were quantified by UPLC-ddHRMS/MS. 4 OPs-nonapeptides and 4 OPs-Tyr adducts were obtained through the process above. The relative mass deviation of incubated adducts between the actual and theoretical exact masses was less than 10 ppm, and further confirmed by fragmentation mass spectra analysis. Calibration curves were linear for all adducts with a coefficient of determination value (R2) ≥0.995. The limits of detection (LOD) and limits of quantification (LOQ) for adducts detected by MS ranged from 0.05 to 1.0 ng/mL, and from 0.1 to 2.0 ng/mL, respectively. The recovery percentages for adducts ranged from 76.1 % to 107.1 %, matrix effects ranged from 83.4 % to 102.1 %. The inter-day and intra-day precision were 6.1-10.1 % and 6.9-12.9 % for adducts. This study provides a new reference method for the detection of organophosphorus pesticide poisoning. In addition, two blood samples with organophosphorus poisoning were tested by the designed method, and the corresponding adducts were detected in both samples.


Assuntos
Butirilcolinesterase , Compostos Organofosforados , Espectrometria de Massas em Tandem , Humanos , Butirilcolinesterase/sangue , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Compostos Organofosforados/química , Compostos Organofosforados/sangue , Compostos Organofosforados/análise , Espectrometria de Massas em Tandem/métodos , Modelos Lineares , Cromatografia Líquida de Alta Pressão/métodos , Praguicidas/sangue , Praguicidas/análise , Praguicidas/química , Limite de Detecção , Albumina Sérica Humana/química , Albumina Sérica Humana/análise , Reprodutibilidade dos Testes
19.
ACS Chem Neurosci ; 15(15): 2756-2778, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39076038

RESUMO

Alzheimer's disease (AD) is the most prevalent cause of dementia and is characterized by low levels of acetyl and butyrylcholine, increased oxidative stress, inflammation, accumulation of metals, and aggregations of Aß and tau proteins. Current treatments for AD provide only symptomatic relief without impacting the pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multitarget molecules for AD, through extensive medicinal chemistry efforts, we have developed 13a, harboring the key functional groups to provide not only symptomatic relief but also targeting oxidative stress, able to chelate iron, inhibiting NLRP3, and Aß1-42 aggregation in various AD models. 13a exhibited promising anticholinesterase activity against AChE (IC50 = 0.59 ± 0.19 µM) and BChE (IC50 = 5.02 ± 0.14 µM) with excellent antioxidant properties in DPPH assay (IC50 = 5.88 ± 0.21 µM) over ferulic acid (56.49 ± 0.62 µM). The molecular docking and dynamic simulations further corroborated the enzyme inhibition studies and confirmed the stability of these complexes. Importantly, in the PAMPA-BBB assay, 13a turned out to be a promising molecule that can efficiently cross the blood-brain barrier. Notably, 13a also exhibited iron-chelating properties. Furthermore, 13a effectively inhibited self- and metal-induced Aß1-42 aggregation. It is worth mentioning that 13a demonstrated no symptom of cytotoxicity up to 30 µM concentration in PC-12 cells. Additionally, 13a inhibited the NLRP3 inflammasome and mitigated mitochondrial-induced reactive oxygen species and mitochondrial membrane potential damage triggered by LPS and ATP in HMC-3 cells. 13a could effectively reduce mitochondrial and cellular reactive oxygen species (ROS) in the Drosophila model of AD. Finally, 13a was found to be efficacious in reversing memory impairment in a scopolamine-induced AD mouse model in the in vivo studies. In ex vivo assessments, 13a notably modulates the levels of superoxide, catalase, and malondialdehyde along with AChE and BChE. These findings revealed that 13a holds promise as a potential candidate for further development in AD management.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Inibidores da Colinesterase , Ácidos Cumáricos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Ácidos Cumáricos/farmacologia , Humanos , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/farmacologia , Antioxidantes/síntese química , Desenho de Fármacos , Camundongos , Ratos , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Butirilcolinesterase/metabolismo , Butirilcolinesterase/efeitos dos fármacos , Células PC12 , Fragmentos de Peptídeos/metabolismo , Acetilcolinesterase/metabolismo , Acetilcolinesterase/efeitos dos fármacos
20.
Anal Chem ; 96(29): 12181-12188, 2024 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-38975840

RESUMO

New strategies for the simultaneous and portable detection of multiple enzyme activities are highly desirable for clinical diagnosis and home care. However, the methods developed thus far generally suffer from high costs, cumbersome procedures, and heavy reliance on large-scale instruments. To satisfy the actual requirements of rapid, accurate, and on-site detection of multiple enzyme activities, we report herein a smartphone-assisted programmable microfluidic paper-based analytical device (µPAD) that utilizes colorimetric and photothermal signals for simultaneous, accurate, and visual quantitative detection of alkaline phosphatase (ALP) and butyrylcholinesterase (BChE). Specifically, the operation of this µPAD sensing platform is based on two sequential steps. Cobalt-doped mesoporous cerium oxide (Co-m-CeO2) with remarkable peroxidase-like activities under neutral conditions first catalytically decomposes H2O2 for effectively converting colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue oxidized TMB (oxTMB). The subsequent addition of ALP or BChE to their respective substrates produces a reducing substance that can somewhat inhibit the oxTMB transformation for compromised colorimetric and photothermal signals of oxTMB. Notably, these two-step bioenzyme-nanozyme cascade reactions strongly support the straightforward and excellent processability of this platform, which exhibit lower detection limits for ALP and BChE with a detection limit for BChE an order of magnitude lower than those of the other reported paper-based detection methods. The practicability and efficiency of this platform are further demonstrated through the analysis of clinical serum samples. This innovative platform exhibits great potential as a facile yet robust approach for simultaneous, accurate, and on-site visual detection of multiple enzyme activities in authentic samples.


Assuntos
Fosfatase Alcalina , Butirilcolinesterase , Colorimetria , Papel , Fosfatase Alcalina/metabolismo , Fosfatase Alcalina/análise , Fosfatase Alcalina/química , Humanos , Butirilcolinesterase/metabolismo , Butirilcolinesterase/sangue , Dispositivos Lab-On-A-Chip , Benzidinas/química , Smartphone , Cério/química , Cobalto/química , Técnicas Analíticas Microfluídicas/instrumentação , Limite de Detecção , Ensaios Enzimáticos/métodos , Ensaios Enzimáticos/instrumentação , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/análise
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