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This study investigated the anxiolytic and anticonvulsant effects and safety profile of limonene enantiomers and their oxidized derivatives. The toxicity test was performed by monitoring the animals for 96 hours, with no deaths or significant toxicity observed up to the highest dose, which allowed the determination of the LD50. Doses of 4, 20 and 40 mg/kg were tested, with no toxicity observed up to 96h (LD50 > 40 mg/kg). Anxiolytic activity was measured in a preference test for light and dark areas, and the effect of the compounds was evaluated in the presence of serotonergic antagonists. The (S)-(-)-LIM and (R)-(+)-LIM enantiomers showed anxiolytic effects, with (S)-(-)-LIM being effective at all doses. In the anticonvulsant test, the oxidized derivatives, such as perilyl acid (PAC), significantly delayed PTZ-induced seizures, an effect blocked by flumazenil (FMZ). The oxidized derivatives, especially perilyl acid (PAC), showed anxiolytic effects at all doses and significantly delayed the three PTZ-induced seizure events. This effect was blocked by FMZ, suggesting a relationship between PAC and the GABAergic pathway. PAC, being the most oxidized derivative, was the most effective for both anxiety and delaying seizure progression, suggesting that oxidation of limonene compounds may increase their therapeutic efficacy.
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The compilation of ligand and structure-based molecular modeling methods has become an important practice in virtual screening applied to drug discovery. This systematic review addresses and ranks various virtual screening strategies to drive the selection of the optimal method for studies that have as their starting point a multi-ligand investigation and investigation based on the protein structure of a therapeutic target. This study shows examples of applications and an evaluation based on the objective and problematic of a series of virtual screening studies present in the ScienceDirect® database. The results showed that the molecular docking technique is widely used in scientific production, indicating that approaches that use protein structure as a starting point are the most promising strategy for drug discovery that relies on virtual screening-based research.
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This work describes the evaluation the potentiating activity of antibiotics by campesterol (1) and its derivatives (2-11) against multiresistant strains of Staphylococcusaureus 10, Escherichia coli 06 and Pseudomonas aeruginosa 24 employing the microdilution test. When subjected to the in vitro potentiating activity bioassay, all compounds showed a potentiating effect associated with norfloxacin against E. coli and P. aeruginosa with a reduction in the MIC of the antibiotic of up to 75%. These compounds also reduced the MIC of gentamicin by 37% to 87% in S. aureus and E. coli. Additionally, molecular docking studies were conducted to gain a deeper understanding of the interactions between the appropriate proteins and the most effective compounds (2, 4, 9, and 10 against E. coli; 1, 2, 3, 5, 8, and 9 against S. aureus), including antibiotics. This paper registers for the first time the in vitro and in silico studies on the action of compounds 1-11 in antibiotic potentiation.
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Anxiety and epilepsy are common worldwide and represent a primary global health concern. Fisetin, a flavonoid isolated from Bauhinia pentandra, has a wide range of biological activities may be a promising alternative to combat diseases related to the central nervous system (CNS). The present study aimed to investigate the anxiolytic and anticonvulsant effects of fisetin on adult zebrafish. Furthermore, molecular docking simulations were performed to improve the results. Fisetin did not present toxicity and caused anxiolytic behavior and delayed seizures in animals. This effect may occur through serotonin neurotransmission at 5-HT3A and/or 5-HT3B receptors. Molecular docking simulations showed that fisetin interacts with the orthosteric site of the 5-HT3A receptor with strong H-bond interactions with the Trp156 residue, with a strong contribution from the catechol ring, a behavior similar to that of the antagonist co-crystallized inhibitor granisetron (CWB). Fisetin may be a promising alternative to combat diseases related to the central nervous system.
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Staphylococcus aureus is a bacterium responsible for resistance to multiple drugs and the efflux system is widely studied among the resistance mechanisms developed by this species. The present study evaluates the inhibition of the MepA efflux pump by thiadiazine-derived compounds. For this purpose, thiadiazine-derived compounds (IJ-14 to IJ-20) were tested against S. aureus K2068 strains. Microdilution tests were initially conducted to assess the Minimum Inhibitory Concentration (MIC) of the compounds and their efflux pump inhibition activity. In addition, fluorimetry tests were performed using BrEt emission and tests were conducted to inhibit the expression of the mepA gene. This involved comparing the bacterial gene expression with the antibiotic alone to the gene expression after combining compounds (IJ-17 and IJ-20) with the antibiotic. Furthermore, membrane permeability assessment tests and in silico molecular docking tests were performed. It was observed that the IJ17 and IJ20 compounds exhibited direct activity against the tested strain. The IJ17 compound produced significant results in the gene inhibition tests, which was also evidenced through the membrane permeability alteration test. These findings suggest that thiadiazine-derived compounds have promising effects against one of the main resistance mechanisms, with the IJ17 compound presenting observable mechanisms of action.
