RESUMO
The Amaryllidaceae family constitutes an interesting source of exclusive alkaloids with a broad spectrum of biological activity. Galanthamine, the most relevant one, has been commercialized for the palliative treatment of Alzheimer's disease symptoms since 2001 due to its potential as an acetylcholinesterase (AChE) inhibitor. In vitro screenings against AChE by applying different Amaryllidaceae species and alkaloids have been reported in the literature; however, they are usually carried out using purified market enzymes. The main goal of this work is to evaluate the AChE inhibitory potential of Hippeastrum papilio (Amaryllidaceae) extracts using zebrafish brain homogenates. The biological assays show that the H. papilio bulb extracts present an interesting AChE inhibitory activity in comparison with the positive reference control galanthamine (IC50 values of 1.20 ± 0.10 and 0.79 ± 0.15 µg/mL, respectively). The chemical profile of H. papilio shows that this species has a high amount of galanthamine, which may contribute to the inhibitory effect on AChE activity of zebrafish brains. Computational experiments were used to build the model for zebrafish AChE and to evaluate the interactions between galanthamine and the enzymic active site. This work suggests that zebrafish could represent an important model in the search for bioactive molecules from the Amaryllidaceae family for the treatment of Alzheimer's disease.
RESUMO
Zephyranthes carinata Herb., a specie of the Amaryllidoideae subfamily, has been reported to have inhibitory activity against acetylcholinesterase. However, scientific evidence related to their bioactive alkaloids has been lacking. Thus, this study describes the isolation of the alkaloids of this plant, and their inhibition of the enzymes acetylcholinesterase (eeAChE) and butyrylcholinesterase (eqBuChE), being galanthine the main component. Additionally, haemanthamine, hamayne, lycoramine, lycorine, tazettine, trisphaeridine and vittatine/crinine were also isolated. The results showed that galanthine has significant activity at low micromolar concentrations for eeAChE (IC50 = 1.96 µg/mL). The in-silico study allowed to establish at a molecular level the high affinity and the way galanthine interacts with the active site of the TcAChE enzyme, information that corroborates the result of the experimental IC50. However, according to molecular dynamics (MD) analysis, it is also suggested that galanthine presents a different inhibition mode that the one observed for galanthamine, by presenting interaction with peripheral anionic binding site of the enzyme, which prevents the entrance and exit of molecules from the active site. Thus, in vitro screening assays plus rapid computer development play an essential role in the search for new cholinesterase inhibitors by identifying unknown bio-interactions between bioactive compounds and biological targets.
Assuntos
Alcaloides , Amaryllidaceae , Acetilcolinesterase/metabolismo , Alcaloides/farmacologia , Amaryllidaceae/química , Amaryllidaceae/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento MolecularRESUMO
Abstract This study reports the action of essential oils (EO) from five plants on the activity of native and recombinant acetylcholinesterases (AChE) from Rhipicephalus microplus. Enzyme activity of native susceptible AChE extract (S.AChE), native resistant AChE extract (R.AChE), and recombinant enzyme (rBmAChE1) was determined. An acetylcholinesterase inhibition test was used to verify the effect of the EO on enzyme activity. EO from Eucalyptus globulus, Citrus aurantifolia, Citrus aurantium var.dulcis inhibited the activity of S.AChE and R.AChE. Oils from the two Citrus species inhibited S.AChE and R.AChE in a similar way while showing greater inhibition on R.AChE. The oil from E. globulus inhibited native AChE, but no difference was observed between the S.AChE and R.AChE; however, 71% inhibition for the rBmAChE1 was recorded. Mentha piperita oil also inhibited S.AChE and R.AChE, but there was significant inhibition at the highest concentration tested. Cymbopogon winterianus oil did not inhibit AChE. Further studies are warranted with the oils from the two Citrus species that inhibited R.AChE because of the problem with R. microplus resistant to organophosphates, which target AChE. C. winterianus oil can be used against R. microplus populations that are resistant to organophosphates because its acaricidal properties act by mechanism(s) other than AChE inhibition.
