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1.
Molecules ; 26(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070099

RESUMO

Wild ginseng has better pharmacological effects than cultivated ginseng. However, its industrialization is limited by the inability to grow wild ginseng on a large scale. Herein, we demonstrate how to optimize ginseng production through cultivation, and how to enhance the concentrations of specific ginsenosides through fermentation. In the study, we also evaluated the ability of fermented cultured wild ginseng root extract (HLJG0701-ß) to inhibit acetylcholinesterase (AChE), as well as its neuroprotective effects and antioxidant activity. In invitro tests, HLJG0701-ß inhibited AChE activity and exerted neuroprotective and antioxidant effects (showing increased catalyst activity but decreased reactive oxygen species concentration). In invivo tests, after HLJG0701-ß was orally administered at doses of 0, 125, 250, and 500 mg/kg in an animal model of memory impairment, behavioral evaluation (Morris water maze test and Y-maze task test) was performed. The levels of AChE, acetylcholine (ACh), blood catalase (CAT), and malondialdehyde (MDA) in brain tissues were measured. The results showed that HLJG0701-ß produced the best results at a dose of 250 mg/kg or more. The neuroprotective mechanism of HLJG0701-ß was determined to involve the inhibition of AChE activity and a decrease in oxidative stress. In summary, both invitro and invivo tests confirmed that HJG0701-ß administration can lead to memory improvement.


Assuntos
Antioxidantes/farmacologia , Fermentação , Fármacos Neuroprotetores/farmacologia , Panax/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Acetilcolina/metabolismo , Acetilcolinesterase/metabolismo , Animais , Encéfalo/metabolismo , Catalase/sangue , Catalase/metabolismo , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Feminino , Galactose , Ginsenosídeos/farmacologia , Masculino , Malondialdeído/sangue , Camundongos , Teste do Labirinto Aquático de Morris , Ovariectomia , Espécies Reativas de Oxigênio/metabolismo , Escopolamina
2.
Molecules ; 26(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070220

RESUMO

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia. Despite research efforts, currently there are no effective pharmacotherapeutic options for the prevention and treatment of AD. Recently, numerous studies highlighted the beneficial effects of curcumin (CUR), a natural polyphenol, in the neuroprotection. Especially, its dual antioxidant and anti-inflammatory properties attracted the interest of researchers. In fact, besides its antioxidant and anti-inflammatory properties, this biomolecule is not degraded in the intestinal tract. Additionally, CUR is able to cross the blood-brain barrier and could therefore to be used to treat neurodegenerative pathologies associated with oxidative stress, inflammation and apoptosis. The present study aimed to assess the ability of CUR to induce neuronal protective and/or recovery effects on a rat model of neurotoxicity induced by aluminum chloride (AlCl3), which mimics the sporadic form of Alzheimer's disease. Our results showed that treatment with CUR enhances pro-oxidant levels, antioxidant enzymes activities and anti-inflammatory cytokine production and decreases apoptotic cells in AlCl3-exposed hippocampus rats. Additionally, histopathological analysis of hippocampus revealed the potential of CUR in decreasing the hallmarks in the AlCl3-induced AD. We also showed that CUR post-treatment significantly improved the behavioral, oxidative stress and inflammation in AlCl3-exposed rats. Taken together, our data presented CUR as a nutraceutical potential through its protective effects that are more interesting than recovery ones in sporadic model of AD.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Curcumina/uso terapêutico , Síndromes Neurotóxicas/complicações , Síndromes Neurotóxicas/tratamento farmacológico , Acetilcolinesterase/metabolismo , Cloreto de Alumínio/administração & dosagem , Animais , Ansiedade/complicações , Ansiedade/tratamento farmacológico , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Curcumina/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/patologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
3.
Environ Res ; 199: 111320, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33991570