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Antibacterianos , Proteínas de Bactérias , Permeabilidade da Membrana Celular , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Staphylococcus aureus , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Tiazinas/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Membrana Transportadoras/genéticaRESUMO
Antimicrobials fight microorganisms, preventing and treating infectious diseases. However, antimicrobial resistance (AMR) is a growing concern due to the inappropriate and excessive use of these drugs. Several mechanisms can lead to resistance, including efflux pumps such as the NorA pump in Staphylococcus aureus, which reduces the effectiveness of fluoroquinolones. Thiadiazines are heterocyclic compounds whose chemical structure resembles that of cephalosporins. Therefore, these compounds and their derivatives have been studied for their potential in combating increased bacterial resistance. To analyze this hypothesis, direct activity assays, antibiotic action-modifying activity, fluorescence assays to evaluate the retention of ethidium bromide inside bacteria, and molecular docking were carried out. These experiments involved serial dilutions in microplates against Staphylococcus aureus strain 1199B under the influence of six thiadiazine derivatives (IJ10, IJ11, IJ21, IJ22, IJ23, and IJ25). The tests revealed that, despite not showing effective direct activity, some thiadiazine derivatives (IJ11, IJ21, and IJ22) inhibited the function of the bromide pump both in microdilution tests and in fluorescence and docking assays. Particularly, the IJ11 compound stood out for its activity similar to efflux inhibitors, as well as its inhibition of the norfloxacin pump of this bacterium. Among the results of this study, it deserves to be highlighted for anchoring future experiments, as it represents the first investigation of this group of thiadiazine derivatives against the NorA pump.
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Antibacterianos , Proteínas de Bactérias , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Staphylococcus aureus , Tiadiazinas , Antibacterianos/farmacologia , Antibacterianos/química , Staphylococcus aureus/efeitos dos fármacos , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/química , Tiadiazinas/farmacologia , Tiadiazinas/química , Simulação por ComputadorRESUMO
Antimicrobial resistance is a global health issue, in which microorganisms develop resistance to antimicrobial drugs, making infections more difficult to treat. This threatens the effectiveness of standard medical treatments and necessitates the urgent development of new strategies to combat resistant microbes. Studies have increasingly explored natural sources of new antimicrobial agents that harness the rich diversity of compounds found in plant species. This pursuit holds promise for the discovery of novel treatments for combating antimicrobial resistance. In this context, the chemical composition, antibacterial, and antibiofilm activities of the essential oil from Croton urticifolius Lam. leaves (CuEO) were evaluated. CuEO was extracted via hydrodistillation, and its chemical constituents were identified via gas chromatography-mass spectrometry (GC/MS). The antibacterial activity of CuEO was evaluated in a 96-well plate via the microdilution method, and the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were determined. The effect of CuEO on biofilm formation was assessed by quantifying the biomass using crystal violet staining and viable cell counting. In addition, alterations in the cellular morphology of biofilms treated with CuEO were examined using scanning electron microscopy (SEM) and laser confocal microscopy. GC/MS analysis identified 26 compounds, with elemicine (39.72%); eucalyptol (19.03%), E-caryophyllene (5.36%), and methyleugenol (4.12%) as the major compounds. In terms of antibacterial activity, CuEO showed bacteriostatic effects against Staphylococcus aureus ATCC 700698, S. aureus ATCC 25923, Staphylococcus epidermidis ATCC 12228, and Escherichia coli ATCC 11303, and bactericidal activity against S. aureus ATCC 700698. In addition, CuEO significantly inhibited bacterial biofilm formation. Microscopic analysis showed that CuEO damaged the bacterial membrane by leaching out the cytoplasmic content. Therefore, the results of this study show that the essential oil of C. urticifolius may be a promising natural alternative for preventing infections caused by bacterial biofilms. This study is the first to report the antibiofilm activity of C. urticifolius essential oil.