Resumo Este estudo relata a ação de óleos essenciais de cinco plantas na atividade de acetilcolinesterases (AChE) nativas e recombinantes de Rhipicephalus microplus. A atividade enzimática do extrato de acetilcolinesterase nativa suscetível (S.AChE) e resistente (R.AChE) e da enzima recombinante (rBmAChE1) foi determinada. Um teste de inibição da AChE foi utilizado, para verificar o efeito dos óleos essenciais sobre a atividade enzimática. Óleos essenciais de Eucalyptus globulus, Citrus aurantifolia, Citrus aurantium var. dulcis inibiram a atividade de S.AChE e R.AChE. Os óleos das duas espécies de Citrus inibiram S.AChE e R.AChE de maneira semelhante, mas mostraram maior inibição sobre R.AChE. O óleo de E. globulus inibiu a AChE nativa, mas sem diferença entre a S.AChE e a R.AChE; no entanto, 71% de inibição para rBmAChE1 foi observada. O óleo de Mentha piperita também inibiu S.AChE e R.AChE, mas houve inibição significativa apenas nas concentrações mais altas testadas. O óleo de Cymbopogon winterianus não inibiu a AChE. Estudos adicionais são necessários com os óleos das duas espécies de Citrus que inibiram a R.AchE, devido ao problema de R. microplus resistente aos organofosforados ter como alvo AChE. O óleo de C. winterianus pode ser usado contra populações de R. microplus, que são resistentes a organofosforados, porque suas propriedades acaricidas agem por mecanismos diferentes.
Assuntos
Animais , Óleos Voláteis/farmacologia , Inibidores da Colinesterase/farmacologia , Cymbopogon , Rhipicephalus/enzimologia , Acaricidas/farmacologia , Acetilcolinesterase , LarvaRESUMO
Highly prized huperzine A (Hup A), a natural alkaloid formerly isolated from the Chinese medicinal plant Huperzia serrata, has been widely used for the treatment of Alzheimer disease, inspiring us to search for endophytic fungi that produce this compound. In this study, we obtained the C17 fungus isolate from the Mexican club moss Phlegmariurus taxifolius, which produced a yield of 3.2 µg/g Hup A in mycelial dry weight, when cultured in potato dextrose broth medium. The C17 isolate was identified as belonging to the genus Fusarium with reference to the colony´s morphological characteristics and the presence of macroconidia and microconidia structures; and this was confirmed by DNA-barcoding analysis, by amplifying and sequencing the ribosomal internal transcribed spacer (rITS).
Assuntos
Alcaloides , Endófitos/química , Fusarium/química , Lycopodiaceae/microbiologia , Sesquiterpenos , Alcaloides/análise , Alcaloides/química , Alcaloides/isolamento & purificação , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/metabolismo , DNA Fúngico/genética , Endófitos/isolamento & purificação , Fusarium/classificação , Fusarium/genética , Fusarium/isolamento & purificação , Sesquiterpenos/análise , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificaçãoRESUMO
Synthetic insecticides applied to control Spodoptera frugiperda (Lepidoptera: Noctuidae) can have negative impacts on environment and human health. Botanical essential oils can be sources of organic molecules with biocontrol potential and advantages, such as minor impacts on the selection of resistant pest insects and low toxicity to humans. The aim of this study was to investigate the biocontrol action of essential oils from Brazilian species and methyl chavicol compounds on the development and metabolism of S. frugiperda. Essential oils of Eremanthus erythropappus (Asteraceae), Ocimum selloi, Hyptis suaveolens, and Hyptis marrubioides (Lamiaceae) were distilled by the steam distillation method and analyzed by gas chromatograph techniques. The essential oils were incorporated into an artificial diet (at 1, 2, and 4 mg mL-1) and offered to S. frugiperda caterpillars. Larvae of S. frugiperda at 48 h of age were fed an artificial diet containing the major constituent of O. selloi (methyl chavicol). The major compounds of the essential oils were methyl chavicol for O. selloi, α-bisabolol for E. erythropappus, bicyclogermacrene for H. suaveolens, and ß-thujone for H. marrubioides. O. selloi caused 100% mortality in S. frugiperda larvae at a concentration of 1 mg mL-1 after 48 h. H. marrubioides essential oil caused 100% mortality in larvae at a concentration of 4 mg mL-1 after 48 h. O. selloi and H. marrubioides inhibited acetylcholinesterase (AchE) activity in 72.87% and 81.69% of larvae, respectively. O. selloi presented the highest toxicity to S. frugiperda and the lowest inhibition of AchE. Methyl chavicol was lethal to all larvae within 24 h at a concentration of 0.92 mg mL-1 of diet. Methyl chavicol showed the best insecticidal activity and potential to be used as a natural insecticide to control S. frugiperda.
