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1.
J Chem Phys ; 151(12): 125103, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31575200

RESUMO

This article reports on a frequency domain analysis of quasielastic neutron scattering spectra from free and Huperzine-A-inhibited human acetylcholinesterase, extending a recent time domain analysis of the same experimental data [M. Saouessi et al., J. Chem. Phys. 150, 161104 (2019)]. An important technical point here is the construction of a semianalytical model for the resolution-broadened dynamic structure factor that can be fitted to the experimental spectra. We find comparable parameters as in our previous study and demonstrate that our model is sensitive to subpercent changes in the experimental data, which are caused by reversible binding of the inhibitor Huperzine A.


Assuntos
Acetilcolinesterase/química , Alcaloides/química , Inibidores da Colinesterase/química , Sesquiterpenos/química , Alcaloides/farmacologia , Inibidores da Colinesterase/farmacologia , Humanos , Difração de Nêutrons , Domínios Proteicos , Sesquiterpenos/farmacologia
2.
Bol. latinoam. Caribe plantas med. aromát ; 18(5): 527-532, sept. 2019. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-1008292

RESUMO

Chemical constituents and biological activities of the aerial parts of Piper erecticaule C.DC. have been studied for the first time. Fractionation and purification of the extracts afforded aristolactam AII (1), aristolactam BII (2), piperolactam A (3), piperolactam C (4), piperolactam D (5), together with terpenoids of ß-sitosterol, ß-sitostenone, taraxerol, and lupeol. The structures of these compounds were obtained by analysis of their spectroscopic data, as well as the comparison with that of reported data. Acetylcholinesterase inhibitory activity revealed that compounds 1 and 3 showed strong AChE inhibitory effects with the percentage inhibition of 75.8% and 74.8%, respectively.


Se estudiaron por primera vez los constituyentes químicos y actividad biológica de las partes aéreas de Piper erecticaule C.DC. El fraccionamiento y la purificación de los extractos proporcionaron aristolactama AII (1), aristolactama BII (2), piperolactama A (3), piperolactama C (4), piperolactama D (5), junto con terpenoides de ß-sitosterol, ß-sitostenona, taraxerol, y el lupeol. Las estructuras de estos compuestos se obtuvieron mediante el análisis de sus datos espectroscópicos, así como mediante la comparación con datos ya informados. La actividad inhibidora de la acetilcolinesterasa reveló que los compuestos 1 y 3 mostraron un potente efecto inhibidor de la AChE con un porcentaje de inhibición del 75.8% y 74.8%, respectivamente.


Assuntos
Aporfinas/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Extratos Vegetais/química , Inibidores da Colinesterase/farmacologia , Piper/química , Alcaloides/farmacologia , Aporfinas/química , Terpenos , Inibidores da Colinesterase/química , Alcaloides Indólicos/química , Alcaloides/química , Lactamas/química
3.
J Agric Food Chem ; 67(33): 9210-9219, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31390203

RESUMO

The insecticidal and antifeedant activities of five 7-chloro-4-(1H-1,2,3-triazol-1-yl)quinoline derivatives were evaluated against the maize armyworm, Spodoptera frugiperda (J.E. Smith). These hybrids were prepared through a copper-catalyzed azide alkyne cycloaddition (CuAAC, known as a click reaction) and displayed larvicidal properties with LD50 values below 3 mg/g insect, and triazolyl-quinoline hybrid 6 showed an LD50 of 0.65 mg/g insect, making it 2-fold less potent than methomyl, which was used as a reference insecticide (LD50 = 0.34 mg/g insect). Compound 4 was the most active antifeedant derivative (CE50 = 162.1 µg/mL) with a good antifeedant index (56-79%) at concentrations of 250-1000 µg/mL. Additionally, triazolyl-quinoline hybrids 4-8 exhibited weak inhibitory activity against commercial acetylcholinesterase from Electrophorus electricus (electric-eel AChE) (IC50 = 27.7 µg/mL) as well as low anti-ChE activity on S. frugiperda larvae homogenate (IC50 = 68.4 µg/mL). Finally, molecular docking simulations suggested that hybrid 7 binds to the catalytic active site (CAS) of this enzyme and around the rim of the enzyme cavity, acting as a mixed (competitive and noncompetitive) inhibitor like methomyl. Triazolyl-quinolines 4-6 and 8 inhibit AChE by binding over the perimeter of the enzyme cavity, functioning as noncompetitive inhibitors. The results described in this work can help to identify lead triazole structures from click chemistry for the development of insecticide and deterrent products against S. frugiperda and related insect pests.