RESUMO

Cholinesterase enzymes such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) cause hydrolysis of acetylcholine (ACh), a neurotransmitter responsible for the cognitive functions of the brain such as acquiring knowledge and comprehension. Therefore, inhibition of these enzymes is an effective process to curb the progressive and fatal neurological Alzheimer's disease (AD). Herein, we explored the potential inhibitory activities of various pyridine, quinoxaline, and triazine derivatives (3a-k, 6a-j and 11a-h) against AChE and BuChE enzymes by following the modified Ellman's method. Further, anti-oxidant property of these libraries was monitored using DPPH (2,2'-diphenyl-1-picryl-hydrazylhydrate) radical scavenging analysis. From the studies, we identified that compounds 6e, 6f, 11b and 11f behaved as selective AChE inhibitors with IC50 values ranging from 7.23 to 10.35 µM. Further studies revealed good anti-oxidant activity by these compounds with IC50 values in the range of 14.80-27.22 µM. The kinetic studies of the active analogues demonstrated mixed-type of inhibition due to their interaction with both the catalytic active sites (CAS) and peripheral anionic sites (PAS) of the AChE. Additionally, molecular simulation in association with fluorescence and circular dichroism (CD) spectroscopic analyses explained strong affinities of inhibitors to bind with AChE enzyme at the physiological pH of 7.2. Binding constant values of 5.4 × 104, 4.3 × 104, 3.2 × 104 and 4.9 × 104 M-1 corresponding to free energy changes -5.593, -6.799, -6.605 and -8.104 KcalM-1 were obtained at 25 °C from fluorescence emission spectroscopic studies of 6e, 6f, 11b and 11f, respectively. Besides, CD spectroscopy deliberately explained the secondary structure of AChE partly unfolded upon binding with these dynamic molecules. Excellent in vitro profiles of distinct quinoxaline and triazine compounds highlighted them as the potential leads compared to pyridine derivatives, suggesting a path towards developing preventive or therapeutic targets to treat the Alzheimer's disease.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Acetilcolinesterase/metabolismo , Antioxidantes , Humanos , Cinética , Piridinas , Quinoxalinas , Triazinas
4.
Anal Chem ; 93(19): 7362-7368, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33961403

RESUMO

Most of the fluorescence sensors require choline oxidase or quenchers to detect organophosphorus pesticides (OPs) based on a single hydrolysate and suffer from high cost, complex procedures, weak stability, and low sensitivity. Here, we proposed a brand-new fluorescence strategy for highly sensitive detection of OPs based on both hydrolysate-response disulfide bond-functionalized gold nanoclusters (S-S-AuNCs) without additional substances. S-S-AuNCs were synthesized via a facile one-step redox reaction and emitted bright red light with ultrasmall size and high water dispersion. Interestingly, S-S-AuNCs displayed a unique response to thiol compounds and low pH values and were thus pioneered as a high-efficiency sensor for OPs based on acetylcholinesterase (AChE)-catalyzed hydrolysis of acetylthiocholine into thiocholine and CH3COOH and OP inhibition of AChE activity. Further, S-S-AuNCs were employed to monitor the residue, distribution, and metabolization of methidathion in pakchoi with acceptable results. We believe that this work supplies a simpler and more highly sensitive approach for OP assay than the known ones and opens a new avenue to development of multistimulus-responsive and high-performance fluorescence substances.


Assuntos
Técnicas Biossensoriais , Praguicidas , Acetilcolinesterase/metabolismo , Dissulfetos , Ouro , Concentração de Íons de Hidrogênio , Compostos Organofosforados , Oxirredução , Praguicidas/análise
5.
Chem Biol Interact ; 344: 109523, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34033838

RESUMO

Acetylcholinesterase (AChE) plays a vital role in Alzheimer's disease (AD), which is one of the most common causes of dementia. Discovering new effective inhibitors against AChE activity is seen to be one of the effective approaches to reduce the suffering from AD. Protoberberine alkaloids isolated from natural resources have previously been reported as potent AChE inhibitors. In order to gain insights into how these alkaloids could inhibit AChE, berberine, palmatine, and cyclanoline were selected to investigate in terms of binding orientation and their key interactions with AChE using molecular docking and molecular dynamics simulations and quantum chemical calculations. The results revealed that the molecular dynamics structures of palmatine and berberine indicated that their equilibrated structures did not occupy the gorge but they slightly moved away from the catalytic site (CAS). For cyclanoline, the binding mode was quite different from those of donepezil and the other protoberberine alkaloids: it preferred to stay deeper in the CAS site. Interaction energies and residual interaction energies confirmed that the key interactions for palmatine and berberine were π-π interactions with Trp286 and Tyr341 and H-bond interactions with Tyr124. Cyclanoline formed π-π interactions with Trp86 and H-bonds to the amino acids in the CAS site. The results suggested the importance of aromaticity in the core structure and the flexibility of the core structure or the substituents in order to fit into the narrow gorge. The HOMO, LUMO, bioavailability, drug-likeness and pharmacokinetics were also predicted. The results obtained will be useful for further AD drug development.


