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1.
Arch Biochem Biophys ; 693: 108574, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-32898566

RESUMO

Studies reported that Δ9-tetrahydrocannabinol (Δ9-THC) is an essential drug as an anti-cancer, neuroprotective, anti-inflammatory, and immune-modulatory agent. However, the mechanism by which Δ9-THC causes these events remains to be elucidated. We attempted to investigate the in vivo studies of Δ9-THC on brain microtubule dynamicity, and acetylcholinesterase (AChE) activity. The microtubule polymerization, secondary and tertiary structures of α/ß-tubulins, as well as the AChE activity, were evaluated in the experimental groups. The significantly lowest optical density and initial rate of polymerization was observed in THC 3 mg/kg, THC 9 mg/kg, and THC 18 mg/kg treated groups. The content of secondary and tertiary structures of α/ß-tubulins was significantly affected in treated groups. The AChE activity was significantly lower in treated groups in a dose-dependent manner. These data highlight the microtubule dynamicity as a molecular target for Δ9-THC, which affects memory dysfunction. However, Δ9-THC can be inhibited the AChE activity and provide an improved therapeutics for neurodegenerative diseases.


Assuntos
Dronabinol/farmacologia , Microtúbulos/efeitos dos fármacos , Acetilcolinesterase/efeitos dos fármacos , Animais , Inibidores da Colinesterase/farmacologia , Dicroísmo Circular , Relação Dose-Resposta a Droga , Polimerização , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ratos , Tubulina (Proteína)/química , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/isolamento & purificação
2.
Arch Insect Biochem Physiol ; 105(2): e21731, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32761928

RESUMO

Jaburetox is a recombinant peptide derived from one of the Canavalia ensiformis urease isoforms. This peptide induces several toxic effects on insects of different orders, including interference on muscle contractility in cockroaches, modulation of UDP-N-acetylglucosamine pyrophosphorylase (UAP) and nitric oxide synthase (NOS) activities in the central nervous system of triatomines, as well as activation of the immune system in Rhodnius prolixus. When injected, the peptide is lethal for R. prolixus and Triatoma infestans. Here, we evaluated Jaburetox toxicity to Nauphoeta cinerea cockroaches, exploring the effects on the central nervous system through the activities of UAP, NOS, acid phosphatases (ACP), and acetylcholinesterase (AChE). The results indicated that N. cinerea is not susceptible to the lethal effect of the peptide. Moreover, both in vivo and in vitro treatments with Jaburetox inhibited NOS activity, without modifying the protein levels. No alterations on ACP activity were observed. In addition, the enzyme activity of UAP only had its activity affected at 18 hr after injection. The peptide increased the AChE activity, suggesting a mechanism involved in overcoming the toxic effects. In conclusion, our findings indicate that Jaburetox affects the nitrinergic signaling as well as the AChE and UAP activities and establishes N. cinerea as a Jaburetox-resistant model for future comparative studies.


Assuntos
Baratas/efeitos dos fármacos , Baratas/enzimologia , Proteínas de Plantas/toxicidade , Urease/toxicidade , Acetilcolinesterase/efeitos dos fármacos , Fosfatase Ácida/efeitos dos fármacos , Animais , Sistema Nervoso Central/efeitos dos fármacos , Feminino , Masculino , Óxido Nítrico Sintase/efeitos dos fármacos , Nucleotidiltransferases/efeitos dos fármacos , Proteínas Recombinantes/toxicidade
3.
Sci Rep ; 10(1): 11058, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632152

RESUMO

An actinomycete strain CSR-4 was isolated from the rhizosphere soil of Zingiber montanum. Taxonomic characterization revealed strain CSR-4 was a member of the genus Microbispora. Whole-genome sequence analysis exhibited the highest average nucleotide identity (ANI) value (95.34%) and digital DNA-DNA hybridization (DDH) value (74.7%) between strain CSR-4 and the closest relative M. hainanensis DSM 45428T, which was in line with the assignment to same species. In addition, a new diterpene compound, 2α-hydroxy-8(14), 15-pimaradien-17, 18-dioic acid, and nine known compounds were isolated from the ethyl acetate crude extract of fermentation broth. Interestingly, a new diterpene displayed the suppressive effect on the recombinant human acetylcholinesterase (rhAChE) enzymes (IC50 96.87 ± 2.31 µg/ml). In silico studies based on molecular docking and molecular dynamics (MD) simulations were performed to predict a binding mode of the new compound into the binding pocket of the rhAChE enzyme and revealed that some amino acids in the peripheral anions site (PAS), anionic subsite, oxyanion site and catalytic active site (CAS) of the rhAChE have interacted with the compound. Therefore, our new compound could be proposed as a potential active human AChE inhibitor. Moreover, the new compound can protect significantly the neuron cells (% neuron viability = 88.56 ± 5.19%) from oxidative stress induced by serum deprivation method at 1 ng/ml without both neurotoxicities on murine P19-derived neuron cells and cytotoxicity against Vero cells.