Assuntos
Inseticidas/síntese química , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Spodoptera/efeitos dos fármacos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Química Click , Simulação por Computador , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Inseticidas/química , Larva/enzimologia , Larva/crescimento & desenvolvimento , Simulação de Acoplamento Molecular , Doenças das Plantas/parasitologia , Spodoptera/enzimologia , Spodoptera/crescimento & desenvolvimento , Zea mays/parasitologia
4.
Chem Biodivers ; 16(8): e1900318, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31364803

RESUMO

Sponges from freshwater environments, unlike marine's, are poorly known producers of natural compounds with medicinal purposes. Amazonian sponges produce massive large specimens and are widely spread, taxonomically diverse and their metabolites could represent a new frontier on unusual natural products to treat diseases such as Alzheimer's and Malaria. Species of Metania and Drulia (Metaniidae) genera are major contributors to the fauna of Amazonian freshwater sponges. Methanolic extracts from several species from these genera had their inhibitory activities evaluated in vitro, for parasite Plasmodium falciparum and acetyl and butyrylcholinesterase enzymes (AChE and BChE). All extracts were able to inhibit AChE, although no activity was observed towards BChE. Drulia uruguayensis extract was the most potent, inhibiting AChE with IC50 =1.04 mg/mL. For antiplasmodial activity, all species showed inhibition to P. falciparum, but Metania reticulata being the most efficient with IC50 =2.7 µg/mL. Mass spectrometry analyses evidenced the presence of fatty acids and sterols in active extracts.


Assuntos
Antiprotozoários/química , Inibidores da Colinesterase/química , Poríferos/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Ácidos Graxos/análise , Ácidos Graxos/química , Plasmodium falciparum/efeitos dos fármacos , Poríferos/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Esteróis/química
5.
Chem Biodivers ; 16(10): e1900341, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31465610

RESUMO

The aim of this work was to investigate the enzyme inhibition, antioxidant activity, and phenolic compounds of Lecokia cretica (Lam.) DC. Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase enzymes were strongly inhibited by the L. cretica extracts. IC50 values for the three enzymes were found as 3.21 mg/mL, 2.1 mg/mL, and 2.07 mg/mL, respectively. Antioxidant activities were examined in both aqueous and ethanol (EtOH) extracts using CUPRAC, FRAP, and DPPH method. Also, the phenolic compounds of the endemic plant were identified and quantified by using HPLC/MS/MS. According to the results, the extracts have remarkable antioxidant activities. The most abundant phenolic acids of L. cretica in EtOH extract were determined as quinic acid (12.76 mg/kg of crude extract), chlorogenic acid (3.39 mg/kg), and malic acid (2.38 mg/kg).


Assuntos
Antioxidantes/farmacologia , Antagonistas Colinérgicos/farmacologia , Hipoglicemiantes/farmacologia , Fenóis/farmacologia , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Acetilcolinesterase/metabolismo , Antioxidantes/química , Antioxidantes/isolamento & purificação , Apiaceae/química , Butirilcolinesterase/metabolismo , Antagonistas Colinérgicos/química , Antagonistas Colinérgicos/isolamento & purificação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeo Hidrolases/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Fenóis/química , Fenóis/isolamento & purificação , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 179: 680-693, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31280020

RESUMO

A series of fifteen acetylcholinesterase inhibitors were designed and synthesised based upon the previously identified lead compound 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (5) which showed good inhibitory activity (IC50 0.03 ±â€¯0.07 µM) against acetylcholinesterase. A series of compounds were prepared wherein the ester linker in the original lead compound was exchanged for a more metabolically stable amide linker and the indanone moiety was exchanged for a range of aryl and aromatic heterocycles. The two most active analogues 1-benzyl-N-(5,6-dimethoxy-8H-indeno[1,2-d]thiazol-2-yl)piperidine-4-carboxamide (28) and 1-benzyl-N-(1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) piperidine-4-carboxamide (20) afforded in vitro IC50 values of 0.41 ±â€¯1.25 and 5.94 ±â€¯1.08 µM, respectively. In silico screening predicts that 20 will be a blood brain-barrier permeant, and molecular dynamic simulations are indicative of a close correlation between the binding of 20 and the Food and Drug Administration-approved cholinesterase inhibitor donepezil (1).