Assuntos
Anisóis/química , Inseticidas , Spodoptera/química , Zea mays , Derivados de Alilbenzenos , Animais , Anisóis/análise , Brasil , Humanos , LarvaRESUMO
BACKGROUND: Chia seeds are gaining increasing interest among food producers and consumers because of their prohealth properties. RESULTS: The aim of this work was to evaluate the potential of chia seeds to act as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The highest inhibitory activity against AChE and BChE was observed for colored seed ethanol extracts. A positive correlation was found between the presence of quercetin and isoquercetin as well as protocatechuic, hydroxybenzoic, and coumaric acids and the activity of extracts as AChE and BChE inhibitors. It has also been shown that grain fragmentation affects the increase in the activity of seeds against cholinesterases (ChE). Furthermore, seeds have been shown to be a source of substances that inhibit microbial growth. CONCLUSIONS: It was found that the chia seed extracts are rich in polyphenols and inhibit the activity of ChEs; therefore, their use can be considered in further research in the field of treatment and prevention of neurodegenerative diseases.
Assuntos
Sementes/química , Butirilcolinesterase , Inibidores da Colinesterase , Salvia/química , Anti-Infecciosos/metabolismo , Técnicas In Vitro , Flavonóis/análise , Compostos Fenólicos/análise , Polifenóis/análise , Aditivos AlimentaresRESUMO
In vitro acetylcholinesterase (AChE) inhibition was studied using novel derivatives of (-)-cytisine derivatives N-allylcytisine-12-carbamide (A-63), cytisine-12-carbamide (A-36), N-1-adamantylcytisine-12-thiocarbamide (U-12), and 1-hydroxyquinopimaric acid (U-201). Inhibition of acetylcholinesterase with compound A-63 was described as mixed inhibition. Substances (A-36) and (U-201) acted as competitive inhibitors with Ki equal to 6.71â¯mM and 3.89â¯mM, respectively, while (U-12) behaved as an uncompetitive inhibitor with Ki at 0.07â¯mM. The IC50 values were estimated at 1.47, 13.73, 3.39, and 7.81â¯mM, respectively. According to toxicity assessment, compound A-63 was non-toxic; it did not affect A. salina viability at a concentration less than 1000â¯ppm, while at 1000â¯ppm, only 3% mortality was observed. Mortality of A. salina was less than 50% in the same concentration range for the other three compounds that allow classifying them as moderately toxic. Although tested compounds have the characteristics of weak inhibitors, they could be useful as protectors against potent organophosphates. The present research may be fundamental to the design of new substances for acetylcholinesterase inhibition.