Assuntos
Actinobacteria/química , Inibidores da Colinesterase/farmacologia , Diterpenos/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/efeitos dos fármacos , Actinobacteria/classificação , Actinobacteria/genética , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Domínio Catalítico , Chlorocebus aethiops , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Simulação por Computador , Diterpenos/química , Diterpenos/isolamento & purificação , Humanos , Técnicas In Vitro , Camundongos , Simulação de Dinâmica Molecular , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Filogenia , RNA Ribossômico 16S/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/efeitos dos fármacos , Células Vero
4.
Exp Eye Res ; 195: 108003, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32184102

RESUMO

Elevated inflammatory cytokines contribute to the pathogenesis of various retinal diseases such as diabetic retinopathy, retinal vasculitis and retinitis. However, the underlying mechanism of retinal inflammation remains largely unknown. Recent studies demonstrated that acetylcholinesterase (ACHE) is an inflammatory indicator in central neural system. This study was aimed to dissect the role of ACHE in retinal inflammation, and its mechanism of action. Retinal inflammation was induced by intravitreal injection of tumor necrosis factor-α (TNF-α) in heterozygous ACHE knockdown mice (ACHE+/-) and wild type mice (ACHE+/+). Donepezil, a well-known ACHE inhibitor, was administrated by daily gavage. Expression of ACHE and intercellular adherent molecule-1 (ICAM-1), infiltration of CD11b+ inflammatory cells, retinal leukostasis and vascular leakage was determined in both ACHE+/- and ACHE+/+ mice. ARPE-19 cells, a human retinal pigment epithelial cell line, were cultured for in vitro assay. Knockdown of ACHE was achieved by lipofectamine-mediated siRNA transfection and pharmaceutical suppression of ACHE was manipulated by donepezil. Cellular expression and distribution of ACHE, ICAM-1, and phosphorylation of NF-κB, IκB and IKKα/ß were detected by western-blot analysis or immunocytochemistry. Retinal expression of ACHE was dramatically upregulated, in parallel with increased ICAM-1 expression, enhanced leukostasis and augmented CD11b+ inflammatory cell infiltration as well as vascular hyperpermeability in ACHE+/+ mice injected with TNF-α. However, TNF-α-injected ACHE+/- mice showed lower level of ICAM-1, less leukostasis and fewer infiltrated CD11b+ cells. Moreover, TNF-α-induced retinal vascular leakage was significantly reduced in ACHE+/- mice. Similarly, TNF-α-induced retinal inflammatory response were also attenuated by donepezil intervention. In addition, TNF-α treatment resulted in significant induction of ACHE, upregulation of ICAM-1 and nuclear translocation of NF-κB, phosphorylation of IκB and IKKα/ß in ARPE-19 cells. However, inhibition of ACHE reduced TNF-α-induced phosphorylation of NF-κB, IκB and IKKα/ß in ARPE-19 cells. The present study reveals a pivotal role of ACHE in retinal inflammation. Inhibition of ACHE attenuates retinal inflammation and retinal leakage likely through suppressing NF-κB signaling activation.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Regulação da Expressão Gênica , NF-kappa B/genética , Retinite/tratamento farmacológico , Acetilcolinesterase/efeitos dos fármacos , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/biossíntese , RNA/genética , Epitélio Pigmentado da Retina/metabolismo , Retinite/metabolismo
5.
J Enzyme Inhib Med Chem ; 35(1): 460-467, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899981