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Antibacterianos , Biofilmes , Croton , Testes de Sensibilidade Microbiana , Óleos Voláteis , Folhas de Planta , Biofilmes/efeitos dos fármacos , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Croton/química , Antibacterianos/farmacologia , Antibacterianos/química , Folhas de Planta/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Cromatografia Gasosa-Espectrometria de Massas , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Membrana Celular/efeitos dos fármacosRESUMO
Parkinson's disease (PD) is a debilitating condition that can cause locomotor problems in affected patients, such as tremors and body rigidity. PD therapy often includes the use of monoamine oxidase B (MAOB) inhibitors, particularly phenylhalogen compounds and coumarin-based semi-synthetic compounds. The objective of this study was to analyze the structural, pharmacokinetic, and pharmacodynamic profile of a series of Triazolo Thiadiazepine-fused Coumarin Derivatives (TDCDs) against MAOB, in comparison with the inhibitor safinamide. To achieve this goal, we utilized structure-based virtual screening techniques, including target prediction and absorption, distribution, metabolism, and excretion (ADME) prediction based on multi-parameter optimization (MPO) topological analysis, as well as ligand-based virtual screening techniques, such as docking and molecular dynamics. The findings indicate that the TDCDs exhibit structural similarity to other bioactive compounds containing coumarin and MAOB-binding azoles, which are present in the ChEMBL database. The topological analyses suggest that TDCD3 has the best ADME profile, particularly due to the alignment between low lipophilicity and high polarity. The coumarin and triazole portions make a strong contribution to this profile, resulting in a permeability with Papp estimated at 2.15 × 10-5 cm/s, indicating high cell viability. The substance is predicted to be metabolically stable. It is important to note that this is an objective evaluation based on the available data. Molecular docking simulations showed that the ligand has an affinity energy of - 8.075 kcal/mol with MAOB and interacts with biological substrate residues such as Pro102 and Phe103. The results suggest that the compound has a safe profile in relation to the MAOB model, making it a promising active ingredient for the treatment of PD.
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This study aims to evaluate the antitrypanosomiasis activity of a synthetic dichloro-substituted aminochalcone via in vitro assays against infected cell cultures, as well as a theoretical characterization of pharmacokinetics and pharmacodynamics against the protein targets of the evolutionary cycle of T. cruzi. The in vitro evaluation of parasite proliferation inhibition was performed via cytotoxicity analysis on mammalian host cells, effect on epimastigote and trypomastigote forms, and cell death analysis, while computer simulations characterized the electronic structure of (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one (DCl), the mechanism of action against the proteins of the evolutionary cycle of T. cruzi: Cruzain, Trypanothione reductase, TcGAPDH, and CYP51 by molecular docking and dynamics and predictive pharmacokinetics by MPO-based ADMET. The in vitro tests showed that the DCl LC50 in order of 178.9 ± 23.9 was similar to the BZN, evidencing the effectiveness of chalcone against Trypomastigotes. Molecular docking and dynamics simulations suggest that DCl acts on the active site of the CYP51 receptor, with hydrogen interactions that showed a high degree of occupation, establishing a stable complex with the target. MPO analysis and ADMET prediction tests suggest that the compound presents an alignment between permeability and hepatic clearance, although it presents low metabolic stability. Chalcone showed stable pharmacodynamics against the CYP51 target, but can form reactive metabolites from N-conjugation and C = C epoxidation, as an indication of controlled oral dose, although the estimated LD50 rate > 500 mg/kg is a indicative of low incidence of lethality by ingestion, constituting a promising therapeutic strategy.
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Chalconas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Tripanossomicidas , Trypanosoma cruzi , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Trypanosoma cruzi/efeitos dos fármacos , Animais , Chalconas/farmacologia , Chalconas/química , Proteínas de Protozoários/metabolismo , Humanos , NADH NADPH Oxirredutases/antagonistas & inibidores , NADH NADPH Oxirredutases/metabolismo , Teoria Quântica , Camundongos , Doença de Chagas/tratamento farmacológicoRESUMO
This study carried out to investigate the anti-inflammatory and antinociceptive effect of tropane alkaloid (EB7) isolated from E. bezerrae. It evaluated the toxicity and possible involvement of ion channels in the antinociceptive effect of EB7, as well as its anti-inflammatory effect in adult zebrafish (Zfa). Docking studies with EB7 and COX-1 and 2 were also performed. The tested doses of EB7 (4, 20 and 40â mg/kg) did not show any toxic effect on Zfa during the 96h of analysis (LD50>40â mg/kg). They did not produce any alteration in the locomotor behavior of the animals. Furthermore, EB7 showed promising pharmacological effects as it prevented the nociceptive behavior induced by hypertonic saline, capsaicin, formalin and acid saline. EB7 had its analgesic effect blocked by amiloride involving the neuromodulation of ASICs in Zfa. In evaluating the anti-inflammatory activity, the edema induced by κ-carrageenan 3.5 % was reduced by the dose of 40â mg/kg of EB7 observed after the fourth hour of analysis, indicating an effect similar to that of ibuprofen. Molecular docking results indicated that EB7 exhibited better affinity energy when compared to ibuprofen control against the two evaluated targets binding at different sites in the cocrystallized COX-1 and 2 inhibitors.
