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1.
Drug Dev Res ; 85(4): e22216, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38831547

RESUMO

A new series of quinoxaline-sulfonamide derivatives 3-12 were synthesized using fragment-based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline-sulfonamide derivatives were evaluated for antidiabetic and anti-Alzheimer's potential against α-glucosidase, α-amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α-amylase and α-glucosidase with inhibitory percentages between 24.34 ± 0.01%-63.09 ± 0.02% and 28.95 ± 0.04%-75.36 ± 0.01%, respectively. Surprisingly, bis-sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against α-glucosidase and α-amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as α-glucosidase and α-amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide-quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.


Assuntos
Inibidores da Colinesterase , Inibidores de Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , Quinoxalinas , Sulfonamidas , alfa-Amilases , alfa-Glucosidases , Quinoxalinas/química , Quinoxalinas/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo , alfa-Glucosidases/química , Sulfonamidas/química , Sulfonamidas/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Relação Estrutura-Atividade , Acetilcolinesterase/metabolismo , Modelos Moleculares , Farmacóforo
2.
J Mol Model ; 30(7): 200, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38850372

RESUMO

CONTEXT: Given the diverse pathophysiological mechanisms underlying Alzheimer's disease, it is improbable that a single targeted drug will prove successful as a therapeutic strategy. Therefore, exploring various hypotheses in drug design is imperative. The sequestration of Fe(II) and Zn(II) cations stands out as a crucial mechanism based on the mitigation of reactive oxygen species. Moreover, inhibiting acetylcholinesterase represents a pivotal strategy to enhance acetylcholine levels in the synaptic cleft. This research aims to investigate the analogs of Huperzine A, documented in scientific literature, considering of these two hypotheses. Consequently, the speciation chemistry of these structures with Fe(II) and Zn(II) was scrutinized using quantum chemistry calculations, molecular docking simulations, and theoretical predictions of pharmacokinetics properties. From the pharmacokinetic properties, only two analogs, HupA-A1 and HupA-A2, exhibited a theoretical permeability across the blood-brain barrier; on the other hand, from a thermodynamic standpoint, the enantiomers of HupA-A2 showed negligible chelation values. The enantiomers with the most favorable interaction parameters were S'R'HupA-A1 (ΔGBIND = -40.0 kcal mol-1, fitness score = 35.5) and R'R'HupA-A1 (ΔGBIND = -35.5 kcal mol-1, fitness score = 22.61), being compared with HupA (ΔGBIND = -41.75 kcal mol-1, fitness score = 39.95). From this study, some prime candidates for promising drug were S'R'HupA-A1 and R'R'HupA-A1, primarily owing to their favorable thermodynamic chelating capability and potential anticholinesterase mechanism. METHODS: Quantum chemistry calculations were carried out at B3LYP/6-31G(d) level, considering the IEF-PCM(UFF) implicit solvent model for water. The coordination compounds were assessed using the Gibbs free energy variation and hard and soft acid theory. Molecular docking calculations were conducted using the GOLD program, based on the crystal structure of the acetylcholinesterase protein (PDB code = 4EY5), where the ChemScore function was employed with the active site defined as the region within a 15-Å radius around the centroid coordinates (X = -9.557583, Y = -43.910473, Z = 31.466687). Pharmacokinetic properties were predicted using SwissADME, focusing on Lipinski's rule of five.


Assuntos
Acetilcolinesterase , Alcaloides , Doença de Alzheimer , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Sesquiterpenos , Doença de Alzheimer/tratamento farmacológico , Alcaloides/química , Sesquiterpenos/química , Humanos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Barreira Hematoencefálica/metabolismo , Termodinâmica , Zinco/química , Modelos Moleculares , Ferro/química , Ferro/metabolismo
3.
Phys Chem Chem Phys ; 26(23): 16898-16909, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38833268

RESUMO

Alzheimer's disease is one of the causes associated with the early stages of dementia. Nowadays, the main treatment available is to inhibit the actions of the acetylcholinesterase (AChE) enzyme, which has been identified as responsible for the disease. In this study, computational methods were used to examine the structure and therapeutic ability of chemical compounds extracted from Millettia brandisiana natural products against AChE. This plant is commonly known as a traditional medicine in Vietnam and Thailand for the treatment of several diseases. Furthermore, machine learning helped us narrow down the choice of 85 substances for further studies by molecular docking and molecular dynamics simulations to gain deeper insights into the interactions between inhibitors and disease proteins. Of the five top-choice substances, γ-dimethylallyloxy-5,7,2,5-tetramethoxyisoflavone emerges as a promising substance due to its large free binding energy to AChE and the high thermodynamic stability of the resulting complex.


Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Millettia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/isolamento & purificação , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Millettia/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Humanos , Termodinâmica
4.
PLoS One ; 19(6): e0304490, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38833492

RESUMO

Inhibition of acetylcholinesterase (AChE) is a crucial target in the treatment of Alzheimer's disease (AD). Common anti-acetylcholinesterase drugs such as Galantamine, Rivastigmine, Donepezil, and Tacrine have significant inhibition potential. Due to side effects and safety concerns, we aimed to investigate a wide range of phytochemicals and structural analogues of these compounds. Compounds similar to the established drugs, and phytochemicals were investigated as potential inhibitors for AChE in treating AD. A total of 2,270 compound libraries were generated for further analysis. Initial virtual screening was performed using Pyrx software, resulting in 638 molecules showing higher binding affinities compared to positive controls Tacrine (-9.0 kcal/mol), Donepezil (-7.3 kcal/mol), Galantamine (-8.3 kcal/mol), and Rivastigmine (-6.4 kcal/mol). Subsequently, ADME properties were assessed, including blood-brain barrier permeability and Lipinski's rule of five violations, leading to 88 compounds passing the ADME analysis. Among the rivastigmine analogous, [3-(1-methylpiperidin-2-yl)phenyl] N,N-diethylcarbamate showed interaction with Tyr123, Tyr336, Tyr340, Phe337, Trp285 residues of AChE. Tacrine similar compounds, such as 4-amino-2-styrylquinoline, exhibited bindings with Tyr123, Phe337, Tyr336, Trp285, Trp85, Gly119, and Gly120 residues. A phytocompound (bisdemethoxycurcumin) showed interaction with Trp285, Tyr340, Trp85, Tyr71, and His446 residues of AChE with favourable binding. These findings underscore the potential of these compounds as novel inhibitors of AChE, offering insights into alternative therapeutic avenues for AD. A 100ns simulation analysis confirmed the stability of protein-ligand complex based on the RMSD, RMSF, ligand properties, PCA, DCCM and MMGBS parameters. The investigation suggested 3 ligands as a potent inhibitor of AChE which are [3-(1-methylpiperidin-2-yl)phenyl] N,N-diethylcarbamate, 4-Amino-2-styrylquinoline and bisdemethoxycurcumin. Furthermore, investigation, including in-vitro and in-vivo studies, is needed to validate the efficacy, safety profiles, and therapeutic potential of these compounds for AD treatment.


Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/farmacocinética , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Humanos , Barreira Hematoencefálica/metabolismo
5.
Nat Commun ; 15(1): 4844, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844466

RESUMO

Farmers from South Asian countries spray insecticides without protective gear, which leads to insecticide exposure through dermal and nasal routes. Acetylcholinesterase plays a crucial role in controlling neuromuscular function. Organophosphate and carbamate insecticides inhibit acetylcholinesterase, which leads to severe neuronal/cognitive dysfunction, breathing disorders, loss of endurance, and death. To address this issue, an Oxime-fabric is developed by covalently attaching silyl-pralidoxime to the cellulose of the fabric. The Oxime-fabric, when stitched as a bodysuit and facemask, efficiently deactivates insecticides (organophosphates and carbamates) upon contact, preventing exposure. The Oxime-fabric prevents insecticide-induced neuronal damage, neuro-muscular dysfunction, and loss of endurance. Furthermore, we observe a 100% survival rate in rats when repeatedly exposed to organophosphate-insecticide through the Oxime-fabric, while no survival is seen when organophosphate-insecticide applied directly or through normal fabric. The Oxime-fabric is washable and reusable for at least 50 cycles, providing an affordable solution to prevent insecticide-induced toxicity and lethality among farmers.


Assuntos
Inseticidas , Oximas , Animais , Inseticidas/toxicidade , Ratos , Oximas/administração & dosagem , Oximas/farmacologia , Masculino , Compostos de Pralidoxima/farmacologia , Compostos de Pralidoxima/administração & dosagem , Têxteis , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/toxicidade , Acetilcolinesterase/metabolismo , Exposição Ocupacional/prevenção & controle , Exposição Ocupacional/efeitos adversos , Carbamatos/farmacologia , Carbamatos/administração & dosagem , Organofosfatos/toxicidade , Administração Intranasal
6.
Planta Med ; 90(7-08): 561-575, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38843796

RESUMO

Acetylcholinesterase (AChE) inhibitors are still an important option for managing symptoms of mild to moderate Alzheimer's disease. In this study, we aimed to evaluate the potential in vitro AChE inhibitory activity of two Argentinian endemic Solanaceae species, Jaborosa bergii and J. runcinata. UHPLC-DAD-HRMS metabolite profiling revealed the presence of withanolides in the active CH2Cl2 subextracts. Their fractionation led to the isolation and identification of two known spiranoid withanolides from J. runcinata and three new withanolides with a skeleton similar to that of trechonolide-type withanolides from J. bergii. The known compounds showed moderate AChE inhibitory activity, while the new ones were inactive.