RESUMO

The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are primary targets in attenuating the symptoms of neurodegenerative diseases. Their inhibition results in elevated concentrations of the neurotransmitter acetylcholine which supports communication among nerve cells. It was previously shown for trans-4/5-arylethenyloxazole compounds to have moderate AChE and BChE inhibitory properties. A preliminary docking study showed that elongating oxazole molecules and adding a new NH group could make them more prone to bind to the active site of both enzymes. Therefore, new trans-amino-4-/5-arylethenyl-oxazoles were designed and synthesised by the Buchwald-Hartwig amination of a previously synthesised trans-chloro-arylethenyloxazole derivative. Additionally, naphthoxazole benzylamine photoproducts were obtained by efficient photochemical electrocyclization reaction. Novel compounds were tested as inhibitors of both AChE and BChE. All of the compounds exhibited binding preference for BChE over AChE, especially for trans-amino-4-/5-arylethenyl-oxazole derivatives which inhibited BChE potently (IC50 in µM range) and AChE poorly (IC50≫100 µM). Therefore, due to the selectivity of all of the tested compounds for binding to BChE, these compounds could be applied for further development of cholinesterase selective inhibitors.HIGHLIGHTSSeries of oxazole benzylamines were designed and synthesisedThe tested compounds showed binding selectivity for BChENaphthoxazoles were more potent AChE inhibitors.


Assuntos
Benzilaminas/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Oxazóis/química , Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Técnicas Eletroquímicas , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Processos Fotoquímicos , Relação Estrutura-Atividade
6.
J Enzyme Inhib Med Chem ; 35(1): 424-431, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899985

RESUMO

A series of 16 novel benzenesulfonamides incorporating 1,3,5-triazine moieties substituted with aromatic amines, dimethylamine, morpholine and piperidine were investigated. These compounds were assayed for antioxidant properties by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, 2,2`-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical decolarisation assay and metal chelating methods. They were also investigated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase, which are associated with several diseases such as Alzheimer, Parkinson and pigmentation disorders. These benzenesulfonamides showed moderate DPPH radical scavenging and metal chelating activity, and low ABTS cation radical scavenging activity. Compounds 2 b, 3d and 3 h showed inhibitory potency against AChE with % inhibition values of >90. BChE was also effectively inhibited by most of the synthesised compounds with >90% inhibition potency. Tyrosinase was less inhibited by these compounds.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Antioxidantes/farmacologia , Butirilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Triazinas/química , Benzotiazóis/química , Compostos de Bifenilo/química , Picratos/química , Ácidos Sulfônicos/química
7.
J Enzyme Inhib Med Chem ; 35(1): 478-488, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31910701

RESUMO

The series of symmetrical and unsymmetrical isoquinolinium-5-carbaldoximes was designed and prepared for cholinesterase reactivation purposes. The novel compounds were evaluated for intrinsic acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) inhibition, when the majority of novel compounds resulted with high inhibition of both enzymes and only weak inhibitors were selected for reactivation experiments on human AChE or BChE inhibited by sarin, VX, or paraoxon. The AChE reactivation for all used organophosphates was found negligible if compared to the reactivation ability of obidoxime. Importantly, two compounds were found to reactivate BChE inhibited by sarin or VX better to obidoxime at human attainable concentration. One compound resulted as better reactivator of NEMP (VX surrogate)-inhibited BChE than obidoxime. The in vitro results were further rationalized by molecular docking studies showing future directions on designing potent BChE reactivators.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/efeitos dos fármacos , Reativadores da Colinesterase/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Inibidores da Colinesterase/farmacologia , Humanos , Isoquinolinas/química , Simulação de Acoplamento Molecular
8.
Nat Prod Res ; 34(16): 2358-2362, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30394109

RESUMO

Pulicaria undulata is used as a traditional herbal remedy in Egypt. We used gas chromatography-mass spectrometry for analysis of essential oil of this plant growing wild in Egypt and 64 compounds were identified. The oil was rich in oxygenated monoterpenes (64.0%) and aromatic derivatives (18.8%). The major components were carvacrol (46.5%), xanthoxylin (18.1%) and carvotanacetone (8.7%). The oil of the Egyptian plant showed significant differences from the oil results reported on this species derived from different accessions. Antioxidant activity was performed by FRAP, DPPH and ABTS assays, and the oil demonstrated a powerful antioxidant properties. Furthermore, cytotoxicity was assessed using MTT assay against three cell lines (A375, T98G, HCT116) and the oil showed moderate results with IC50 of 18.53, 40.64 and 22.23 µg/ml; respectively. The oil showed a good anti-acetylcholinesterase activity (IC50 = 139.2 µg/ml) using Ellman method. In conclusion, the studied oil exhibited a peculiar fingerprint and promising biological activities.