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Analgésicos , Simulação de Acoplamento Molecular , Peixe-Zebra , Animais , Analgésicos/farmacologia , Analgésicos/química , Analgésicos/isolamento & purificação , Tropanos/farmacologia , Tropanos/isolamento & purificação , Tropanos/química , Edema/tratamento farmacológico , Edema/induzido quimicamente , Carragenina/farmacologia , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 1/metabolismo , Bignoniaceae/química , Relação Dose-Resposta a Droga , Relação Estrutura-Atividade , Alcaloides/farmacologia , Alcaloides/isolamento & purificação , Alcaloides/química , Canais Iônicos Sensíveis a Ácido/metabolismo , Canais Iônicos Sensíveis a Ácido/química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Estrutura MolecularRESUMO
The study focuses on the anxiolytic potential of chalcone (2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-one (CHALCNM) in adult zebrafish. Successfully synthesized in 58 % yield, CHALCNM demonstrated no toxicity after 96â h of exposure. In behavioral tests, CHALCNM (40â mg/kg) reduced locomotor activity and promoted less anxious behavior in zebrafish, confirmed by increased permanence in the light zone of the aquarium. Flumazenil reversed its anxiolytic effect, indicating interaction with GABAA receptors. Furthermore, CHALCNM (4 and 20â mg/kg) preserved zebrafish memory in inhibitory avoidance tests. Virtual screening and ADMET profile studies suggest high oral bioavailability, access to the CNS, favored by low topological polarity (TPSA≤75â Å2) and low incidence of hepatotoxicity, standing out as a promising pharmacological agent against the GABAergic system. In molecular coupling, CHALCNM demonstrated superior affinity to diazepam for the GABAA receptor. These results reinforce the therapeutic potential of CHALCNM in the treatment of anxiety, highlighting its possible future clinical application.
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Ansiolíticos , Comportamento Animal , Chalcona , Peixe-Zebra , Animais , Comportamento Animal/efeitos dos fármacos , Chalcona/química , Chalcona/farmacologia , Chalcona/análogos & derivados , Ansiolíticos/farmacologia , Ansiolíticos/química , Ansiolíticos/síntese química , Receptores de GABA-A/metabolismo , Acroleína/análogos & derivados , Acroleína/química , Acroleína/farmacologia , Estrutura Molecular , Simulação de Acoplamento Molecular , Chalconas/farmacologia , Chalconas/química , Chalconas/síntese química , Locomoção/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
This is the first study to analyze the anti-inflammatory and antinociceptive effect of withanicandrin, isolated from Datura Ferox leaves, and the possible mechanism of action involved in adult zebrafish (ZFa). To this end, the animals were treated intraperitoneally (i. p.) with withanicandrin (4; 20 and 40â mg/kg; 20â µL) and subjected to locomotor activity and acute toxicity. Nociception tests were also carried out with chemical agents, in addition to tests to evaluate inflammatory processes induced by κ-Carrageenan 1.5 % and a Molecular Docking study. As a result, withanicandrin reduced nociceptive behavior by capsaicin at a dose of 40â mg/kg and by acid saline at doses of 4 and 40â mg/kg, through neuromodulation of TRPV1 channels and ASICs, identified through blocking the antinociceptive effect of withanicandrin by the antagonists capsazepine and naloxone. Furthermore, withanicandrin caused an anti-inflammatory effect through the reduction of abdominal edema, absence of leukocyte infiltrate in the liver tissue and reduction of ROS in thel liver tissue and presented better affinity energy compared to control morphine (TRPV1) and ibuprofen (COX-1 and COX-2).
