Navegando por Autor "Liao, Luciano Morais"
Agora exibindo 1 - 20 de 125
Resultados por página
Opções de Ordenação
Item 1H HR-MAS NMR and S180 cells: metabolite assignment and evaluation of pulse sequence(2014-04) Oliveira, Aline Lima de; Martinelli, Bruno César Barbosa; Liao, Luciano Morais; Pereira, Flávia de Castro; Lacerda, Elisângela de Paula Silveira; Alcantara, Glaucia BrazHigh resolution magic angle spinning 1H nuclear magnetic resonance spectroscopy (HR-MAS NMR) is a useful technique for evaluation of intact cells and tissues. However, optimal NMR parameters are crucial in obtaining reliable results. To identify the key steps for the optimization of HR-MAS NMR parameters, we assessed different pulse sequences and NMR parameters using sarcoma 180 (S180) cells. A complete assignment of the metabolites of S180 is given to assist future studies.Item 1H HRMAS NMR spectroscopy and chemometrics for evaluation of metabolic changes in citrus sinensis caused by xanthomonas axonopodis pv. citri(2012-05) Silva, Lorena Mara Alexandre e; Alves Filho, Elenilson de Godoy; Choze, Rafael; Liao, Luciano Morais; Alcantara, Glaucia BrazXanthomonas axonopodis (Xac) bacterium causes one of the most feared and untreatable diseases in citriculture: citrus canker. To understand the response mechanisms of orange trees when attacked by Xac, leaves and fruits of Citrus sinensis were directly evaluated by HRMAS NMR (high resolution magic angle spinning nuclear magnetic resonance) spectroscopy. This technique allows the analysis of samples without laborious pre-treatments and also allows access to important information about chemical composition of samples. The orange tree leaves and fruit peels investigated in this study demonstrated the biochemical changes caused by Xac. Aided by chemometric analysis, the HRMAS NMR results show relevant changes in amino acids, carbohydrates, organic acids and terpenoids content.Item 25I-NBOH: a new potent serotonin 5-HT2A receptor agonist identified in blotter paper seizures in Brazil(2017-02-16) Arantes, Luciano Chaves; Ferrari Júnior, Ettore; Souza, Luciano Figueiredo de; Cardoso, Andriele Costa; Alcantara, Thaynara Lino Fernandes; Liao, Luciano Morais; Machado, Yuri; Lordeiro, Rogério Araújo; Coelho Neto, José; Andrade, Ana Flávia Belchior deA new potent serotonin 5-HT2A receptor agonist was identified in blotter papers by several state level forensic laboratories in Brazil. The 25I-NBOH is a labile molecule, which fragments into 2C-I when analyzed by routine seized material screening gas chromatography (GC) methods. GC–mass spectrometry (MS), liquid chromatography–quadrupole time-of-flight-MS, and Fourier transform infrared and nuclear magnetic resonance analyses were performed to complete molecular characterization. Individual doses range from 300 to 1000 lg. Despite its being a potent 5-HT2A receptor agonist, 25I-NBOH is neither registered in the United Nations Office on Drugs and Crime (UNODC) nor classified as a scheduled substance in most countries. Sweden and Brazil seem to be the only countries to control 25I-NBOH. To our knowledge, this is the first scientific report dealing with identification of 25I-NBOH in actual seizures.Item A database for automatic classification of gender in Araucaria angustifolia plants(2021) Martins, Jefferson Gustavo; Oliveira, Luiz Eduardo Soares de; Weingaertner, Daniel; Barison, Andersson; Oliveira, Gerlon de Almeida Ribeiro; Liao, Luciano MoraisForests have been disorderly exploited, and many species are considered endangered. Some initiatives have been taken in order to prevent forests from being destroyed. A good alternative would be to plan a spatial distribution of plants, with higher number of females than males. Determining the gender of seedlings would provide important information for a possible strategy. Another common problem that researchers in this field very often face, in order to perform their experiments, is the lack of a representative database. To overcome this difficulty, we introduce a new database in this work, which is composed of nuclear magnetic resonance of adult Araucaria angustifolia plants. In order to gain better insight into this database, we have tested different strategies and classifiers. A first set of experiments took three classifiers trained to discriminate males from females considering the original database. A second round of experiments applied the genetic algorithm technique to select subsets of