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Piperidinas/farmacologia , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Enguias , Cavalos , Humanos , Modelos Moleculares , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 180: 238-252, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31310916

RESUMO

A series of novel chalcone derivatives was designed, synthesized and evaluated as multifunctional agents for the treatment of AD. Among of these synthesized compounds, compound TM-2 was a selective BuChE inhibitor (IC50 = 2.6 µM) and selective MAO-B inhibitor (IC50 = 5.3 µM), which were supported by docking study. Compound TM-2 also showed good antioxidant activity, and was a selective metal chelator, as well as a neuroprotectant. Moreover, compound TM-2 could significantly inhibit self-induced and Cu2+-induced Aß1-42 aggregation with 70.2% and 80.7% inhibition rate, respectively, and could disaggregate Cu2+-induced Aß1-42 aggregation (73.5%), the further TEM images observed provided rational explanation. Besides, compound TM-2 displayed good PAMPA-BBB permeability and conformed to the Lipinski's rule of five. Further, compound TM-2 presented precognitive effect on scopolamine-induced memory impairment in vivo assay. Therefore, compound TM-2 might be a promising multifunctional hit compound for the treatment of AD, and the further structure optimization are in progress.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Chalcona/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Chalcona/síntese química , Chalcona/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Enguias , Cavalos , Humanos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos
8.
J Enzyme Inhib Med Chem ; 34(1): 1373-1379, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31347933

RESUMO

Butyrylcholinesterase (BChE) plays an important role in the progression of the Alzheimer's disease. In this study, we used a structure-based virtual screening (VS) approach to discover new BChE inhibitors. A ligand database was filtered and docked to the BChE protein using Glide program. The outcome from VS was filtered and the top ranked hits were thoroughly examined for their fitting into the protein active site. Consequently, the best 38 hits were selected for in vitro testing using Ellman's method, and six of which showed inhibition activity for BChE. Interestingly, the most potent hit (Compound 4) exhibited inhibitory activity against the BChE enzyme in the low micromolar level with an IC50 value of 8.3 µM. Hits obtained from this work can act as a starting point for future SAR studies to discover new BChE inhibitors as anti-Alzheimer agents.


Assuntos
Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Descoberta de Drogas/métodos , Simulação de Acoplamento Molecular , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Inibidores da Colinesterase/química , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 179: 404-422, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265934

RESUMO

A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11-16) and (indazole-5-yl)methanimines (17-22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson's disease (PD) and other neurological disorders. Compounds 15 (Ki = 170 pM, SI = 25907) and 17 (Ki = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE enzymes. Compound 15 was found to be the most potent and selective AChE inhibitor in all series (hAChE IC50 = 78.3 ±â€¯1.7 µM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17-22 as the amide spacer in their carboxamide analogs 11-16. Amplified photophysical evaluation of compounds 17 and 20, including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties.


Assuntos
Acetilcolinesterase/metabolismo , Amidas/farmacologia , Inibidores da Colinesterase/farmacologia , Iminas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Amidas/química , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Iminas/química , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
10.
Phytochemistry ; 165: 112055, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31261031

RESUMO

Twenty-one known Amaryllidaceae alkaloids of various structural types and one undescribed alkaloid, named narcimatuline, have been isolated from fresh bulbs of Narcissus pseudonarcissus L. cv. Dutch Master. The chemical structures were elucidated by combination of MS, HRMS, 1D and 2D NMR spectroscopic techniques, and by comparison with literature data. Narcimatuline amalgamates two basic scaffolds of Amaryllidaceae alkaloids in its core, namely galanthamine and galanthindole. All isolated compounds were evaluated for their in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), prolyl oligopeptidase (POP), and glycogen synthase kinase-3ß (GSK-3ß) inhibitory activities. The most interesting biological profile was demonstrated by newly isolated alkaloid narcimatuline.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Alcaloides de Amaryllidaceae/farmacologia , Inibidores da Colinesterase/farmacologia , Narcissus/química , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/isolamento & purificação , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Serina Endopeptidases/metabolismo , Relação Estrutura-Atividade
11.
Chem Commun (Camb) ; 55(66): 9797-9800, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31360962

RESUMO

Molecular tubes with hydrogen bonding donors in their deep hydrophobic cavities are able to selectively bind organophosphorus compounds in water through hydrogen bonding and the hydrophobic effect. They can also be used as a fluorescent sensor for nerve agent simulants and as an inhibitor to reduce the toxicity of paraoxon to acetylcholinesterase.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Agentes Neurotóxicos/química , Agentes Neurotóxicos/toxicidade , Paraoxon/química , Paraoxon/toxicidade , Calorimetria , Corantes Fluorescentes/química , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética/métodos , Termodinâmica , Água/química
12.
Toxicol Lett ; 314: 124-132, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31362050