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Analgésicos , Peixe-Zebra , Animais , Analgésicos/farmacologia , Analgésicos/química , Analgésicos/isolamento & purificação , Canais Iônicos Sensíveis a Ácido/metabolismo , Simulação de Acoplamento Molecular , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Carragenina , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Edema/tratamento farmacológico , Edema/induzido quimicamente , Folhas de Planta/química , Estrutura MolecularRESUMO
Stingless bees belong to the Meliponini tribe and are widely distributed in the tropics and subtropics, where they perform important ecological services. Among the best distributed groups of stingless bees is the genus Scaptotrigona, which includes 22 species distributed throughout the neotropical region, including the area from Mexico to Argentina. Bees of this genus are responsible for the production of products such as honey, propolis, geopropolis and fermented pollen ("saburá"). This review aimed to provide an overview of the chemical composition and biological activities associated with derived products from stingless bees of the genus Scaptotrigona. The bibliographic review was carried out through searches in the Scopus, Web of Science, ScienceDirect and PubMed databases, including publications from 2003 to January 2023. The study of the chemodiversity of products derived from Scaptotrigona demonstrated the mainly presence of flavonoids, phenolic acids, terpenoids and alkaloids. It was also demonstrated that products derived from bees of the genus Scaptotrigona exhibit a wide range of biological effects, such as antibacterial, antioxidant, anti-inflammatory and antifungal activities, among other bioactivities. This review provides an overview of phytochemical and pharmacological investigations of the genus Scaptotrigona. However, it is essential to clarify the toxicity and food safety of these products.
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Mel , Himenópteros , Própole , Animais , Antibacterianos/farmacologia , Abelhas , México , Própole/farmacologia , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Hidroxibenzoatos/química , Hidroxibenzoatos/isolamento & purificação , Hidroxibenzoatos/farmacologia , Terpenos/química , Terpenos/isolamento & purificação , Terpenos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologiaRESUMO
Griffinia gardneriana Ravenna, Griffinia liboniana Morren and Griffinia nocturna Ravenna (Amarillydaceae) are bulbous plants found in tropical regions of Brazil. Our work aimed to determine the alkaloid profiles of Griffinia spp. and evaluate their anxiolytic potential through inâ vivo and in silico assays. The plants grown in greenhouses were dried and their ground bulbs were subjected to liquid-liquid partitions, resulting in alkaloid fractions that were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). Anxiolytic activity was evaluated in zebrafish (Danio rerio) through intraperitoneal injection at doses of 40, 100 and 200â mg/kg in light-dark box test. GC-MS analyses revealed 23 alkaloids belonging to different skeleton types: lycorine, homolychorine, galanthamine, crinine, haemanthamine, montanine and narcisclasine. The chemical profiles were relatively similar, presenting 8 alkaloids common to the three species. The major component for G. gardneriana and G. liboniana was lycorine, while G. nocturna consisted mainly of anhydrolycorine. All three alkaloid fractions demonstrated anxiolytic effect. Furthermore, pre-treatment with diazepam and pizotifen drugs was able to reverse the anxiolytic action, indicating involving the GABAergic and serotonergic receptors. Molecular docking showed that the compounds vittatine, lycorine and 11,12-dehydro-2-methoxyassoanine had high affinity with both receptors, suggesting them to be responsible for the anxiolytic effect.
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Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Ansiolíticos , Fenantridinas , Animais , Amaryllidaceae/química , Peixe-Zebra , Ansiolíticos/farmacologia , Simulação de Acoplamento Molecular , Cromatografia Gasosa-Espectrometria de Massas/métodos , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/química , Alcaloides/farmacologia , Alcaloides/química , Extratos Vegetais/farmacologia , Extratos Vegetais/químicaRESUMO
The xanthone lichenxanthone did not show toxic effects (LC50>1.0â mg/mL). lichenxanthone prevented nociceptive behavior induced by acidic saline, and its analgesic effect was blocked by amiloride, highlighting the involvement of neuromodulation of acid-sensitive ion channels (ASICs). In the analysis of anti-inflammatory activity, concentrations of 0.1 and 0.5â mg/mL of lichenxanthone reduced the edema induced by k-carrageenan 3.5 %, observed from the fourth hour of analysis. This effect was similar to that observed with ibuprofen (positive control). No leukocyte infiltrates were observed in lichenxanthone, suggesting that the compound acts in the acute inflammatory response. The results of the molecular docking study revealed that lichenxanthone exhibited better affinity energy when compared to the ibuprofen control against the two targets evaluated.