Assuntos
Antioxidantes/isolamento & purificação , Óleos Voláteis/química , Pulicaria/química , Acetilcolinesterase/efeitos dos fármacos , Antioxidantes/química , Antioxidantes/farmacologia , Asteraceae , Linhagem Celular , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/farmacologia , Cimenos/análise , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Egito , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/farmacologia , Terpenos/análise
9.
Nat Prod Res ; 34(10): 1380-1388, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30456989

RESUMO

α-mangostin, a polyphenol xanthone derivative, was mainly isolated from pericarps of the mangosteen fruit (Garcinia mangostana L.). In present investigation, a series of derivatives were designed, synthesised and evaluated in vitro for their inhibitory activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among the synthesised xanthones, compounds 1, 9, 13 and 16 showed AChE selective inhibitory activity, 15 was a BuChE selective inhibitor while 2, 3, 5, 6, 7, 12 and 14 were dual inhibitors. The most potent inhibitor of AChE was 16 while 5 was the most potent inhibitor of BuChE with IC50 values of 5.26 µM and 7.55 µM respectively.


Assuntos
Inibidores da Colinesterase/química , Garcinia mangostana/química , Xantonas/síntese química , Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Frutas/química , Xantonas/química , Xantonas/farmacologia
10.
Nat Prod Res ; 34(14): 2001-2006, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30721084

RESUMO

Two new alkaloids, fluevirines E (1) and F (2), along with six known Securinega alkaloids, were isolated from the methanol extract of the twigs and leaves of Flueggea virosa. The structures and absolute configurations of the new compounds were elucidated by means of MS, NMR, and ECD analyses. Compound 1 is a new dimeric indole alkaloid while 2 is a new securinega-type alkaloid. The in vitro cytotoxic activities of the isolated alkaloids against several human cancer cell lines and their acetylcholinesterase inhibitory activity were also evaluated.


Assuntos
Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Inibidores da Colinesterase/isolamento & purificação , Euphorbiaceae/química , Acetilcolinesterase/efeitos dos fármacos , Alcaloides/química , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Humanos , Alcaloides Indólicos , Conformação Molecular , Estrutura Molecular , Folhas de Planta/química , Análise Espectral
11.
Curr Comput Aided Drug Des ; 16(1): 54-72, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30827255

RESUMO

BACKGROUND: There are over 44 million persons who suffer with Alzheimer's disease (AD) worldwide, no existence of cure and only symptomatic treatments are available for it. The aim of this study is to evaluate the anti-Alzheimer potential of designed AChEI analogues using computer simulation docking studies. AChEIs are the most potential standards for treatment of AD, because they have proven efficacy. Among all AChEIs donepezil possesses lowest adverse effects, it can treat mildmoderate- severe AD and only once-daily dosing is required. Therefore, donepezil is recognized as a significant prototype for design and development of new drug molecule. METHODS: In this study the Inhibitory potential of the design compounds on acetylcholinesterase enzyme has been evaluated. Docking studies has been performed which further analyzed by in-silico pharmacokinetic evaluation through pharmacopredicta after that Interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds. RESULTS: As a result 26 compounds have been indicates better inhibitory activity on AChE enzyme and all the screening parameters have also been satisfied by all 26 compounds. From these 26 compounds, six compounds 17, 18, 24, 30, 36 and 56 are found to be the most potent inhibitors of this series by insilico study through INVENTUS v 1.1 software, having highest bio-affinities i.e. - 8.51, - 7.67, - 8.30, - 7.59, - 8.71 and -7.62 kcal/mol respectively, while the standard or reference drug donepezil had binding affinity of - 6.32 kcal/mol. CONCLUSION: Computer aided drug design approach has been playing an important role in the design and development of novel anti- AD drugs. With the help of structure based drug design some novel analogues of donepezil have been designed and the molecular docking studies with structure based ADME properties prediction studies is performed for prediction of AChE inhibitory activity. The binding mode of proposed compounds with target protein i.e. AChE has been evaluated and the resulting data from docking studies explains that all of the newly designed analogues had significantly high affinity towards target protein compared to donepezil as a reference ligand.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Acetilcolinesterase/efeitos dos fármacos , Doença de Alzheimer/enzimologia , Sítios de Ligação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Simulação por Computador , Desenho Assistido por Computador , Donepezila/farmacologia , Humanos
12.
Int J Mol Sci ; 20(21)2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31717775