RESUMO
BACKGROUND: Acetylcholinesterase inhibition prevents autonomic imbalance, reduces inflammation, and attenuates the development of hypertension. Considering that vascular dysfunction is a crucial feature of arterial hypertension, we investigated the effects of chronic administration of acetylcholinesterase inhibitors-pyridostigmine or donepezil-on vascular reactivity of spontaneously hypertensive rats (SHR). METHODS: Endothelium-dependent relaxant responses to acetylcholine (ACh) and contractile responses induced by electric field stimulation (EFS) and alpha-adrenergic agonist were studied in mesenteric resistance arteries from SHR and Wistar Kyoto rats. SHR were treated for 16 weeks with vehicle, pyridostigmine (1.5 mg/kg/day) or donepezil (1.4 mg/kg/day). RESULTS: Pyridostigmine and donepezil decreased the vasoconstrictor responses to EFS, which were increased in vehicle-treated SHR. Acetylcholinesterase inhibition increased the modulatory effects of nitric oxide (NO) on SHR vascular reactivity, that is, N(ω)-nitro-(L)-arginine methyl ester (L-NAME) increased EFS-induced contractions and reduced ACh-induced relaxation, with more significant effects in pyridostigmine- and donepezil-treated SHR. The acetylcholinesterase inhibitors also decreased vascular reactive oxygen species levels. CONCLUSIONS: This study demonstrates for the first time that long-term administration of acetylcholinesterase inhibitors, pyridostigmine or donepezil, attenuates vascular reactivity dysfunction in SHR by decreasing reactive oxygen species generation and increasing NO bioavailability; possibly via increased endothelial NO synthase activity, and inhibition of NADPH oxidase activity.
Assuntos
Anti-Hipertensivos/farmacologia , Inibidores da Colinesterase/farmacologia , Donepezila/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipertensão/prevenção & controle , Artérias Mesentéricas/efeitos dos fármacos , Brometo de Piridostigmina/farmacologia , Acetilcolinesterase/metabolismo , Animais , Pressão Arterial/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Artérias Mesentéricas/enzimologia , Artérias Mesentéricas/fisiopatologia , NADPH Oxidases/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Espécies Reativas de Oxigênio/metabolismo , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Alzheimer's disease (AD) is one of the most common age-related neurodegenerative disorders. Aggregation of amyloid-ß peptide into extracellular plaques with incorporation of metal ions, such as Cu2+, and reduction of the neurotransmitter acetylcholine levels are among the factors associated to the AD brain. Hence, a series of 7-chloro-4-aminoquinoline Schiff bases (HLa-e) were synthesized and their cytotoxicity and anti-cholinesterase activity, assessed for Alzheimer's disease. The intrinsic relationship between Cu2+ and the amyloidogenic plaques encouraged us to investigate the chelating ability of HLa-e. Dimeric tetracationic compounds, [Cu2(NHLa-e)4]Cl4, containing quinoline protonated ligands were isolated from the reactions with CuCl2·2H2O and fully characterized in the solid state, including an X ray diffraction study, whereas EPR data showed that the complexes exist as monomers in DMSO solution. The inhibitory activity of all compounds was evaluated by Ellman's spectrophotometric method in acetylcholinesterase (AChE) from Electrophorus electricus and butyrylcholinesterase (BChE) from equine serum. HLa-e and [Cu(NHLd)2]Cl2 were selective for AChE (IC50â¯=â¯4.61-9.31⯵M) and were not neurotoxic in primary brain cultures. Docking and molecular dynamics studies of HLa-e inside AChE were performed and the results suggested that these compounds are able to bind inside AChE similarly to other AChE inhibitors, such as donepezil. Studies of the affinity of HLd for Cu2+ in DMSO/HEPES at pHâ¯6.6 and pHâ¯7.4 in µM concentrations showed formation of analogous 1:2 Cu2+/ligand complexes, which may suggest that in the AD-affected brain HLd may scavenge Cu2+ and the complex, also inhibit AChE.
Assuntos
Aminoquinolinas/química , Inibidores da Colinesterase/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Bases de Schiff/química , Animais , Células Cultivadas , Inibidores da Colinesterase/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Técnicas In Vitro , Camundongos , Simulação de Acoplamento Molecular , Análise Espectral/métodosRESUMO
Two new iridoids (1-2) and a new decomposition product of valepotriates (3), together with fifteen known compounds (4-18) were isolated from the roots and rhizomes of Valeriana polystachya Smith, a native species from the Pampa Biome. Their structures were elucidated by means of NMR spectroscopy, mass spectrometry and optical rotation. The structures of 3 and 18 were further confirmed by single crystal X-ray diffraction analysis. In the group of the isolated compounds, 6ß-hydroxysitostenone, hydroxymaltol and isovillosol were isolated from the Valeriana genus for the first time. The extracts and isolated compounds were evaluated for their in vitro activities against acetylcholinesterase (AChE) and prolyloligopeptidase (POP). Compounds 7, 9 and 11 showed weak inhibitory activity against AChE, while 3 and 5 displayed exceptional POP inhibitory activity, with IC50 values of 5.3⯱â¯0.07 and 7.9⯱â¯0.4⯵M, respectively.