Assuntos
Acetilcolinesterase/metabolismo , Alcaloides de Berberina/metabolismo , Inibidores da Colinesterase/metabolismo , Acetilcolinesterase/química , Alcaloides de Berberina/farmacocinética , Sítios de Ligação , Inibidores da Colinesterase/farmacocinética , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Teoria Quântica
6.
Artigo em Inglês | MEDLINE | ID: mdl-33992880

RESUMO

The lack of direct connection between traditional herbal medicines and multiple biological targets is a bottleneck in herbal research and quality evaluation. To solve this problem, a strategy for the discovery of active ingredients from function-similar herbal medicines based on multiple biological targets was proposed in this article. The technical route includes chromatographic separation, mass spectrometry analysis, enzymatic activity detection, pharmacophore analysis and molecular docking. Five citrus herbs of Citri Reticulatae Pericarpium (CRP), Citri Exocarpium Rubrum (CER), Citri Grandis Exocarpium (CGE), Aurantii Fructus Immaturus (AFI) and Aurantii Fructus (AF) were used as the research objects. A total of 136 chemical components were identified from above five herbs based on LC-Q-TOF-MS/MS and database matching. The extracts of the five herbs showed obvious inhibitory effects on α-glucosidase and acetylcholinesterase in a concentration-dependent manner. Interestingly, the different types of components in the herbs exhibited selectivity for different targets: flavanone glycosides are effective on α-glucosidase but ineffective on acetylcholinesterase; polymethoxyflavonoids are effective on acetylcholinesterase but ineffective on α-glucosidase. Furthermore, we found for the first time that the components in citrus herbs exhibit opposite structure-activity relationships on the above two targets. For example, the methoxy group can enhance the activity of compounds on acetylcholinesterase but weaken the activity of compounds on α-glucosidase. The selective action is a supplement to the "multi-components, multi-targets" system of herbal medicines. Pharmacophore analysis and molecular docking were applied to explore the interaction between active ingredients and biological targets from the perspective of ligands and receptors, respectively. By combining the above multiple technologies, a strong connection among herbal medicines, chemical components and multiple biological targets was established. This work not only helps to understand the similar function of citrus herbs for the treatment of diabetes and Alzheimer's disease, but also provides selective lead compounds for the development of related drugs. This strategy is also helpful to improve the quality evaluation of citrus herbs from the perspective of biological activity.


Assuntos
Bioensaio/métodos , Inibidores da Colinesterase , Cromatografia Líquida/métodos , Citrus/química , Inibidores de Glicosídeo Hidrolases , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Flavonoides , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
7.
Molecules ; 26(7)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916760

RESUMO

Despite extensive and intensive research efforts in recent decades, there is still no effective treatment for neurodegenerative diseases. On this background, the use of drugs inhibiting the enzyme acetylcholinesterase (AChE) remains an eternal evergreen in the symptomatic treatment of mild to moderate cognitive impairments. Even more, the cholinergic hypothesis, somewhat forgotten in recent years due to the shift in focus on amyloid cascade, is back to life, and the search for new, more effective AChE inhibitors continues. We generated a fragment-based library containing aromatic moieties and linkers originating from a set of novel AChE inhibitors. We used this library to design 1220 galantamine (GAL) derivatives following the model GAL (binding core) - linker (L) - aromatic fragment (Ar). The newly designed compounds were screened virtually for blood-brain barrier (BBB) permeability and binding to AChE. Among the top 10 best-scored compounds, a representative lead molecule was selected and tested for anti-AChE activity and neurotoxicity. It was found that the selected compound was a powerful non-toxic AChE inhibitor, 68 times more active than GAL, and could serve as a lead molecule for further optimization and development.