RESUMO

The joint toxicities of [BMIM]BF4, [BMIM]PF6, and [HMIM]BF4 on acetylcholinesterase (AChE) were systematically investigated by using a progressive approach from 1D single effect point, 2D concentration-response curve (CRC), to 3D equivalent-surface (ES) level. The equipartition equivalent-surface design (EESD) method was used to design 10 ternary mixtures, and the direct equipartition ray (EquRay) design was used to design 15 binary mixtures. The toxicities of ionic liquids (ILs) and their mixtures were determined using the microplate toxicity analysis (MTA) method. The concentration addition (CA), independent action (IA), and co-toxicity coefficient (CTC) were used as the additive reference model to analyze the toxic interaction of these mixtures. The results showed that the Weibull function fitted well the CRCs of the three ILs and their mixtures with the coefficient of determination (R2) greater than 0.99 and root-mean-square error (RMSE) less than 0.04. According to the CTC integrated with confidence interval (CI) method (CTCICI) developed in this study, the 25 mixtures were almost all additive action at 20% and 80% effect point levels. At 50% effect, at least half of the 25 mixtures were slightly synergistic action, and the remaining mixtures were additive action. Furthermore, the ESs and CRCs predicted by CA and IA were all within the CIs of mixture observed ESs and CRCs, respectively. Therefore, the toxic interactions of these 25 mixtures were actually additive action. The joint toxicity of the three ILs can be effectively evaluated by the ES method. We also studied the relationship between the mixture toxicities and component concentration proportions. This study can provide reference data for IL risk assessment of combined pollution.


Assuntos
Inibidores da Colinesterase/toxicidade , Líquidos Iônicos/toxicidade , Acetilcolinesterase/efeitos dos fármacos , Boratos/química , Boratos/toxicidade , Inibidores da Colinesterase/química , Sinergismo Farmacológico , Imidazóis/química , Imidazóis/toxicidade , Concentração Inibidora 50 , Líquidos Iônicos/química , Cinética , Modelos Químicos , Testes de Toxicidade
13.
Drug Des Devel Ther ; 13: 3029-3036, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692531

RESUMO

Background: Traditionally, Grewia optiva is widely used for the treatment of many diseases like dysentery, fever, typhoid, diarrhea, eczema, smallpox, malaria and cough. Methods: Shade-dried roots of G. optiva were extracted with methanol. Based on HPLC results, chloroform and ethyl acetate fractions were subjected to silica column isolation and four compounds: glutaric acid (V), 3,5 dihydroxy phenyl acrylic acid (VI), (2,5 dihydroxy phenyl) 3',6',8'-trihydroxyl-4H chromen-4'-one (VII) and hexanedioic acid (VIII) were isolated in pure form. Ellman's assay was used to determine the anticholinesterase potential of isolated compounds while their antioxidant potential was estimated by DPPH and ABTS scavenging assays. Results: Amongst the isolated compounds, VI and VII exhibited excellent percent inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) (83.23±1.11, 82.72±2.20 and 82.11±2.11, 82.23±1.21, respectively, at 1000 µg/mL) with IC50 of 76, 90, 78 and 92 µg/mL, respectively. Highest percent radicals scavenging against DPPH and ABTS (87.41±1.20 and 86.13±2.31) with IC50 of 64 and 65 µg/mL, respectively, were observed for compound VII. Molecular docking studies also supported the binding of compound VI and VII with the target enzyme. The para-hydroxyl group of the phenolic moiety is formed hydrogen bonds with the active site water molecule and the side chain carbonyl and hydroxyl residues of enzyme. Conclusion: The isolated compounds inhibited the DPPH and ABTS-free radicals, and AChE and BChE enzymes. It was concluded that these compounds could be used in relieving the oxidative stress and pathological symptoms associated with excessive hydrolysis of acetyl and butyryl choline. The results of the study were supported by docking studies for compounds VI and VII.