RESUMO

Organophosphates are chemical pollutants that are existed widely in the environment, but the reactions of these agents with blood proteins are still not fully clarified. The current story was to analyze the static and dynamic interactions between human serum albumin (HSA) and phenthoate and then uncover the impact of the conjugations on the acetylcholinesterase (AChE) activity at the microscopic scale. Experimental results revealed clearly that the bioconjugate of the HSA-phenthoate was yielded and the conformation of HSA can produce autoregulation during the reaction. Dynamic reaction processes suggested that the conformational flexibility of the specific protein domain was changed significantly in equilibrium, and the electrostatic interaction energy played a major role in total energy of the biosystems, which matches the results of wet experiment and molecular docking. We also found that the modes of homologous proteins-phenthoate have obvious distinctions, and this point is related closely to the local dynamic flexibility of biomolecular structures. Additionally, the degree of bioconjugation of the HSA-phenthoate is positively associated with the enzymatic activity of target AChE, which may be attributed to the competitive reactions between HSA and AChE. Evidently, this scenario could provide useful molecular information for the systematic exploration of the toxicokinetics of organophosphorus compounds.


Assuntos
Inibidores da Colinesterase/sangue , Inseticidas/sangue , Modelos Biológicos , Simulação de Acoplamento Molecular , Compostos Organotiofosforados/sangue , Albumina Sérica Humana/metabolismo , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Sítios de Ligação , Ligação Competitiva , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Humanos , Inseticidas/química , Inseticidas/toxicidade , Compostos Organotiofosforados/química , Compostos Organotiofosforados/toxicidade , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Albumina Sérica Humana/química
13.
Chem Biol Interact ; 309: 108698, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31176713

RESUMO

Structure-guided design of novel pharmacologically active molecules relies at least in part on functionally relevant accuracy of macromolecular structures for template based drug design. Currently, about 95% of all macromolecular X-ray structures available in the PDB (Protein Data Bank) were obtained from diffraction experiments at low, cryogenic temperatures. However, it is known that functionally relevant conformations of both macromolecules and pharmacological ligands can differ at higher, physiological temperatures. We describe in this article development and properties of new human acetylcholinesterase (AChE) crystals of space group P31 and a new unit cell, amenable for room-temperature X-ray diffraction studies. We co-crystallized hAChE in P31 unit cell with the reversible inhibitor 9-aminoacridine that binds at the base of the active center gorge in addition to inhibitors that span the full length of the gorge, donepezil (Aricept, E2020) and AChE specific inhibitor BW284c51. Their new low temperature P31 space group structures appear similar to those previously obtained in the different P3121 unit cell. Successful solution of the new room temperature 3.2 Å resolution structure of BW284c51*hAChE complex from large P31 crystals enables us to proceed with studying room temperature structures of lower affinity complexes, such as oxime reactivators bound to hAChE, where temperature-related conformational diversity could be expected in both oxime and hAChE, which could lead to better informed structure-based design under conditions approaching physiological temperature.


Assuntos
Acetilcolinesterase/química , Cristalografia por Raios X , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Aminacrina/química , Aminacrina/metabolismo , Sítios de Ligação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Dimerização , Humanos , Simulação de Dinâmica Molecular , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Temperatura Ambiente
14.
Eur J Med Chem ; 178: 243-258, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185414

RESUMO

To address the multifactorial nature of Alzheimer's Disease (AD), a multi-target-directed ligand approach was herein developed. As a follow-up of our previous studies, a small library of newly designed 2-arylbenzofuran derivatives was evaluated towards cholinesterases and cannabinoid receptors. The two most promising compounds, 8 and 10, were then assessed for their neuroprotective activity and for their ability to modulate the microglial phenotype. Compound 8 emerged as able to fight AD from several directions: it restored the cholinergic system by inhibiting butyrylcholinesterase, showed neuroprotective activity against Aß1-42 oligomers, was a potent and selective CB2 ligand and had immunomodulatory effects, switching microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype. Derivative 10 was a potent CB2 inverse agonist with promising immunomodulatory properties and could be considered as a tool for investigating the role of CB2 receptors and for developing potential immunomodulating drugs addressing the endocannabinoid system.