Assuntos
Inibidores da Colinesterase/análise , Desenho de Fármacos , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Interface Usuário-Computador , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Inibidores da Colinesterase/química , Galantamina/química , Galantamina/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neurotoxinas/toxicidade , Bibliotecas de Moléculas Pequenas
8.
Mol Biol Rep ; 48(3): 2335-2350, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33811574

RESUMO

Mounting evidences have shown that nicotinamide adenine dinucleotide phosphate oxidase-2 (Nox-2) pathway modifies glutamic-acid decarboxylase-67 (GAD67) (GABAergic enzyme) and cholinergic systems via oxidative-nitrergic mechanisms in schizophrenia pathology. Rutin, a neuroactive antioxidant compound, with proven neuroprotective property has been shown to reduce schizophrenic-like behavior in mice. This study sought to investigate the mechanisms of action of the psychopharmacological activity of rutin in the preventive and reversal effects of ketamine-induced schizophrenic-like behavior, oxidative-nitrergic stress, cholinergic and GABAergic derangements in mice. In the preventive treatment, male mice were given rutin (0.1, 0.2 and 0.4 mg/kg) or risperidone (0.5 mg/kg) orally for 14 days prior to ketamine (20 mg/kg, i.p.) treatment from the 8 to 14th day. However, in the reversal treatment, ketamine was given for 14 days prior to rutin and risperidone. Behavioral (open-field, social-interaction and Y-maze tests), biochemical (oxidative/nitrergic stress markers, acetylcholinesterase activity), immunohistochemical (GAD67, Nox-2) and neuronal cell deaths in the striatum, prefrontal cortex, and hippocampus were evaluated. Ketamine-induced behavioral impairments were prevented and reversed by rutin. Exposure of mice to ketamine increased malondialdehyde, nitrite contents, acetylcholinesterase activity, neuronal cell death and Nox-2 expressions in the striatum, prefrontal cortex and hippocampus. Conversely, these derangements were prevented and reversed by rutin. The decreased glutathione levels due to ketamine were marked increased by rutin. Rutin only prevented ketamine-induced decrease in GAD67 expression in the striatal-hippocampal region. Altogether, the study showed that the prevention and reversal treatments of mice with rutin attenuated ketamine-induced schizophrenic-like behaviors via reduction of Nox-2 expression, oxidative/nitrergic stresses, acetylcholinesterase activity, and increased GAD67 enzyme.


Assuntos
Colinérgicos/metabolismo , Glutamato Descarboxilase/metabolismo , NADPH Oxidase 2/metabolismo , Estresse Oxidativo , Rutina/uso terapêutico , Esquizofrenia/genética , Esquizofrenia/prevenção & controle , Acetilcolinesterase/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Regulação para Baixo/efeitos dos fármacos , Glutationa/metabolismo , Ketamina , Locomoção/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Camundongos , Nitritos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Rutina/farmacologia , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Interação Social , Memória Espacial/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
9.
ACS Chem Neurosci ; 12(9): 1698-1715, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33852284

RESUMO

Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called "multitarget directed ligand" approach and designed 36 novel tacrine-phenothiazine heterodimers which were in vitro evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound 1dC as a potent and selective acetylcholinesterase inhibitor with IC50 = 8 nM and 1aA as a potent butyrylcholinesterase inhibitor with IC50 = 15 nM. Selected hybrids, namely, 1aC, 1bC, 1cC, 1dC, and 2dC, showed a significant inhibitory activity toward τ(306-336) peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, 1dC and 2dC exerted a remarkable ability to inhibit self-induced Aß1-42 aggregation. Notwithstanding, in vitro studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when 1dC was administered to mice at 14 mg/kg (i.p.). 1dC was also able to permeate to the CNS as shown by in vitro and in vivo models. The maximum brain concentration was close to the IC50 value for acetylcholinesterase inhibition with a relatively slow elimination half-time. 1dC showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile.