Assuntos
Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Grewia/química , Extratos Vegetais/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Antioxidantes/administração & dosagem , Butirilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/administração & dosagem , Depuradores de Radicais Livres/farmacologia , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Raízes de Plantas
14.
Molecules ; 24(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775359

RESUMO

The orphan drug dantrolene (DAN) is the only therapeutic treatment for malignant hyperthermia (MH), a pharmacogenetic pathology affecting 0.2 over 10,000 people in the EU. It acts by inhibiting ryanodine receptors, which are responsible for calcium recruitment in striatal muscles and brain. Because of its involvement in calcium homeostasis, DAN has been successfully investigated for its potential as neuroprotecting small molecule in several animal models of Alzheimer's disease (AD). Nevertheless, its effects at a molecular level, namely on putative targets involved in neurodegeneration, are still scarcely known. Herein, we present a prospective study on repurposing of DAN involving, besides the well-known calcium antagonism, inhibition of monoamine oxidase B and acetylcholinesterase, cytoprotection from oxidative insult, and activation of carnitine/acylcarnitine carrier, as concurring biological activities responsible for neuroprotection.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cálcio/metabolismo , Dantroleno/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Doença de Alzheimer/patologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Carnitina/análogos & derivados , Carnitina/metabolismo , Linhagem Celular , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Dantroleno/química , Reposicionamento de Medicamentos , Humanos , Hipertermia Maligna/tratamento farmacológico , Monoaminoxidase/química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/química
15.
J Biochem Mol Toxicol ; 33(10): e22385, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31478295

RESUMO

In this work, the inhibitory activity of Voriconazole was measured against some metabolic enzymes, including human carbonic anhydrase (hCA) I and II isoenzymes, acetylcholinesterase (AChE), and α-glycosidase; the results were compared with standard compounds including acetazolamide, tacrine, and acarbose. Half maximal inhibition concentration (IC50 ) values were obtained from the enzyme activity (%)-[Voriconazole] graphs, whereas Ki values were calculated from the Lineweaver-Burk graphs. According to the results, the IC50 value of Voriconazole was 40.77 nM for α-glycosidase, while the mean inhibition constant (Ki ) value was 17.47 ± 1.51 nM for α-glycosidase. The results make an important contribution to drug design and have pharmacological applications. In addition, the Voriconazole compound demonstrated excellent inhibitory effects against AChE and hCA isoforms I and II. Voriconazole had Ki values of 29.13 ± 3.57 nM against hCA I, 15.92 ± 1.90 nM against hCA II, and 10.50 ± 2.46 nM against AChE.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Antifúngicos/farmacologia , Anidrase Carbônica II/efeitos dos fármacos , Anidrase Carbônica I/efeitos dos fármacos , Inibidores da Anidrase Carbônica/farmacologia , Glicosídeo Hidrolases/efeitos dos fármacos , Voriconazol/farmacologia , Humanos
16.
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/isolamento & purificação , Inibidores da Colinesterase/química , Alcaloides Indólicos/química , Alcaloides/química , Lactamas/química
17.
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 , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética/métodos , Termodinâmica , Água/química
18.
Pharm Biol ; 57(1): 460-469, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31335235