Assuntos
Inibidores da Colinesterase/isolamento & purificação , Iridoides/isolamento & purificação , Inibidores de Serina Proteinase/isolamento & purificação , Valeriana/química , Acetilcolinesterase , Brasil , Inibidores da Colinesterase/farmacologia , Iridoides/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Raízes de Plantas/química , Prolil Oligopeptidases , Rizoma/química , Serina Endopeptidases , Inibidores de Serina Proteinase/farmacologiaRESUMO
BACKGROUND: Trichilia catigua A. Juss. (Meliaceae) is a species known as catuaba and used in folk medicine for the treatment of fatigue, stress, impotence and memory deficit. The main phytochemical compounds identified in the barks of T. catigua are flavalignans, flavan-3-ols and flavonoids which are associated with its antioxidant activity. Pre-clinical studies with T. catigua extracts have identified many pharmacological properties, such as anti-inflammatory, antidepressant, antinociceptive, pro-memory and neuroprotective against ischemia and oxidative stress. This study was designed in order to compare the chemical composition and in vitro antioxidant and anticholinesterase activity of four different polarity extracts and selected the one most active for in vivo studies in rodent models of stress, fatigue and memory. METHODS: Hexane, chloroform, hydroalcoholic and aqueous extracts from bark of Trichilia catigua were analyzed by RPHPLC-DAD-ESI-MS/MS. Antioxidant activity was assessed by 2,2-diphenyl-1-picryl hydrazyl (DPPH) assay and acetylcholinesterase inhibition by Ellman's modified method. In vivo studies (stress, fatigue and memory) were carried out with adult male mice and rats treated with hydroalcoholic extract in doses of 25-300 mg/kg (p.o.). RESULTS: We confirmed the presence of cinchonain IIa, Ia and Ib, as main constituents in the four extracts, while procyanidins were detected only in hydroalcoholic extract. Antioxidant and anticholinesterase activity were observed for all extracts, with most potent activity found on the hydroalcoholic extract (EC50 = 43 µg/mL and IC50 = 142 µg/mL for DPPH scavenger and acetylcholinesterase inhibition, respectively). The treatment of laboratory animals with hydroalcoholic extract did not protect rats from cold immobilization stress and did not prevent the scopolamine-induced amnesia in mice. However, the treatment of mice with the hydroalcoholic extract partially reduced the fatigue induced by treadmill, since the highest dose increased the spontaneous locomotor activity and reduced the deficit on grip strength after the forced exercise (p < 0.05), in some observation times. CONCLUSIONS: These data suggest the hydroalcoholic extract as the most suitable for plant extraction and partially support the folk use of T. catigua as antifatigue drug. . Trichilia catigua hydroalcoholic extract exhibits antioxidant and anticholinesterase activity in vitro and reduces the fatigue induced by forced exercise.
Assuntos
Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Meliaceae/química , Extratos Vegetais/farmacologia , Animais , Biflavonoides , Catequina , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Casca de Planta/química , Extratos Vegetais/química , Polifenóis , Proantocianidinas , Ratos , Estresse Fisiológico/efeitos dos fármacos , Estresse Psicológico/fisiopatologiaRESUMO
With the purpose of expanding the structural variety of chemical compounds available as pharmacological tools for the treatment of Alzheimer's disease, we synthesized and evaluated a novel series of indole-benzoxazinones (Family I) and benzoxazine-arylpiperazine derivatives (Family II) for potential human acetylcholinesterase (hAChE) inhibitory properties. The most active compounds 7a and 7d demonstrated effective inhibitory profiles with Ki values of 20.3 ± 0.9 µM and 20.2 ± 0.9 µM, respectively. Kinetic inhibition assays showed non-competitive inhibition of AChE by the tested compounds. According to our docking studies, the most active compounds from both series (Families I and II) showed a binding mode similar to donepezil and interact with the same residues.