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Ibuprofeno , Peixe-Zebra , Animais , Simulação de Acoplamento Molecular , Anti-Inflamatórios/farmacologia , Canais IônicosRESUMO
The Enterobacteriaceae family is recognized as a primary group of Gram-negative pathogens responsible for foodborne illnesses and is frequently associated with antibiotic resistance. The present study explores the natural-based compound trans-cinnamaldehyde (TC) against drug-resistant Enterobacteriaceae and its synergism with gentamicin (GEN) to address this issue. The research employs three strains of Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae, previously isolated from shrimp. The antibacterial activity was evaluated by the disk diffusion method, microdilution test, kinetics of growth, and time-kill curve. In addition, the synergistic effect between TC/GEN was investigated by checkerboard assay. All strains showed sensitivity to TC with an inhibition zone diameter > 35 mm. The TC showed inhibitory and bactericidal action in the most tested bacteria around 625 µg/mL. Sub-inhibitory amounts (1/2 and 1/4 MIC) of TC interfered with the growth kinetics by lag phase extension and decreased the log phase. Time-kill curves show a reduction of viable cells after the first hour of TC treatment at bactericidal concentrations. The synergistic effect between TC/GEN was observed for E. coli and E. cloacae strains with FICi ranging from 0.15 to 0.50. These findings, therefore, suggest TC as a promising alternative in the fight against drug-resistant Enterobacteriaceae that can cause foodborne illnesses.
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Acroleína , Antibacterianos , Sinergismo Farmacológico , Enterobacteriaceae , Gentamicinas , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Gentamicinas/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/crescimento & desenvolvimento , Acroleína/análogos & derivados , Acroleína/farmacologia , Animais , Microbiologia de Alimentos , Doenças Transmitidas por Alimentos/microbiologia , Doenças Transmitidas por Alimentos/prevenção & controleRESUMO
Background: Staphylococcus aureus is a human pathogen responsible for high mortality rates. The development of new antimicrobials is urgent. Materials & methods: The authors evaluated the activity of hydralazine along with its synergism with other drugs and action on biofilms. With regard to action mechanisms, the authors evaluated cell viability, DNA damage and molecular docking. Results: MIC and minimum bactericidal concentration values ranged from 128 to 2048 µg/ml. There was synergism with oxacillin (50%) and vancomycin (25%). Hydralazine reduced the viability of biofilms by 50%. After exposure to hydralazine 2× MIC, 58.78% of the cells were unviable, 62.07% were TUNEL positive and 27.03% presented damage in the comet assay (p < 0.05). Hydralazine showed affinity for DNA gyrase and TyrRS. Conclusion: Hydralazine is a potential antibacterial.
Staphylococcus aureus is a bacterium that can cause infection. Infections of S. aureus are becoming difficult to treat, but developing new drugs is a challenge. Repurposing them may be easier. This study looks at the possibility of using hydralazine, a type of medicine used to treat high blood pressure, against S. aureus. The authors found that hydralazine can kill S. aureus and can be used with other antibiotics, including oxacillin and vancomycin. Hydralazine interferes with important processes for the multiplication and survival of this bacterium. These results are preliminary but encouraging. Further studies are needed to confirm the use of hydralazine as a new treatment for S. aureus infections.
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Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Staphylococcus aureus , Meticilina , Resistência a Meticilina , Simulação de Acoplamento Molecular , Antibacterianos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Anxiety disorders represent the complex interaction between biological, psychological, temperamental, and environmental factors; drugs available to treat anxiety such as benzodiazepines (BZDs) are associated with several unwanted side effects. Although there are useful treatments, there is still a need for more effective anxiolytics with better safety profiles than BZDs. Chalcones or 1,3-diphenyl-2-proper-1-ones can be an alternative since this class of compounds has shown therapeutic potential mainly due to interactions with GABAA receptors and serotonergic system. OBJECTIVES: This study evaluated the anxiolytic potential of chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (C2OHPDA) in adult zebrafish (Danio rerio) (ZFa). METHODS: Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 µL) with the chalcone (4, 20, and 40 mg/kg) and with the vehicle (DMSO 3%; 20 µL), being submitted to the tests of locomotor activity and 96-h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR1 , 5-HTR2A/2C , and 5-HTR3A/3B receptors. It was investigated the prediction of the chalcone's position and preferential orientation concerning its receptor, as well as the pharmacokinetic parameters (ADMET) involved in the process after administration. RESULTS: As a result, C2OHPDA was not toxic and reduced the locomotor activity of ZFa. Furthermore, chalcone demonstrated an anxiolytic effect on the central nervous system (CNS), mediated by the serotonergic system, with action on 5-HT2A and 5-HTR3A/3B receptors. The interaction of C2OHPDA with 5-HT2A R and 5-HT3A receptors was confirmed by molecular docking study, the affinity energy observed was -8.7 and -9.1 kcal/mol, respectively. CONCLUSION: Thus, this study adds new evidence and highlights that chalcone can potentially be used to develop compounds with anxiolytic properties.