Assuntos
Inibidores da Colinesterase , Solanaceae , Vitanolídeos , Vitanolídeos/farmacologia , Vitanolídeos/química , Vitanolídeos/isolamento & purificação , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Solanaceae/química , Argentina , Acetilcolinesterase/metabolismo , Acetilcolinesterase/efeitos dos fármacos , Estrutura Molecular , Extratos Vegetais/farmacologia , Extratos Vegetais/química
7.
J Tradit Chin Med ; 44(3): 496-504, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38767633

RESUMO

OBJECTIVE: To investigate the effects of Hippeastrum hybridum (HH) as a free radical scavenger, and an inhibitor of the two enzymes i-e Alpha-amylase (α-amylase) and acetylcholinesterase (AChE). METHODS: In this study, HH plant was preliminary analyzed for phytochemical screening and then tested for its antioxidant, anti-α-amylase, and anti-AChE efficiency via standard procedures. RESULTS: Phytochemical analysis shows the existence of different compounds; while Coumarins and quinones were absent. The total phenolic, flavonoid, and tannins content were found to be (78.52 ± 0.69) mg GAE/g, (2.01 ± 0.04) mg RUE/g, and (58.12 ± 0.23) mg TAE/g of plant extract respectively. 28.02% ± 0.02% alkaloid and 2.02% ± 0.05% saponins were present in the HH extract. The HH extract showed the anti-oxidant property with IC50 (50% inhibition) of (151.01 ± 0.13) (HH), (79.01 ± 0.04) (Ascorbic acid) for ferric reducing, (91.48 ± 0.13) (HH), (48.02 ± 0.11) (Ascorbic acid) against Ammonium molybdenum, (156.02 ± 0.31) (HH), (52.38 ± 0.21) (Ascorbic acid) against DPPH, 136.01 ± 0.21 (HH), 52.02± 0.31 (Ascorbic acid) against H2O2, and 154.12 ± 0.03 (HH), (40.05 ± 0.15) (Ascorbic acid) µg/mL against ABTS respectively. Statistical analysis indicated that HH caused a competitive type of inhibition of α-amylase (Vmax remained constant and Km increases from 10.65 to 84.37%) while Glucophage caused the un-competitive type of inhibition i-e both Km and Vmax decreased from 40.49 to 69.15% and 38.86 to 69.61% respectively. The Ki, (inhibition constant); KI, (dissociation constant), Km, (Michaelis-Menten constant), and IC50 were found to be 62, 364, 68.1, and 38.08 ± 0.22 for HH and 12, 101.05, 195, 34.01 ± 0.21 for Glucophage. Similarly, HH causes an anon-competitive type of inhibition of AChE i-e Km remains constant while Vmax decreases from 60.5% to 74.1%. The calculated Ki, KI, Km, and IC50 were found to be 32, 36.2, 0.05, and 18.117 ± 0.018. CONCLUSION: From the current results, it is concluded that HH extract contains bioactive compounds, and could be a good alternative to controlling oxidants, Alzheimer's and Type-II diabetic diseases.


Assuntos
Acetilcolinesterase , Antioxidantes , Inibidores da Colinesterase , Extratos Vegetais , alfa-Amilases , Antioxidantes/química , Antioxidantes/farmacologia , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Humanos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia
8.
Front Biosci (Landmark Ed) ; 29(5): 183, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38812295