Assuntos
Acetilcolinesterase/efeitos dos fármacos , Benzoxazinas/farmacologia , Inibidores da Colinesterase/farmacologia , Piperazinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Benzoxazinas/síntese química , Benzoxazinas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Donepezila , Desenho de Fármacos , Humanos , Indanos/farmacologia , Simulação de Acoplamento Molecular , Piperazinas/síntese química , Piperazinas/química , Piperidinas/farmacologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Major health challenges as the increasing number of cases of infections by antibiotic multiresistant microorganisms and cases of Alzheimer's disease have led to searching new control drugs. The present study aims to verify a new way of obtaining bioactive extracts from filamentous fungi with potential antimicrobial and acetylcholinesterase inhibitory activities, using epigenetic modulation to promote the expression of genes commonly silenced. For such finality, five filamentous fungal species (Talaromyces funiculosus, Talaromyces islandicus, Talaromyces minioluteus, Talaromyces pinophilus, Penicillium janthinellum) were grown or not with DNA methyltransferases inhibitors (procainamide or hydralazine) and/or a histone deacetylase inhibitor (suberohydroxamic acid). Extracts from T. islandicus cultured or not with hydralazine inhibited Listeria monocytogenes growth in 57.66 ± 5.98% and 15.38 ± 1.99%, respectively. Increment in inhibition of acetylcholinesterase activity was observed for the extract from P. janthinellum grown with procainamide (100%), when compared to the control extract (39.62 ± 3.76%). Similarly, inhibition of acetylcholinesterase activity increased from 20.91 ± 3.90% (control) to 92.20 ± 3.72% when the tested extract was obtained from T. pinophilus under a combination of suberohydroxamic acid and procainamide. Concluding, increases in antimicrobial activity and acetylcholinesterase inhibition were observed when fungal extracts in the presence of DNA methyltransferases and/or histone deacetylase modulators were tested.(AU)
Assuntos
Acetilcolinesterase/química , Anti-Infecciosos , Cromatina , Penicillium , Talaromyces , Estruturas Fúngicas , Epigênese GenéticaRESUMO
ABSTRACT Major health challenges as the increasing number of cases of infections by antibiotic multiresistant microorganisms and cases of Alzheimer's disease have led to searching new control drugs. The present study aims to verify a new way of obtaining bioactive extracts from filamentous fungi with potential antimicrobial and acetylcholinesterase inhibitory activities, using epigenetic modulation to promote the expression of genes commonly silenced. For such finality, five filamentous fungal species (Talaromyces funiculosus, Talaromyces islandicus, Talaromyces minioluteus, Talaromyces pinophilus, Penicillium janthinellum) were grown or not with DNA methyltransferases inhibitors (procainamide or hydralazine) and/or a histone deacetylase inhibitor (suberohydroxamic acid). Extracts from T. islandicus cultured or not with hydralazine inhibited Listeria monocytogenes growth in 57.66 ± 5.98% and 15.38 ± 1.99%, respectively. Increment in inhibition of acetylcholinesterase activity was observed for the extract from P. janthinellum grown with procainamide (100%), when compared to the control extract (39.62 ± 3.76%). Similarly, inhibition of acetylcholinesterase activity increased from 20.91 ± 3.90% (control) to 92.20 ± 3.72% when the tested extract was obtained from T. pinophilus under a combination of suberohydroxamic acid and procainamide. Concluding, increases in antimicrobial activity and acetylcholinesterase inhibition were observed when fungal extracts in the presence of DNA methyltransferases and/or histone deacetylase modulators were tested.