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Ansiolíticos , Chalcona , Chalconas , Animais , Ansiolíticos/farmacologia , Peixe-Zebra , Simulação de Acoplamento Molecular , Serotonina , Benzodiazepinas , Receptores de GABA-ARESUMO
Tinnitus is a syndrome that affects the human auditory system and is characterized by a perception of sounds in the absence of acoustic stimuli, or in total silence. Research indicates that muscarinic acetylcholine receptors (mAChRs), especially the M1 type, have a fundamental role in the alterations of auditory perceptions of tinnitus. Here, a series of computer-aided tools were used, from molecular surface analysis software to services available on the web for estimating pharmacokinetics and pharmacodynamics. The results infer that the low lipophilicity ligands, that is, the 1a-d alkyl furans, present the best pharmacokinetic profile, as compounds with an optimal alignment between permeability and clearance. However, only ligands 1a and 1b have properties that are safe for the central nervous system, the site of cholinergic modulation. These ligands showed similarity with compounds deposited in the European Molecular Biology Laboratory chemical (ChEMBL) database acting on the mAChRs M1 type, the target selected for the molecular docking test. The simulations suggest that the 1 g ligand can form the ligand-receptor complex with the best affinity energy order and that, together with the 1b ligand, they are competitive agonists in relation to the antagonist Tiotropium, in addition to acting in synergism with the drug Bromazepam in the treatment of chronic tinnitus.
Assuntos
Receptor Muscarínico M1 , Zumbido , Humanos , Receptor Muscarínico M1/química , Acetilcolina/farmacologia , Simulação de Acoplamento Molecular , Ligantes , Zumbido/tratamento farmacológicoRESUMO
General anxiety disorders are among the most prevalent mental health problems worldwide. The emergence and development of anxiety disorders can be due to genetic (30-50%) or non-genetic (50-70%) factors. Despite medical progress, available pharmacotherapies are sometimes ineffective or can cause undesirable side effects. Thus, it becomes necessary to discover new safe and effective drugs against anxiety. This study evaluated the anxiolytic effect in adult zebrafish (Danio rerio) of a natural pyrroloformamide (PFD), N-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-N-methylformamide, isolated from a Streptomyces sp. bacterium strain recovered from the ascidian Eudistoma vannamei. The complete structure of PFD was determined by a detailed NMR analysis, including 1H-13C and 1H-15N-HBMC data. In addition, conformational and DFT computational studies also were performed. A group of fishes (n = 6) was treated orally with PFD (0.1, 0.5 and 1.0 mg/mL; 20 µL) and subjected to locomotor activity and light/dark tests, as well as, acute toxicity 96 h. The involvement of the GABAergic and serotonergic (5-HT) systems was investigated using flumazenil (a silent modulator of GABA receptor) and 5-HT1, 5-HT2A/2C and 5-HTR3A/3B receptors antagonists, known as pizotifen, granisetron and cyproheptadine, respectively. PFD was nontoxic, reduced locomotor activity and promoted the anxiolytic effect in zebrafish. Flumazenil did not inhibit the anxiolytic effect of the PFD via the GABAergic system. This effect was reduced by a pretreatment with pizotifen and granisetron, and was not reversed after treatment with cyproheptadine. Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.Communicated by Ramaswamy H. Sarma.
Pyrroloformamide (PFD), isolated from the marine Streptomyces sp. associated ascidian Eudistoma vannamei, showed no toxicity in adult zebrafish but reduced its locomotor activity.The structural elucidation of PFD was determined by the analysis of 1D and 2D NMR and HRESIMS data.The density functional theory (DFT) study confirmed the existence of two conformers as determined by NMR spectra.The serotonergic system modulated the anxiolytic effect of PFD via the 5-HT receptor in adult zebrafish.Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.