Assuntos
Doença de Alzheimer , Tacrina , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Camundongos , Fenotiazinas/farmacologia , Relação Estrutura-Atividade , Tacrina/farmacologia
10.
ACS Chem Neurosci ; 12(9): 1648-1666, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33852798

RESUMO

Cholinesterases are significant biological targets for the regulation of cholinergic neurotransmission, and their inhibitors are being exploited for the management of cognitive decline in various neurological conditions. The 1,4-benzoquinone scaffold possesses antioxidant potential along with AChE inhibition activity in various neurological disorders. To design novel and potent selective 1,4-benzoquinone analogues as cholinesterase inhibitors, a ligand-based drug design strategy was followed to develop a 3D quantitative structure-selectivity relationship (QSSR) model. On the basis of the best fit model, eight novel 1,4-benzoquinone derivatives were designed and synthesized implementing appropriate synthetic procedures and were characterized by various spectral and elemental techniques. All the synthesized compounds were evaluated for their selective in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential at different concentrations using mice brain homogenate as the source of the enzyme. Out of these compounds, the three most selective compounds were further evaluated for behavioral variations using step down passive avoidance and escape learning procedure at a dose of 0.5 mg/kg taking donepezil as the reference drug. Biochemical estimation of the markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione, and catalase) has also been carried out to determine the role of the synthesized molecules on the scopolamine induced oxidative damage. Compound 2a displayed appreciable selectivity index values as predicted through the 3D-QSSR model. Further, docked complexes of compound 2a with AChE and BChE were subjected to molecular dynamic simulations for a period of 30 ns to study the orientations and stable conformations of the most active molecules in the catalytic domain of these enzymes. The results obtained from the 3D-QSSR analysis, docking, and molecular dynamic studies were found to be appreciable and provided a deep insight into the structural features required for the selectivity of AChE inhibitors over BChE. The outcome of this study may be used as a novel tool to design new highly selective and more potent molecules.


Assuntos
Acetilcolinesterase , Disfunção Cognitiva , Acetilcolinesterase/metabolismo , Animais , Benzoquinonas/farmacologia , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Simulação por Computador , Camundongos , Simulação de Acoplamento Molecular , Estudos Prospectivos , Relação Estrutura-Atividade
11.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810550

RESUMO

A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl (3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC50 = 36.05 µM in the series, while benzyl {3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 µM) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure-activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. π-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group.


Assuntos
Acetilcolinesterase/química , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/síntese química , Simulação de Acoplamento Molecular , Acetilcolinesterase/metabolismo , Ácido Aminossalicílico/química , Butirilcolinesterase/metabolismo , Carbamatos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Análise por Conglomerados , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Moleculares , Simulação de Dinâmica Molecular , Análise de Componente Principal , Solventes , Relação Estrutura-Atividade , Células THP-1
12.
Toxins (Basel) ; 13(3)2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33809820

RESUMO

Concerns about resistance development to conventional insecticides in diamondback moth (DBM) Plutella xylostella (L.), the most destructive pest of Brassica vegetables, have stimulated interest in alternative pest management strategies. The toxicity of Bacillus thuringiensis subsp. aizawai (Bt GO33A) combined with chlorantraniliprole (Chl) has not been documented. Here, we examined single and combined toxicity of chlorantraniliprole and Bt to assess the levels of resistance in four DBM strains. Additionally, enzyme activities were tested in field-original highly resistant (FOH-DBM), Bt-resistant (Bt-DBM), chlorantraniliprole-resistant (CL-DBM), and Bt + chlorantraniliprole-resistant (BtC-DBM) strains. The Bt product had the highest toxicity to all four DBM strains followed by the mixture of insecticides (Bt + Chl) and chlorantraniliprole. Synergism between Bt and chlorantraniliprole was observed; the combination of Bt + (Bt + Chl) (1:1, LC50:LC50) was the most toxic, showing a synergistic effect against all four DBM strains with a poison ratio of 1.35, 1.29, 1.27, and 1.25. Glutathione S-transferase (GST) and carboxyl-esterase (CarE) activities showed positive correlations with chlorantraniliprole resistance, but no correlation was observed with resistance to Bt and Bt + Chl insecticides. Expression of genes coding for PxGST, CarE, AChE, and MFO using qRT-PCR showed that the PxGST and MFO were significantly overexpressed in Bt-DBM. However, AChE and CarE showed no difference in the four DBM strains. Mixtures of Bt with chlorantraniliprole exhibited synergistic effects and may aid the design of new combinations of pesticides to delay resistance in DBM strains substantially.