RESUMO

BACKGROUND: The present study aimed to investigate the in-vitro anti-diabetic, anti-cholinesterase, and anti-inflammatory potential of extracts from different parts of Ficus benghalensis, including leaves, stem, and roots, as well as isolated column fractions (F-B-1 C, F-B-2 C, F-B-3 C, and F-B-4 C). METHODS: The extracts and subsequent fractions were evaluated for their inhibitory activity against key enzymes involved in diabetes [α-glucosidase and α-amylase], neurodegenerative diseases [acetylcholinesterase and butyrylcholinesterase], and inflammation (cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX)). RESULTS: The results showed that F. benghalensis leaf extract exhibited the highest α-glucosidase inhibitory activity (73.84%) and α-amylase inhibitory activity (76.29%) at 1000 µg/mL. The stem extract (65.50%) and F-B-2 C fraction (69.67%) also demonstrated significant α-glucosidase inhibitory activity. In terms of anti-cholinesterase activity, the extracts of roots, leaves, and stem showed promising inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with half maximal inhibitory concentration (IC50) values ranging from 50.50 to 474.83 µg/mL. The derived fractions (F-B-1 C, F-B-2 C, F-B-3 C, and F-B-4 C) also exhibited notable inhibition of AChE and BChE, with IC50 values from 91.85 to 337.94 µg/mL. Moreover, the F-B-3 C fraction demonstrated the highest COX-2 inhibitory potential (85.72%), followed by F-B-1 C (83.13%), the stem extract (80.85%), and the leaves extract (79.00%). The F-B-1 C fraction showed the highest 5-LOX inhibitory activity (87.63%), while the root extract exhibited the lowest inhibition (73.39%). CONCLUSIONS: The results demonstrated promising bioactivity, suggesting the potential of F. benghalensis as a source of natural compounds with therapeutic applications. Further studies are required to identify and isolate the active components responsible for these effects and to evaluate their in-vivo efficacy and safety.


Assuntos
Anti-Inflamatórios , Inibidores da Colinesterase , Ficus , Hipoglicemiantes , Extratos Vegetais , Ficus/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Folhas de Planta/química , Butirilcolinesterase/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , alfa-Amilases/antagonistas & inibidores , Inibidores de Lipoxigenase/farmacologia , Inibidores de Lipoxigenase/isolamento & purificação , Acetilcolinesterase/metabolismo , Araquidonato 5-Lipoxigenase/metabolismo , Raízes de Plantas/química
9.
World J Microbiol Biotechnol ; 40(7): 215, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38802663

RESUMO

Withanolides are steroidal lactones with diverse bioactive potential and their production from plant sources varies with genotype, age, culture conditions, and geographical region. Endophytic fungi serve as an alternative source to produce withanolides, like their host plant, Withania somnifera (L.) Dunal. The present study aimed to isolate endophytic fungi capable of producing withanolides, characterization and investigation of biological activities of these molecules. The methanolic fungal crude extract of one of the fungal isolates WSE16 showed maximum withanolide production (219 mg/L). The fungal isolate WSE16 was identified as Penicillium oxalicum based on its morphological and internal transcribed spacer (ITS) sequence analysis and submitted in NCBI (accession number OR888725). The methanolic crude extract of P. oxalicum was further purified by column chromatography, and collected fractions were assessed for the presence of withanolides. Fractions F3 and F4 showed a higher content of withanolides (51.8 and 59.1 mg/L, respectively) than other fractions. Fractions F3 and F4 exhibited antibacterial activity against Staphylococcus aureus with an IC50 of 23.52 and 17.39 µg/ml, respectively. These fractions also showed antioxidant activity (DPPH assay with IC50 of 39.42 and 38.71 µg/ml, superoxide anion scavenging assay with IC50 of 41.10 and 38.84 µg/ml, and reducing power assay with IC50 of 42.61 and 41.40 µg/ml, respectively) and acetylcholinesterase inhibitory activity (IC50 of 30.34 and 22.05 µg/ml, respectively). The withanolides present in fraction 3 and fraction 4 were identified as (20S, 22R)-1a-Acetoxy-27-hydroxywitha-5, 24-dienolide-3b-(O-b-D-glucopyranoside) and withanamide A, respectively, using UV, FTIR, HRMS, and NMR analysis. These results suggest that P. oxalicum, an endophytic fungus isolated from W. somnifera, is a potential source for producing bioactive withanolides.


Assuntos
Endófitos , Penicillium , Withania , Vitanolídeos , Withania/microbiologia , Withania/química , Vitanolídeos/metabolismo , Vitanolídeos/isolamento & purificação , Vitanolídeos/farmacologia , Penicillium/metabolismo , Penicillium/genética , Endófitos/metabolismo , Endófitos/isolamento & purificação , Endófitos/genética , Endófitos/classificação , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Antioxidantes/isolamento & purificação , Antioxidantes/química , Antibacterianos/farmacologia , Antibacterianos/biossíntese , Antibacterianos/isolamento & purificação , Filogenia , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/isolamento & purificação , Testes de Sensibilidade Microbiana
10.
Drug Dev Res ; 85(4): e22214, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38816986

RESUMO

In this study, the synthesis of N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives (3a-3k) and to investigate their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and ß-secretase 1 (BACE-1) inhibition activity were aimed. Mass, 1H NMR, and 13C NMR spectra were utilized to determine the structure of the synthesized compounds. Compounds 3b, 3c, 3f, and 3j showed AChE inhibitory activity which compound 3c (IC50 = 0.030 ± 0.001 µM) showed AChE inhibitory activity as high as the reference drug donepezil (IC50 = 0.0201 ± 0.0010 µM). Conversely, none of the compounds showed BChE activity. Compounds 3c and 3j showed the highest BACE-1 inhibitory activity and IC50 value was found as 0.119 ± 0.004 µM for compound 3j whereas IC50 value was 0.110 ± 0.005 µM for donepezil, which is one of the reference substance. Molecular docking studies have been carried out using the data retrieved from the server of the Protein Data Bank (PDBID: 4EY7 and 2ZJM). Using in silico approach behavior active compounds (3c and 3j) and their binding modes clarified.