Assuntos
Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Células CHO , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Cricetulus , Desenho de Drogas , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Ligação Proteica , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
15.
Chem Biol Interact ; 308: 216-223, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150627

RESUMO

In this study, 68 crystal structures of complexes between acetylcholinesterase (AChE, EC 3.1.1.7) and its ligands, deposited in the PDB, were analyzed by scoring the functions: LigScore1, LigScore2, PLP1, PLP2, Jain, PMF and PMF04. The scores derived from scoring functions were correlated with an inhibition constant for each ligand (Ki or IC50) in a broad range 10-3 - 10-12 M. The linear correlation model resulted in the highest coefficient of determination (r2) for the PLP2 function, 0.591. The LigScore1 function resulted in the lowest r2 value of 0.226. The PubChem database was the source of in silico computed ligand properties which were then correlated with an inhibition constant for each ligand. For the purposes of this study, two additional non-PubChem parameters were evaluated: total and relative number of sp2 hybridized atoms in the ligand. A high coefficient of determination (r2 > 0.5) was calculated for the following parameters: the number of heavy atoms, molecular mass, and number of atoms with sp2 hybridization. The PLP2 scoring function is a good candidate for drug discovery related to AChE, although a better scoring function could be developed with a higher number of crystal structures of AChE complexes and more reliable kinetic data.


Assuntos
Acetilcolinesterase/metabolismo , Ligantes , Acetilcolinesterase/química , Sítios de Ligação , Domínio Catalítico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Bases de Dados de Proteínas , Humanos , Cinética , Modelos Moleculares , Ligação Proteica
16.
Chem Biol Interact ; 308: 372-376, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31152736

RESUMO

According to recent research advance, it is interesting to identify new, potent and selective inhibitors of human butyrylcholinesterase (BChE) for therapeutic treatment of both the Alzheimer's disease (AD) and heroin abuse. In this study, we carried out a structure-based virtual screening followed by in vitro activity assays, with the goal to identify new inhibitors that are selective for BChE over acetylcholinesterase (AChE). As a result, a set of new, selective inhibitors of human BChE were identified from natural products with solanaceous alkaloid scaffolds. The most active one of the natural products (compound 1) identified has an IC50 of 16.8 nM against BChE. It has been demonstrated that the desirable selectivity of these inhibitors for BChE over AChE is mainly controlled by three key residues in the active site cavity, i.e. residues Q119, A277, and A328 in BChE versus the respective residues Y124, W286, and Y337 in AChE. Based on this structural insight, future rational design of new, potent and selective BChE inhibitors may focus on these key structural differences in the active site cavity.


Assuntos
Butirilcolinesterase/química , Inibidores da Colinesterase/química , Alcaloides de Solanáceas/química , Sítios de Ligação , Butirilcolinesterase/metabolismo , Domínio Catalítico , Inibidores da Colinesterase/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Alcaloides de Solanáceas/metabolismo , Relação Estrutura-Atividade
17.
Chem Biol Interact ; 308: 350-356, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31173753

RESUMO

Activation of human butyrylcholinesterase by small quaternary ammonium ions is known. Here, additional ligands in this series are presented: edrophonium and choline, and the reactivator pyridine-2-aldoxime methochloride. Kinetic analysis of the progress curves with these compounds indicates the mechanism of enhanced deacylation by the ligand bound to the catalytic anionic site (Trp82) at the base of the active site. The larger, bis-quaternary ligands examined, as propidium, hexamethonium, decamethonium, and bis-thiocholine, show only competitive inhibition of butyrylcholinesterase, by preventing substrate approach. This hypothesis of enhanced deacylation was tested for reactivation of methanesulfonylfluoride-inactivated butyrylcholinesterase, a complex analogous to organophosphate-aged cholinesterases. The combination of substrate/products and pyridine-2-aldoxime methochloride improved butyrylcholinesterase activity over 2 h of continuous measurements, before which time substrate depletion prevailed. Similar reactivation of Torpedo californica acetylcholinesterase was unsuccessful, but both of these cholinesterases regain some activity if they have been inhibited and aged for days by diisopropylfluorophosphate.