Assuntos
Bacillus thuringiensis/metabolismo , Brassica/parasitologia , Resistência a Inseticidas , Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Mariposas/microbiologia , Controle Biológico de Vetores , ortoaminobenzoatos/farmacologia , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Bacillus thuringiensis/genética , Carboxilesterase/genética , Carboxilesterase/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Regulação Enzimológica da Expressão Gênica , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Resistência a Inseticidas/genética , Mariposas/enzimologia , Mariposas/genética
13.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923726

RESUMO

Alzheimer's disease (AD) is a complex multifactorial disorder, mainly characterized by the progressive loss of memory and cognitive, motor, and functional capacity. The absence of effective therapies available for AD alongside the consecutive failures in the central nervous system (CNS) drug development has been motivating the search for new disease-modifying therapeutic strategies for this disease. To address this issue, the multitarget directed ligands (MTDLs) are emerging as a therapeutic alternative to target the multiple AD-related factors. Following this concept, herein we describe the design, synthesis, and biological evaluation of a family of chromeno[3,4-b]xanthones as well as their (E)-2-[2-(propargyloxy)styryl]chromone precursors, as first-in-class acetylcholinesterase (AChE) and ß-amyloid (Aß) aggregation dual-inhibitors. Compounds 4b and 10 emerged as well-balanced dual-target inhibitors, with IC50 values of 3.9 and 2.9 µM for AChE and inhibitory percentages of 70 and 66% for Aß aggregation, respectively. The molecular docking showed that most of the compounds bound to AChE through hydrogen bonds with residues of the catalytic triad and π-stacking interactions between the main scaffold and the aromatic residues present in the binding pocket. The interesting well-balanced activities of these compounds makes them interesting templates for the development of new multitarget compounds for AD.


Assuntos
Amiloide/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Fármacos Neuroprotetores/síntese química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Amiloide/química , Amiloide/metabolismo , Sítios de Ligação , Inibidores da Colinesterase/farmacologia , Cromonas/química , Humanos , Fármacos Neuroprotetores/farmacologia , Ligação Proteica , Multimerização Proteica , Xantonas/química
14.
Molecules ; 26(8)2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33920326

RESUMO

Neurodegenerative diseases (ND), including Alzheimer's (AD) and Parkinson's Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Dopaminérgicos/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Antiparkinsonianos/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Inibidores da Colinesterase/síntese química , Ensaios Clínicos como Assunto , Simulação por Computador , Dopaminérgicos/síntese química , Desenho de Fármacos , Antagonistas de Aminoácidos Excitatórios/síntese química , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica , Humanos , Fármacos Neuroprotetores/síntese química , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Sirtuínas/antagonistas & inibidores , Sirtuínas/genética , Sirtuínas/metabolismo
15.
Molecules ; 26(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926141

RESUMO

The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer's disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT4 receptor agonist. In order to explore the structural diversity around this preclinical candidate we have explored the preparation of novel constrained analogs through late-stage rigidification strategy. A series of phenylpyrazoles was prepared in a late-stage functionalization process and all compounds were evaluated in vitro towards AChE and 5-HTRs. A docking study was performed in order to better explain the observed SAR towards AChE, 5-HT4R and 5-HT6R and this study led to the description of novel ligand targeting both AChE and 5-HT6R.


Assuntos
Inibidores da Colinesterase/química , Desenvolvimento de Medicamentos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Sítios de Ligação , Técnicas de Química Sintética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Humanos , Ligação de Hidrogênio , Ligantes , Conformação Molecular , Ligação Proteica , Relação Estrutura-Atividade
16.
J Med Chem ; 64(8): 4972-4990, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33829779

RESUMO

The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 µM), confirming the design rationale.