Assuntos
Antibacterianos/farmacologia , Inibidores da Colinesterase/farmacologia , Penicillium/química , Talaromyces/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Antibacterianos/química , Antibacterianos/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Cromatina/metabolismo , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/enzimologia , Listeria monocytogenes/crescimento & desenvolvimento , Penicillium/metabolismo , Talaromyces/metabolismoRESUMO
A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AßO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AßO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores da Colinesterase/farmacologia , Descoberta de Drogas , Hidrazonas/farmacologia , Indanos/farmacologia , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Donepezila , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Hidrazonas/química , Indanos/síntese química , Indanos/química , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
Major health challenges as the increasing number of cases of infections by antibiotic multiresistant microorganisms and cases of Alzheimer's disease have led to searching new control drugs. The present study aims to verify a new way of obtaining bioactive extracts from filamentous fungi with potential antimicrobial and acetylcholinesterase inhibitory activities, using epigenetic modulation to promote the expression of genes commonly silenced. For such finality, five filamentous fungal species (Talaromyces funiculosus, Talaromyces islandicus, Talaromyces minioluteus, Talaromyces pinophilus, Penicillium janthinellum) were grown or not with DNA methyltransferases inhibitors (procainamide or hydralazine) and/or a histone deacetylase inhibitor (suberohydroxamic acid). Extracts from T. islandicus cultured or not with hydralazine inhibited Listeria monocytogenes growth in 57.66±5.98% and 15.38±1.99%, respectively. Increment in inhibition of acetylcholinesterase activity was observed for the extract from P. janthinellum grown with procainamide (100%), when compared to the control extract (39.62±3.76%). Similarly, inhibition of acetylcholinesterase activity increased from 20.91±3.90% (control) to 92.20±3.72% when the tested extract was obtained from T. pinophilus under a combination of suberohydroxamic acid and procainamide. Concluding, increases in antimicrobial activity and acetylcholinesterase inhibition were observed when fungal extracts in the presence of DNA methyltransferases and/or histone deacetylase modulators were tested.
Assuntos
Antibacterianos/farmacologia , Inibidores da Colinesterase/farmacologia , Penicillium/química , Talaromyces/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Antibacterianos/química , Antibacterianos/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Cromatina/metabolismo , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/enzimologia , Listeria monocytogenes/crescimento & desenvolvimento , Penicillium/metabolismo , Talaromyces/metabolismoRESUMO
Abstract Alzheimer's disease affects nearly 36.5 million people worldwide, and acetylcholinesterase inhibition is currently considered the main therapeutic strategy against it. Seaweed biodiversity in Brazil represents one of the most important sources of biologically active compounds for applications in phytotherapy. Accordingly, this study aimed to carry out a quantitative and qualitative assessment of Hypnea musciformis (Wulfen) J.V. Lamouroux, Ochtodes secundiramea (Montagne) M.A. Howe, and Pterocladiella capillacea (S.G. Gmelin) Santelices & Hommersand (Rhodophyta) in order to determine the AChE effects from their extracts. As a matter of fact, the O. secundiramea extract showed 48% acetylcholinesterase inhibition at 400 μg/ml. The chemical composition of the bioactive fraction was determined by gas chromatography–mass spectrometry (GC–MS); this fraction is solely composed of halogenated monoterpenes, therefore allowing assignment of acetylcholinesterase inhibition activity to them.