attributes based on single-objective and two-objective functions. After analyzing the achieved results, we have also proposed a new strategy based on statistical measures for selecting subsets from the attributes. A comprehensive set of experiments has shown that the proposed selecting strategy has achieved better performances, with an accuracy of 80.3% (AUC = 79.4). We believe that researchers will find this database a useful tool in their work on determining the Araucaria angustifolia gender. On the other hand, the proposed selecting strategy would be useful for reducing the complexity of databases and accelerating the process of building classification models.Item A novel polymer-lipid hybrid nanoparticle for the improvement of topotecan hydrochloride physicochemical properties(2018) Silva, Emanuelle Jesus; Souza, Leonardo Gomes; Silva, Luís Antônio Dantas; Taveira, Stephânia Fleury; Liao, Luciano Morais; Queiroz Júnior, Luiz Henrique Keng; Santana, Mábio João; Marreto, Ricardo NevesBackground: Topotecan (TPT) is a water-soluble derivate of camptothecin, which undergoes ring-opening hydrolysis in neutral solutions, leading to stability loss and poor cellular uptake. Lipid nanoencapsulation can improve TPT stability, and polymer-lipid hybrid nanoparticles (PLN) are interesting alternatives to improve TPT nanoencapsulation. Objective: This study seeks to prepare complexes between the cationic TPT and the negatively charged dextran sulfate (DS) with a view of improving drug loading, chemical stability and release control. Methods: The optimum ionic molar ratio in DS-TPT complexation was determined, and the selected complex was characterized by FTIR and solid-state 13C NMR. TPT solubility in the free and complexed forms was also assayed. TPT-PLN was then obtained via a microemulsion technique, and particle size, zeta potential, encapsulation efficiency, drug loading and drug recovery were determined. Additionally, the TPT stability and in vitro release were determined from PLN and compared with free TPT, TPT-DS complex and TPT encapsulated in nanostructured lipid carriers (NLC) of similar composition. Results: TPT-DS complexation was confirmed by FTIR and NMR. TPT solubility in the complex was drastically decreased when compared to free TPT. TPT-PLN had high encapsulation efficiency (97%) and drug loading capacity (5.5%). Additionally, TPT-PLN showed a mean diameter, polidispersivity index e zeta potential of 140 nm, 0.2 and -22 mV, respectively. The TPT chemical stability and release from PLN were observed to be superior when compared to NLC. Conclusion: PLN has shown to be a more effective nanosystem for TPT nanoencapsulation because TPT loading, stability and release were superior when compared to TPT-NLC.Item A polyalanine peptide derived from polar fish with anti-infectious activities(2016-02-26) Cardoso, Marlon Henrique e Silva; Ribeiro, Suzana Meira; Silva, Diego Oliveira Nolasco da; Fuente Nunez, César de la; Felício, Mário Romão; Gonçalves, Sónia; Matos, Carolina Oliveira; Liao, Luciano Morais; Santos, Nuno C.; Franco, Octavio Luiz; Migliolo, Ludovico; Hancock, Robert E. W.Due to the growing concern about antibiotic-resistant microbial infections, increasing support has been given to new drug discovery programs. A promising alternative to counter bacterial infections includes the antimicrobial peptides (AMPs), which have emerged as model molecules for rational design strategies. Here we focused on the study of Pa-MAP 1.9, a rationally designed AMP derived from the polar fish Pleuronectes americanus. Pa-MAP 1.9 was active against Gram-negative planktonic bacteria and biofilms, without being cytotoxic to mammalian cells. By using AFM, leakage assays, CD spectroscopy and in silico tools, we found that Pa-MAP 1.9 may be acting both on intracellular targets and on the bacterial surface, also being more efficient at interacting with anionic LUVs mimicking Gram-negative bacterial surface, where this peptide adopts α-helical conformations, than cholesterol-enriched LUVs mimicking mammalian cells. Thus, as bacteria present varied physiological features that favor antibiotic-resistance, Pa-MAP 1.9 could be a promising candidate in the development of tools against infections caused by pathogenic bacteria.Item A structural perspective of plant antimicrobial peptides(2018) Campos, Marcelo Lattarulo; Liao, Luciano Morais; Alves, Eliane Santana Fernandes; Migliolo, Ludovico; Dias, Simoni Campos; Franco, Octavio