Assuntos
Ligantes , Fármacos Neuroprotetores/química , Extratos Vegetais/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Anacardium/química , Anacardium/metabolismo , Sítios de Ligação , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Desenho de Fármacos , Humanos , Lipopolissacarídeos/farmacologia , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Nozes/química , Nozes/metabolismo , Relação Estrutura-Atividade , Tacrina/química , Tacrina/metabolismo
17.
Molecules ; 26(7)2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33800622

RESUMO

Croton hirtus L'Hér methanol extract was studied by NMR and two different LC-DAD-MSn using electrospray (ESI) and atmospheric pressure chemical ionization (APCI) sources to obtain a quali-quantitative fingerprint. Forty different phytochemicals were identified, and twenty of them were quantified, whereas the main constituents were dihydro α ionol-O-[arabinosil(1-6) glucoside] (133 mg/g), dihydro ß ionol-O-[arabinosil(1-6) glucoside] (80 mg/g), ß-sitosterol (49 mg/g), and isorhamnetin-3-O-rutinoside (26 mg/g). C. hirtus was extracted with different solvents-namely, water, methanol, dichloromethane, and ethyl acetate-and the extracts were assayed using different in vitro tests. The methanolic extracts presented the highest 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS), and ferric reducing antioxidant power (FRAP) values. All the tested extracts exhibited inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with a higher activity observed for dichloromethane (AChE: 5.03 and BChE: 16.41 mgGALAE/g), while the methanolic extract showed highest impact against tyrosinase (49.83 mgKAE/g). Taken together, these findings suggest C. hirtus as a novel source of bioactive phytochemicals with potential for commercial development.


Assuntos
Antioxidantes/química , Inibidores da Colinesterase/química , Croton/química , Glucosídeos/química , Compostos Fitoquímicos/química , Fitosteróis/química , Terpenos/química , Acetatos/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Antioxidantes/classificação , Antioxidantes/isolamento & purificação , Benzotiazóis/antagonistas & inibidores , Benzotiazóis/química , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/química , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/isolamento & purificação , Croton/metabolismo , Glucosídeos/classificação , Glucosídeos/isolamento & purificação , Humanos , Metanol/química , Cloreto de Metileno/química , Compostos Fitoquímicos/classificação , Compostos Fitoquímicos/isolamento & purificação , Fitosteróis/classificação , Fitosteróis/isolamento & purificação , Picratos/antagonistas & inibidores , Picratos/química , Extratos Vegetais/química , Solventes/química , Relação Estrutura-Atividade , Ácidos Sulfônicos/antagonistas & inibidores , Ácidos Sulfônicos/química , Terpenos/classificação , Terpenos/isolamento & purificação , Água/química
18.
Molecules ; 26(7)2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33800652

RESUMO

In Thailand, people in the highland communities whose occupational exposure to pesticides used the root of Litsea martabanica as a detoxifying agent. However, the scientific data to support the traditional use of this plant are insufficient. This study aimed to evaluate the antioxidant activity and anti-pesticide potential of L. martabanica root extract. Antioxidant properties were investigated by 2,2'-diphenyl-1-picrylhydrazyl (DPPH) assay, superoxide radicals scavenging assay, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay, ferric reducing antioxidant power (FRAP), and total phenolic content determination. In all assays, L. martabanica extracts and their fractions exhibited high antioxidant activities differently. The water extract is traditionally used as a detoxifying agent. Therefore, it was chosen for in vivo experiments. The rats received the extract in a way that mimics the traditional methods of tribal communities followed by chlorpyrifos for 16 days. The results showed that acetylcholinesterase activity decreases in pesticide-exposed rats. Treatment with the extract caused increasing acetylcholinesterase activity in the rats. Therefore, L. martabanica extract may potentially be used as a detoxifying agent, especially for the chlorpyrifos pesticide. The antioxidant properties of L. martabanica may provide a beneficial effect by protecting liver cells from damage caused by free radicals. Histopathology results revealed no liver cell necrosis and showed the regeneration of liver cells in the treatment group. L. martabanica extract did not cause changes in behavior, liver weight, hematological and biochemical profiles of the rats.