Assuntos
Acetilcolinesterase , Secretases da Proteína Precursora do Amiloide , Butirilcolinesterase , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Butirilcolinesterase/metabolismo , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Humanos , Relação Estrutura-Atividade , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/farmacologia , Acetamidas/química , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/síntese química
11.
Food Chem ; 453: 139666, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-38759443

RESUMO

Pesticide residues in agricultural products pose a significant threat to human health. Herein, a sensitive fluorescence method employing upconversion nanoparticles was developed for detecting organophosphorus pesticides (OPs) based on the principle of enzyme inhibition and copper-triggered o-phenylenediamine (OPD) oxidation. Copper ions (Cu2+) oxidized the colorless OPD to a yellow 2,3-diaminophenazine (oxOPD). The yellow solution oxOPD quenched the fluorescence of upconversion nanoparticles due to the fluorescence resonance energy transfer. The high affinity of Cu2+ for thiocholine reduced the level of oxOPD, resulting in almost no fluorescence quenching. The addition of dimethoate led to the inhibition of acetylcholinesterase activity and thus prevented the formation of thiocholine. Subsequently, Cu2+ oxidized OPD to form oxOPD, which attenuated the fluorescence signal of the system. The detection system has a good linear range of 0.01 ng/mL to 50 ng/mL with a detection limit of 0.008 ng/mL, providing promising applications for rapid detection of dimethoate.


Assuntos
Acetilcolinesterase , Cobre , Dimetoato , Oxirredução , Praguicidas , Fenilenodiaminas , Cobre/química , Fenilenodiaminas/química , Dimetoato/química , Dimetoato/análise , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Praguicidas/química , Praguicidas/análise , Nanopartículas/química , Limite de Detecção , Técnicas Biossensoriais/instrumentação , Fluorescência , Inibidores da Colinesterase/química , Inibidores da Colinesterase/análise
12.
Pak J Pharm Sci ; 37(1): 25-32, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38741397

RESUMO

In the present study, antioxidant activity and inhibition of acetylcholinesterase (AChE) and paraoxonase (hPON 1) of Alchemilla lithophila extracts were evaluated for the first time. Besides, there is no research on the contents of phenolic compounds except for fatty acids. In this context, phenolic compounds of A. lithophila were investigated by liquid chromatography/ mass spectrometry (LC-MS/MS). The methanol extract of the A. lithophila exhibited significant inhibition on the AChE (IC50 value for methanol extract 0.162 ± 0.25 mg /mL, R2:0.992). Besides, antioxidant activities of the A. lithophila extracts were examined using by the methods ABTS•+ and DPPH• free radical scavenging potentials, FRAP and CUPRAC metal-reducing activities. ABTS•+ and DPPH• scavenging activities were found for methanol extract at 70.67% and water extract at 75.38%, respectively. Also, FRAP and CUPRAC metal-reducing were determined for water extract 0.796 and hexane extract 1.570 as absorbance. According to LC-MS/MS analyses, the amounts of ellagic acid, catechin hydrate, gallic acid, fumaric acid, luteolin, quercetin, kaempferol, acetohydroxamic acid, caffeic acid, syringic acid, hydroxybenzoic acid and salicylic acid were determined by LC-MS/MS, respectively. As a consequence, this study will be a useful resource for determining bioactivity and phenolic compound profile for natural medicine research.