LuizAmong the numerous strategies plants have developed to fend off enemy attack, antimicrobial peptides (AMPs) stand out as one of the most prominent defensive barriers that grant direct and durable resistance against a wide range of pests and pathogens. These small proteins are characterized by a compact structure and an overall positive charge. AMPs have an ancient origin and widespread occurrence in the plant kingdom but show an unusually high degree of variation in their amino acid sequences. Interestingly, there is a strikingly conserved topology among the plant AMP families, suggesting that the defensive properties of these peptides are not determined by their primary sequences but rather by their tridimensional structure. To explore and expand this idea, we here discuss the role of AMPs for plant defense from a structural perspective. We show how specific structural properties, such as length, charge, hydrophobicity, polar angle and conformation, are essential for plant AMPs to act as a chemical shield that hinders enemy attack. Knowledge on the topology of these peptides is facilitating the isolation, classification and even structural redesign of AMPs, thus allowing scientists to develop new peptides with multiple agronomical and pharmacological potential.Item Adsorption of organic acids from offshore produced water using microporous activated carbon from babassu pericarp: a low-cost alternative(2023) Mônaco, Felipe Santos; Aguiar, Deborah Victória Alves de; Oliveira, Gerlon de Almeida Ribeiro; Vaz, Boniek Gontijo; Liao, Luciano Morais; Andrade, Laiane Alves de; Ostroski, Indianara ConceiçãoCurrently, in different regions of the world, there is a growth on the rate of produced water for each barrel of oil extracted. Among the compounds observed in this water are naphthenic acids (NAs). Efforts to remove NAs from produced water must comply with local legislation and avoid damage to the environment since NAs have great toxicity. This study aimed to investigate the ability of activated carbon from the pericarp of babassu coconut (Atallea speciosa Mart. ex Spreng.) to act as an absorbent of NAs in commercial and natural (offshore) produced waters. The activated carbon was physically and chemically characterized. The maximum adsorption capacity of commercial NAs at equilibrium obtained experimentally was 25 mg g−1. The activated carbon removed both NAs and other contaminants for produced water, as revealed by infrared and NMR techniques. In high-resolution mass spectrometry analysis, the abundance of the acids in the produced water was in the C9 and C10 range, being favorable for the adsorbent with a microporous structure. For the produced water kinetics experiments a maximum amount of adsorbed compounds of 17.91 mg g−1 was reached, and the time to achieve equilibrium was approximately 180 min. Thus, the results show that activated charcoal from babassu coconut pericarp can be used as an adsorbent and can potentially compete with other adsorbents to remove NAs in an aqueous solution. Also, the separation process can be adopted at a low cost on platforms, complementing the operations of hydrocyclones and flotation.Item Amine/carboxylic acid ionic liquid composite membranes for CO2 separation(2021) Alcantara, Murilo Leite; Oliveira, Gerlon de Almeida Ribeiro; Liao, Luciano Morais; Borges, Cristiano Piacsek; Silva, Silvana Mattedi eAlkanolamine + carboxylic acid-based ionic liquids have shown promising high CO2 selectivities. Their addition to cellulose acetate (CA) and polyvinyl alcohol (PVA) was investigated in the present study. The N-methyl-2-hydroxyethylammonium propionate IL [m-2HEA][Pr] significantly enhances the CO2 separation performance of PVA. Scanning electron microscopy, Fourier transform infrared spectroscopy, and nuclear magnetic resonance analyses indicate that the IL–PVA combination produced IL composite membranes with interactions being predominantly physical. Furthermore, the IL addition to CA produced porous membranes with apparent low CO2 separation efficiency. Pure gas permeation experiments indicate that increasing IL concentration of PVA-based membranes promotes higher gas permeabilities. The membranes were prepared containing up to 60.3 wt % of [m-2HEA][Pr], which resisted pressure differentials up to 6 barg. PVA containing 45.5 wt % of IL produced the most promising results, achieving 26 barrer of CO2 permeability and permselectivities of 122 and 213 for CO2/CH4 