RESUMO
OBJECTIVES: The inhibition of acetylcholinesterase (AChE), the key enzyme in the breakdown of acetylcholine, is currently the main pharmacological strategy available for Alzheimer's disease (AD). In this sense, many alkaloids isolated from natural sources, such as physostigmine, have been long recognized as acetyl- and butyrylcholinesterase (BChE) inhibitors. Since the approval of galantamine for the treatment of AD patients, the search for new anticholinesterase alkaloids has escalated, leading to promising candidates such as huperzine A. This review aims to summarize recent advances in current knowledge on alkaloids as AChE and BChE inhibitors, highlighting structure-activity relationship (SAR) and docking studies. KEY FINDINGS: Natural alkaloids belonging to the steroidal/triterpenoidal, quinolizidine, isoquinoline and indole classes, mainly distributed within Buxaceae, Amaryllidaceae and Lycopodiaceae, are considered important sources of alkaloids with anti-enzymatic properties. Investigations into the possible SARs for some active compounds are based on molecular modelling studies, predicting the mode of interaction of the molecules with amino acid residues in the active site of the enzymes. Following this view, an increasing interest in achieving more potent and effective analogues makes alkaloids good chemical templates for the development of new cholinesterase inhibitors. SUMMARY: The anticholinesterase activity of alkaloids, together with their structural diversity and physicochemical properties, makes them good candidate agents for the treatment of AD.
Assuntos
Alcaloides/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/metabolismo , Colinesterases/fisiologia , Humanos , Isoquinolinas/uso terapêutico , Simulação de Acoplamento Molecular , Monoterpenos/uso terapêutico , Quinolizidinas/uso terapêutico , Relação Estrutura-Atividade , Triterpenos/uso terapêutico , Proteínas tau/fisiologiaRESUMO
Neurotoxic organophosphorus compounds (OPs), which are used as pesticides and chemical warfare agents lead to more than 700,000 intoxications worldwide every year. The main target of OPs is the inhibition of acetylcholinesterase (AChE), an enzyme necessary for the control of the neurotransmitter acetylcholine (ACh). The control of ACh function is performed by its hydrolysis with AChE, a process that can be completely interrupted by inhibition of the enzyme by phosphylation with OPs. Compounds used for reactivation of the phosphylated AChE are cationic oximes, which usually possess low membrane and hematoencephalic barrier permeation. Neutral oximes possess a better capacity for hematoencephalic barrier permeation. NMR spectroscopy is a very confident method for monitoring the inhibition and reactivation of enzymes, different from the Ellman test, which is the common method for evaluation of inhibition and reactivation of AChE. In this work (1)H NMR was used to test the effect of neutral oximes on inhibition of AChE and reactivation of AChE inhibited with ethyl-paraoxon. The results confirmed that NMR is a very efficient method for monitoring the action of AChE, showing that neutral oximes, which display a significant AChE inhibition activity, are potential drugs for Alzheimer disease. The NMR method showed that a neutral oxime, previously indicated by the Ellman test as better in vitro reactivator of AChE inhibited with paraoxon than pralidoxime (2-PAM), was much less efficient than 2-PAM, confirming that NMR is a better method than the Ellman test.
Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Reativadores da Colinesterase/metabolismo , Electrophorus/metabolismo , Oximas/metabolismo , Acetilcolinesterase/química , Animais , Inibidores da Colinesterase/química , Reativadores da Colinesterase/química , Espectroscopia de Ressonância Magnética , Oximas/química , Paraoxon/análogos & derivados , Paraoxon/metabolismo , FosforilaçãoRESUMO
Capsella bursa-pastoris (L.) Medik. (Brassicaceae) is a wild herb with high nutritional value that can be eaten raw or cooked. A metabolomic study was performed with different extracts of its aerial parts that were tested concerning their antiradical, acetylcholinesterase inhibitory and antibacterial activities. Phenolic compounds were identified and quantified by HPLC-DAD, organic acids and amino acids were determined by HPLC-UV, while free fatty acids and sterols were analysed by GC-ITMS. The vegetal material was rich in kaempferol-3-O-rutinoside (mean value 2247.09 mg/kg of dry plant), quinic acid (95628.00 mg/kg of dry plant), arginine (mean value of 1.18 mg/kg of dry plant), palmitic acid (284.48 mg/kg) and β-sitosterol (28 percent). The extracts presented a concentration-dependent antiradical activity (against DPPH, O2- and LOO), being most effective against NO (EC25 0.20 µg/mL). In addition, the extracts were also acetylcholinesterase inhibitors and antibacterial active, revealing that, besides the plant's good nutritional value, it presents important biological properties as well.