Assuntos
Acetilcolinesterase , Antioxidantes , Arildialquilfosfatase , Inibidores da Colinesterase , Fenóis , Extratos Vegetais , Inibidores da Colinesterase/farmacologia , Fenóis/análise , Fenóis/farmacologia , Antioxidantes/farmacologia , Antioxidantes/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/efeitos dos fármacos , Arildialquilfosfatase/metabolismo , Arildialquilfosfatase/antagonistas & inibidores , Espectrometria de Massas em Tandem
13.
Sci Rep ; 14(1): 10675, 2024 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-38724667

RESUMO

Trillium govanianum is traditionally used to treat innumerable alignments like sexual disorders, cancer, inflammation etc. Mainly rhizomes of T. govanianum have been explored for phytochemical profiling but comprehensive metabolomics of other parts has not been yet deeply investigated. Thus, current study was aimed for organs-specific (roots, rhizomes, rhizomatous buds, stems, leaves, and fruits) phytochemical profiling of T. govanianum via metabolomics approach. Targeted (steroidal saponins and free sugars) and non-targeted metabolomics were performed by UPLC-PDA/ELSD & UHPLC-Q-TOF-IMS. Among steroidal compounds, 20-hydroxyecdysone, pennogenin-3-O-ß-chacotrioside, dioscin were found predominantly in all samples while diosgenin was identified only in rhizomes. Further, four free sugars viz. 2-deoxyribose (116.24 ± 1.26 mg/g: leaves), fructose (454.76 ± 12.14 mg/g: rhizomes), glucose (243.21 ± 7.53 mg/g: fruits), and galactose (69.06 ± 2.14 mg/g: fruits) were found significant in respective parts of T. govanianum. Elemental analysis of targeted samples was determined by atomic absorption spectrophotometer. Heavy metals (Cd, Hg, Pd, As) were absent while micro- (Mn, Na, Zn, Cu) and macro- (Ca, Fe, Mg, K) elements were found in all samples. Furthermore, UHPLC-Q-TOF-IMS had identified 103 metabolites based on their mass fragmentation patterns and 839 were tentatively predicted using METLIN database. The multivariate statistical analysis showed organs specific clustering and variance of metabolites. Apart from this, extracts were evaluated for in vitro anticholinesterase activity, and found potentials inhibitors with IC50 values 2.02 ± 0.15 to 27.65 ± 0.89 mg/mL and 3.58 ± 0.12 to 16.81 ± 2.48 mg/mL of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzyme, respectively. Thus, comprehensive metabolomics and anti-cholinesterase activity of different parts of T. govanianum would lay the foundation for improving medicinal importance and health benefits of T. govanianum.


Assuntos
Inibidores da Colinesterase , Metabolômica , Trillium , Metabolômica/métodos , Inibidores da Colinesterase/farmacologia , Trillium/química , Trillium/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Folhas de Planta/química , Folhas de Planta/metabolismo , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/análise , Cromatografia Líquida de Alta Pressão , Rizoma/química , Raízes de Plantas/química , Raízes de Plantas/metabolismo
14.
Eur J Med Chem ; 271: 116450, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38701714

RESUMO

The complexity and multifaceted nature of Alzheimer's disease (AD) have driven us to further explore quinazoline scaffolds as multi-targeting agents for AD treatment. The lead optimization strategy was utilized in designing of new series of derivatives (AK-1 to AK-14) followed by synthesis, characterization, and pharmacological evaluation against human cholinesterase's (hChE) and ß-secretase (hBACE-1) enzymes. Amongst them, compounds AK-1, AK-2, and AK-3 showed good and significant inhibitory activity against both hAChE and hBACE-1 enzymes with favorable permeation across the blood-brain barrier. The most active compound AK-2 revealed significant propidium iodide (PI) displacement from the AChE-PAS region and was non-neurotoxic against SH-SY5Y cell lines. The lead molecule (AK-2) also showed Aß aggregation inhibition in a self- and AChE-induced Aß aggregation, Thioflavin-T assay. Further, compound AK-2 significantly ameliorated Aß-induced cognitive deficits in the Aß-induced Morris water maze rat model and demonstrated a significant rescue in eye phenotype in the Aꞵ-phenotypic drosophila model of AD. Ex-vivo immunohistochemistry (IHC) analysis on hippocampal rat brains showed reduced Aß and BACE-1 protein levels. Compound AK-2 suggested good oral absorption via pharmacokinetic studies and displayed a good and stable ligand-protein interaction in in-silico molecular modeling analysis. Thus, the compound AK-2 can be regarded as a lead molecule and should be investigated further for the treatment of AD.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Inibidores da Colinesterase , Desenho de Fármacos , Quinazolinas , Quinazolinas/farmacologia , Quinazolinas/síntese química , Quinazolinas/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Humanos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Acetilcolinesterase/metabolismo , Ratos , Relação Estrutura-Atividade , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Dose-Resposta a Droga , Butirilcolinesterase/metabolismo , Masculino
15.
Molecules ; 29(9)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38731452