Assuntos
Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Oximas/metabolismo , Butirilcolinesterase/química , Domínio Catalítico , Colina/química , Colina/metabolismo , Inibidores da Colinesterase/química , Edrofônio/química , Edrofônio/metabolismo , Humanos , Cinética , Ligantes , Oximas/química , Especificidade por Substrato
18.
Chem Biodivers ; 16(7): e1900144, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31155827

RESUMO

A new series of coumarin-3-carboxamide-N-morpholine hybrids 5a-5l was designed and synthesized as cholinesterases inhibitors. The synthetic approach for title compounds was started from the reaction between 2-hydroxybenzaldehyde derivatives and Meldrum's acid to afford corresponding coumarin-3-carboxylic acids. Then, amidation of the latter compounds with 2-morpholinoethylamine or N-(3-aminopropyl)morpholine led to the formation of the compounds 5a-5l. The in vitro inhibition screen against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) revealed that most of the synthesized compounds had potent AChE inhibitory while their BuChE inhibitions are moderate to weak. Among them, propylmorpholine derivative 5g (N-[3-(morpholin-4-yl)propyl]-2-oxo-2H-chromene-3-carboxamide) bearing an unsubstituted coumarin moiety and ethylmorpholine derivative 5d (6-bromo-N-[2-(morpholin-4-yl)ethyl]-2-oxo-2H-chromene-3-carboxamide) bearing a 6-bromocoumarin moiety showed the most activity against AChE and BuChE, respectively. The inhibitory activity of compound 5g against AChE was 1.78 times more than that of rivastigmine and anti-BuChE activity of compound 5d is approximately same as rivastigmine. Kinetic and docking studies confirmed the dual binding site ability of compound 5g to inhibit AChE.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Morfolinas/farmacologia , Doença de Alzheimer/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Cavalos , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Morfolinas/síntese química , Morfolinas/química
19.
Chem Biol Interact ; 309: 108682, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31163137

RESUMO

Casualties caused by nerve agents, potent acetylcholinesterase inhibitors, have attracted attention from media recently. Poisoning with these chemicals may be fatal if not correctly addressed. Therefore, research on novel antidotes is clearly warranted. Pyridinium oximes are the only clinically available compounds, but poor penetration into the blood-brain barrier hampers efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in SAR studies, we synthesized and evaluated neutral aryloximes as reactivators for acetylcholinesterase inhibited by NEMP, a VX surrogate. Although few tested compounds reached comparable reactivation results with clinical standards, they may be considered as leads for further optimization.


Assuntos
Acetilcolinesterase/metabolismo , Reativadores da Colinesterase/síntese química , Oximas/química , Pirrolidinas/química , Acetilcolinesterase/química , Animais , Antídotos/síntese química , Antídotos/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Reativadores da Colinesterase/metabolismo , Enguias , Compostos Organotiofosforados/química , Compostos Organotiofosforados/metabolismo , Oximas/metabolismo , Pirrolidinas/metabolismo , Relação Estrutura-Atividade
20.
Chem Biol Interact ; 309: 108714, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31228470

RESUMO

Acetylcholinesterase (AChE) is an enzyme which terminates the cholinergic neurotransmission, by hydrolyzing acetylcholine at the nerve and nerve-muscle junctions. The reversible inhibition of AChE was suggested as the pre-treatment option of the intoxications caused by nerve agents. Based on our derived 3D-QSAR model for the reversible AChE inhibitors, we designed and synthesized three novel compounds 8-10, joining the tacrine and aroylacrylic acid phenylamide moieties, with a longer methylene chain to target two distinct, toplogically separated anionic areas on the AChE. The targeted compounds exerted low nanomolar to subnanomolar potency toward the E. eel and human AChE's as well as the human BChE and showed mixed inhibition type in kinetic studies. All compounds were able to slow down the irreversible inhibition of the human AChE by several nerve agents including tabun, soman and VX, with the estimated protective indices around 5, indicating a valuable level of protection. Putative noncovalent interactions of the selected ligand 10 with AChE active site gorge were finally explored by molecular dynamics simulation suggesting a formation of the salt bridge between the protonated linker amino group and the negatively charged Asp74 carboxylate side chain as a significant player for the successful molecular recognition in line with the design strategy. The designed compounds may represent a new class of promising leads for the development of more effective pre-treatment options.


Assuntos
Substâncias para a Guerra Química/química , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Substâncias Protetoras/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Sítios de Ligação , Domínio Catalítico , Substâncias para a Guerra Química/metabolismo , Inibidores da Colinesterase/metabolismo , Colinesterases/química , Humanos , Cinética , Simulação de Dinâmica Molecular , Compostos Organofosforados/química , Compostos Organofosforados/metabolismo , Substâncias Protetoras/metabolismo , Relação Quantitativa Estrutura-Atividade , Soman/química , Soman/metabolismo
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