Assuntos
Antídotos/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Clorpirifos/toxicidade , Inseticidas/toxicidade , Litsea/química , Acetilcolinesterase/metabolismo , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Antídotos/isolamento & purificação , Antioxidantes/isolamento & purificação , Aspartato Aminotransferases/metabolismo , Benzotiazóis/antagonistas & inibidores , Benzotiazóis/química , Bilirrubina/metabolismo , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/química , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Clorpirifos/antagonistas & inibidores , Creatinina/metabolismo , Inseticidas/antagonistas & inibidores , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Fitoterapia/métodos , Picratos/antagonistas & inibidores , Picratos/química , Extratos Vegetais/química , Raízes de Plantas/química , Ratos , Ratos Sprague-Dawley , Ácidos Sulfônicos/antagonistas & inibidores , Ácidos Sulfônicos/química
19.
Int J Nanomedicine ; 16: 2849-2877, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33883895

RESUMO

Background: Exosomes are endosome-derived nano-sized vesicles that have emerged as important mediators of intercellular communication and play significant roles in various diseases. However, their applications are rigorously restricted by the limited secretion competence of cells. Therefore, strategies to enhance the production and functions of exosomes are warranted. Studies have shown that nanomaterials can significantly enhance the effects of cells and exosomes in intercellular communication; however, how palladium nanoparticles (PdNPs) enhance exosome release in human leukemia monocytic cells (THP-1) remains unclear. Therefore, this study aimed to address the effect of PdNPs on exosome biogenesis and release in THP-1 cells. Methods: Exosomes were isolated by ultracentrifugation and ExoQuickTM and characterized by dynamic light scattering, nanoparticle tracking analysis system, scanning electron microscopy, transmission electron microscopy, EXOCETTM assay, and fluorescence polarization. The expression levels of exosome markers were analyzed via quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Results: PdNP treatment enhanced the biogenesis and release of exosomes by inducing oxidative stress, endoplasmic reticulum stress, apoptosis, and immunomodulation. The exosomes were spherical in shape and had an average diameter of 50-80 nm. Exosome production was confirmed via total protein concentration, exosome counts, acetylcholinesterase activity, and neutral sphingomyelinase activity. The expression levels of TSG101, CD9, CD63, and CD81 were significantly higher in PdNP-treated cells than in control cells. Further, cytokine and chemokine levels were significantly higher in exosomes isolated from PdNP-treated THP-1 cells than in those isolated from control cells. THP-1 cells pre-treated with N-acetylcysteine or GW4869 showed significant decreases in PdNP-induced exosome biogenesis and release. Conclusion: To our knowledge, this is the first study showing that PdNPs stimulate exosome biogenesis and release and simultaneously increase the levels of cytokines and chemokines by modulating various physiological processes. Our findings suggest a reasonable approach to improve the production of exosomes for various therapeutic applications.


Assuntos
Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático , Exossomos/metabolismo , Imunomodulação/efeitos dos fármacos , Leucemia/patologia , Nanopartículas Metálicas/toxicidade , Estresse Oxidativo , Paládio/toxicidade , Acetilcolinesterase/metabolismo , Acetilcisteína/farmacologia , Compostos de Anilina/farmacologia , Antioxidantes/metabolismo , Compostos de Benzilideno/farmacologia , Biomarcadores Tumorais/metabolismo , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Dano ao DNA , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia/sangue , Nanopartículas Metálicas/ultraestrutura , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Esfingomielina Fosfodiesterase/metabolismo , Células THP-1
20.
Molecules ; 26(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809771

RESUMO

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-ß (Aß) aggregation. Some of these hybrids also prevented Aß-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 µM); Aß aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Donepezila/farmacologia , Sulfonamidas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Linhagem Celular Tumoral , Inibidores da Colinesterase/farmacologia , Humanos , Ligantes , Piperazinas/farmacologia , Piperidinas/farmacologia , Relação Estrutura-Atividade
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