RESUMO

Context: Seaweeds contain bioactive compounds with different biological activities. They are used as functional ingredients for the development of therapeutic agents to combat degenerative diseases. Objective: This study investigated the phenolic composition, antioxidant activity, cholinesterase inhibitory and anti-amyloidogenic activities of aqueous extracts of Gracilaria beckeri (J.Agardh) Papenfuss (Gracilariaceae) (RED-AQ), Ecklonia maxima (Osbeck) Papenfuss (Lessoniaceae) (ECK-AQ), Ulva rigida (C.Agardh) Linnaeus (Ulvaceae) (URL-AQ) and Gelidium pristoides (Turner) Kützing (Gelidiaceae) (GEL-AQ). Materials and methods: Phenolic composition of the seaweed extracts was determined using liquid chromatography mass spectrometry. Radical scavenging and metal chelating activities were assessed in vitro. The effect of the extracts (21-84 µg/mL) on acetylcholinesterase and butyrylcholinesterase activities were also investigated using an in vitro colorimetric assay. Transmission electron microscope and thioflavin-T fluorescence assay were used to examine the anti-amyloidogenic activities of the extracts. Results: Phloroglucinol, catechin, epicatechin 3-glucoside were identified in the extracts. ECK-AQ (IC50=30.42 and 280.47 µg/mL) exhibited the highest OH• scavenging and metal chelating activities, while RED-AQ (41.23 and 334.45 µg/mL) exhibited the lowest. Similarly, ECK-AQ (IC50 = 49.41 and 52.11 µg/mL) exhibited higher inhibitory effects on acetylcholinesterase and butyrylcholinesterase activities, while RED-AQ (64.56 and 63.03 µg/mL) showed the least activities. Rapid formation of ß-amyloid (Aß1-42) fibrils and aggregates was observed in electron micrographs of the control after 72 and 96 h. The reduction of Aß1-42 aggregates occurred after co-treatment with the seaweed extracts. Discussion and conclusion: ECK-AQ, GEL-AQ, URL-AQ and RED-AQ may possess neuroprotective potential and could be explored for the management of Alzheimer's disease.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/efeitos dos fármacos , Fenóis/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Alga Marinha/química , Peptídeos beta-Amiloides/efeitos dos fármacos , Antioxidantes , Depuradores de Radicais Livres/farmacologia , Espectrometria de Massas
19.
Molecules ; 24(12)2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234400

RESUMO

A new series of thiazolo[3,2-a]pyrimidine bromide salt derivatives 7a-d were synthesized from 3,4-dihydropyrimidinethione precursors. The target compounds were fully characterized by 1D- and 2D-NMR, high resolution ESI-MS/MS and single crystal X-ray diffraction analysis, which confirmed a regioselective 5H cyclization of the dihydropyrimidinethiones. All target compounds were evaluated in vitro as human acetylcholinesterase (hAChE) inhibitors via an Ellman-based colorimetric assay and showed good inhibition activities (better than 70% at 10 µM and IC50 values in the 1 µM range). Molecular docking simulations for all target products into hAChE were performed and confirmed strong binding to the enzyme. These results provide a promising and new starting point to improve acetylcholinesterase inhibitors and explore novel treatment options against Alzheimer's disease.


Assuntos
Acetilcolinesterase/química , Inibidores da Colinesterase/síntese química , Pirimidinas/síntese química , Acetilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/química , Cristalografia por Raios X , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/química , Espectrometria de Massas em Tandem
20.
Phytochem Anal ; 30(6): 679-686, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31183917

RESUMO

INTRODUCTION: Acetylcholinesterase (AChE) inhibitors are considered an important strategy in the treatment of neurological disorders such as Alzheimer's disease. A simple and fast planar chromatography-bioassay methodology has been established to detect bioactive molecules in cherimoya fruit. OBJECTIVE: Detect and identify AChE inhibitors in cherimoya by high-performance thin-layer chromatography (HPTLC)-bioassay-mass spectrometry (MS) and related techniques. METHODOLOGY: Effect-directed analysis by planar chromatography-bioassay-mass spectrometry was applied to detect and identify AChE inhibitors in pulp, peel and cherimoya seed. Bioassay was optimised establishing the following conditions: enzymatic solution (1.0 U mL-1 ), 1-naphtyl acetate substrate (1.5 mg mL-1 ) and Fast Blue B salt (1.0 mg mL-1 ). TLC-MS interface was used to directly elute the active zones into a mass spectrometer or to a micro-vial for further off-line studies. RESULTS: Two AChE inhibitory bands were detected in peel extracts. An analysis via HPTLC-MS and high-performance liquid chromatography diode array detector tandem mass spectrometry (HPLC-DAD-MS/MS) allowed to characterise three potential AChE inhibitors: anonaine (m/z 266 [M + H]+ ; UV λmax = 269.6 nm), glaucine (m/z 256 [M + H]+ ; UV λmax = 282.9 and 300.6 nm) and xylopine (m/z 296 [M + H]+ ; UV λmax = 278.5 nm). CONCLUSIONS: The application of this optimised high throughput method allowed to establish the presence of three potential AChE inhibitors in cherimoya peel. For the first time AChE inhibitory capacity of these alkaloids is reported.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Annona/química , Bioensaio/métodos , Inibidores da Colinesterase/análise , Cromatografia em Camada Delgada/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Inibidores da Colinesterase/farmacologia
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