RESUMO

In this study, two "on-off" probes (BF2-cur-Ben and BF2-cur-But) recognizing acetylcholinesterase (AChE) were designed and synthesized. The obtained probes can achieve recognition of AChE with good selectivity and pH-independence with a linear range of 0.5~7 U/mL and 0.5~25 U/mL respectively. BF2-cur-Ben has a lower limit of detection (LOD) (0.031 U/mL), higher enzyme affinity (Km = 16 ± 1.6 µM), and higher inhibitor sensitivity. A responsive mechanism of the probes for AChE was proposed based on HPLC and mass spectra (MS) experiments, as well as calculations. In molecular simulation, BF2-cur-Ben forms more hydrogen bonds (seven, while BF2-cur-But has only four) and thus has a more stable enzyme affinity, which is mirrored by the results of the comparison of Km values. These two probes could enable recognition of intracellular AChE and probe BF2-cur-Ben has superior cell membrane penetration due to its higher log p value. These probes can monitor the overexpression of AChE during apoptosis of lung cancer cells. The ability of BF2-cur-Ben to monitor AChE in vivo was confirmed by a zebrafish experiment.


Assuntos
Acetilcolinesterase , Corantes Fluorescentes , Peixe-Zebra , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Animais , Humanos , Limite de Detecção , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química
16.
Alzheimers Res Ther ; 16(1): 117, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38812028

RESUMO

BACKGROUND: A large proportion of nursing home (NH) residents suffer from dementia and effects of conventional anti-dementia drugs on their health is poorly known. We aimed to investigate the associations between exposure to anti-dementia drugs and mortality among NH residents. METHODS: This retrospective longitudinal observational study involved 329 French NH and the residents admitted in these facilities since 2014 and having major neurocognitive disorder. From their electronic health records, we obtained their age, sex, level of dependency, Charlson comorbidity index, and Mini mental examination score at admission. Exposure to anti-dementia drugs was determined using their prescription into 4 categories: none, exposure to acetylcholinesterase inhibitors (AChEI) alone, exposure to memantine alone, exposure to AChEI and memantine. Survival until the end of 2019 was studied in the entire cohort by Cox proportional hazards. To alleviate bias related to prescription of anti-dementia drugs, we formed propensity-score matched cohorts for each type of anti-dementia drug exposure, and studied survival by the same method. RESULTS: We studied 25,358 NH residents with major neurocognitive disorder. Their age at admission was 87.1 + 7.1 years and 69.8% of them were women. Exposure to anti-dementia drugs occurred in 2,550 (10.1%) for AChEI alone, in 2,055 (8.1%) for memantine alone, in 460 (0.2%) for AChEI plus memantine, whereas 20,293 (80.0%) had no exposure to anti-dementia drugs. Adjusted hazard ratios for mortality were significantly reduced for these three groups exposed to anti-dementia drugs, as compared to reference group: HR: 0.826, 95%CI 0.769 to 0.888 for AChEI; 0.857, 95%CI 0.795 to 0.923 for memantine; 0.742, 95%CI 0.640 to 0.861 for AChEI plus memantine. Results were consistent in propensity-score matched cohorts. CONCLUSION: The use of conventional anti-dementia drugs is associated with a lower mortality in nursing home residents with dementia and should be widely used in this population.


Assuntos
Inibidores da Colinesterase , Demência , Memantina , Casas de Saúde , Humanos , Memantina/uso terapêutico , Casas de Saúde/estatística & dados numéricos , Feminino , Masculino , Demência/tratamento farmacológico , Demência/mortalidade , Estudos Longitudinais , Idoso de 80 Anos ou mais , Inibidores da Colinesterase/uso terapêutico , Estudos Retrospectivos , Idoso , Instituição de Longa Permanência para Idosos/estatística & dados numéricos , França/epidemiologia
17.
Eur J Med Chem ; 272: 116463, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38704944

RESUMO

Butyrylcholinesterase (BChE) has attracted wide interest as a promising target in Alzheimer's disease (AD) investigation. BChE is considered to play a compensable role of hydrolyzing acetylcholine (ACh), and its positive correlation with ß-amyloid (Aß) deposition also promotes disease progression. Herein, we uncovered a selective potent BChE inhibitor S21-1011 (eqBChE IC50 = 0.059 ± 0.006 µM, hBChE IC50 = 0.162 ± 0.069 µM), which presented satisfactory druggability and therapeutic efficacy in AD models. In pharmacokinetics (PK) studies, S21-1011 showed excellent blood-brain barrier (BBB) permeability, metabolism stability and high oral-bioavailability. In pharmacodynamic (PD) studies, it protected neural cells from toxicity and inflammation stimulation in vitro. Besides, it also exerted anti-inflammatory effect and alleviated cognitive impairment in mice models induced by lipopolysaccharides (LPS) and Aß. Generally, this compound has been confirmed to function as a neuroprotector and cognition improver in various AD pathology-like models. Therefore, S21-1011, a novel potent BChE inhibitor, could be considered as a potential anti-AD candidate worthy of more profound investigation.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Inibidores da Colinesterase , Quinolinas , Butirilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/síntese química , Camundongos , Humanos , Relação Estrutura-Atividade , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/síntese química , Descoberta de Drogas , Estrutura Molecular , Masculino , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Relação Dose-Resposta a Droga , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/síntese química , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/síntese química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Inflamação/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos
18.
Int J Mol Sci ; 25(10)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38791206

RESUMO

Dementia exists as a 'progressive clinical syndrome of deteriorating mental function significant enough to interfere with activities of daily living', with the most prevalent type of dementia being Alzheimer's disease (AD), accounting for about 80% of diagnosed cases. AD is associated with an increased risk of comorbidity with other clinical conditions such as hypertension, diabetes, and neuropsychiatric symptoms (NPS) including, agitation, anxiety, and depression as well as increased mortality in late life. For example, up to 70% of patients diagnosed with AD are affected by anxiety. As aging is the major risk factor for AD, this represents a huge global burden in ageing populations. Over the last 10 years, significant efforts have been made to recognize the complexity of AD and understand the aetiology and pathophysiology of the disease as well as biomarkers for early detection. Yet, earlier treatment options, including acetylcholinesterase inhibitors and glutamate receptor regulators, have been limited as they work by targeting the symptoms, with only the more recent FDA-approved drugs being designed to target amyloid-ß protein with the aim of slowing down the progression of the disease. However, these drugs may only help temporarily, cannot stop or reverse the disease, and do not act by reducing NPS associated with AD. The first-line treatment options for the management of NPS are selective serotonin reuptake inhibitors/selective noradrenaline reuptake inhibitors (SSRIs/SNRIs) targeting the monoaminergic system; however, they are not rational drug choices for the management of anxiety disorders since the GABAergic system has a prominent role in their development. Considering the overall treatment failures and side effects of currently available medication, there is an unmet clinical need for rationally designed therapies for anxiety disorders associated with AD. In this review, we summarize the current status of the therapy of AD and aim to highlight novel angles for future drug therapy in our ongoing efforts to alleviate the cognitive deficits and NPS associated with this devastating disease.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/etiologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Animais , Inibidores da Colinesterase/uso terapêutico
19.
Int J Mol Sci ; 25(10)2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38791458

RESUMO

Amblyomma sculptum is a species of tick in the family Ixodidae, with equids and capybaras among its preferred hosts. In this study, the acaricidal activity of the essential oil (EO) from Piper aduncum and its main component, Dillapiole, were evaluated against larvae of A. sculptum to establish lethal concentration values and assess the effects of these compounds on tick enzymes. Dillapiole exhibited slightly greater activity (LC50 = 3.38 mg/mL; 95% CI = 3.24 to 3.54) than P. aduncum EO (LC50 = 3.49 mg/mL; 95% CI = 3.36 to 3.62) against ticks. The activities of α-esterase (α-EST), ß-esterase (ß-EST), and glutathione-S-transferase (GST) enzymes in A. sculptum larvae treated with Dillapiole showed a significant increase compared to the control at all concentrations (LC5, LC25, LC50 and LC75), similar results were obtained with P. aduncum EO, except for α-EST, which did not differ from the control at the highest concentration (LC75). The results of the acetylcholinesterase (AChE) activity show an increase in enzyme activity at the two lower concentrations (LC5 and LC25) and a reduction in activity at the two higher, lethal concentrations (LC50 and LC75) compared to the control. These results suggest potential mechanisms of action for these natural acaricides and can provide guidance for the future development of potential plant-derived formulations.


Assuntos
Acaricidas , Acetilcolinesterase , Larva , Óleos Voláteis , Piper , Animais , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Acetilcolinesterase/metabolismo , Piper/química , Larva/efeitos dos fármacos , Acaricidas/farmacologia , Glutationa Transferase/metabolismo , Amblyomma , Inativação Metabólica , Inibidores da Colinesterase/farmacologia , Benzodioxóis/farmacologia , Esterases/metabolismo , Compostos Alílicos , Dioxóis
20.
Biomolecules ; 14(5)2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38785995

RESUMO

Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood-brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10-30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , Humanos , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Ligantes , Oximas/química , Oximas/farmacologia , Reativadores da Colinesterase/farmacologia , Reativadores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Colestenonas/farmacologia , Colestenonas/química , Cinética , Sarina/química , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/antagonistas & inibidores , Antídotos/farmacologia , Antídotos/química , Colesterol/metabolismo , Colesterol/química , Compostos Organofosforados
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