and CO2/N2, respectively. This result was compared to promising materials from the literature and indicated the overall high CO2/CH4 and CO2/N2 selectivities of PVA/[m-2HEA][Pr] membranes, which overcome even the 2008 Robeson’s upper boundary.Item Analgesic and anti-inflammatory effects of Cheiloclinium cognatum root barks(2007-12) Costa, Elson Alves; Santos, Lúcio R.; Pontes, Itamar S.; Matos, Lécia Garcia de; Silva, Gilmar Aires da; Liao, Luciano MoraisCheiloclinium cognatum (Hippocrateaceae) has been used in folk medicine to treat fever and edema. In this paper, we report the anti-infl ammatory and analgesic activities of the crude dichloromethane extract (DECc) from C. cognatum root barks collected in Auguste de Saint Hilaire wood at Universidade Federal de Goiás. Doses of 0.1, 0.3 and 1.0 g/kg caused a dose-dependent inhibition of croton oil-induced ear edema in mice equivalent to 21, 30 and 51%, respectively. There was a signifi cant increase in analgesic-meter-induced tail fl ick test equivalent to 105, 189 and 200% of increase tail fl ick reaction time. These results allowed to suggest that C. cognatum could be a source of new compounds which anti-infl ammatory and analgesic activities.Item Analysis of thermal degradation of Brazilian palm oil by quantitative 1H NMR and chemometrics(2021) Pinto, Vinícius Silva; Anjos, Murilo Machado dos; Pinto, Nelson Silva; Liao, Luciano MoraisPalm oil (Elaeis guineensis Jacq.) is an edible vegetable oil widely used in the processing industries and Afro-Brazilian culture. Due to its chemical composition rich in lipids, it is susceptible to hydrolytic and oxidative degradation. In this context, the present study describes an analytical method based on the high resolution nuclear magnetic resonance spectroscopy and the statistical analysis for the qualitative and quantitative monitoring of the thermostability of palm oil, subjected to heat treatment at temperatures 80, 100, 120, 140, 160, 180, and 200 °C. The palm oil profiles were characterized by 1H NMR spectra, which were used as data matrices for the statistical analysis. The NMR-based PCA allowed the identification of lipid descriptors related to the degradation mechanisms that were preponderant during the heating of palm oil. The NMR-based PCA allowed identifying the chemical shifts of lipid descriptors related to the mechanisms of degradation and secondary oxidation products observed in samples heated from 140 °C. The results showed the restrictions on the use of palm oil, commonly classified as a stable edible oil, given that the secondary oxidation products identified may present health risks.Item Anti-inflammatory and antinociceptive activity profile of a new lead compound – LQFM219(2020) Galvão, Gustavo Mota; Florentino, Iziara Ferreira; Sanz Lobón, Germán; Vaz, Boniek Gontijo; Liao, Luciano Morais; Sabino, José Ricardo; Cardoso, Cariina Sofia; Silva, Daiany Priscilla Bueno da; Costa, Elson Alves; Silva, Andreia Luiza Pereira; Silva, Artur Christian Garcia da; Valadares, Marize Campos; Leite, Jacqueline Alves; Gil, Eric de Souza; Menegatti, RicardoLQFM219 is a molecule designed from celecoxibe (COX-2 inhibitor) and darbufelone (inhibitor of COX-2 and 5-LOX) lead compounds through a molecular hybridisation strategy. Therefore, this work aimed to investigate the antinociceptive and anti-inflammatory activities of this new hybrid compound. The acute oral systemic toxicity of LQFM219 was evaluated via the neutral red uptake assay. Acetic acid-induced abdominal writhing and CFA-induced mechanical hyperalgesia were performed to evaluate the antinociceptive activity, and the anti-oedematogenic activity was studied by CFA-induced paw oedema and croton oil-induced ear oedema. Moreover, the acute anti-inflammatory activity was determined by carrageenan-induced pleurisy. In addition, cell migration, myeloperoxidase enzyme activity, and TNF-α and IL-1β levels were determined in pleural exudate. Moreover, a redox assay was conducted using electroanalytical and DPPH methods. The results demonstrated that LQFM219 was classified as GHS category 4, and it showed better free radical scavenger activity compared to BHT. Besides, LQFM219 decreased the number of writhings induced by acetic acid and the response to the mechanical stimulus in the CFA-induced mechanical hyperalgesia test. Furthermore, LQFM219 reduced oedema formation, cell migration, and IL-1β and TNF-α levels in the pleural cavity and inhibited myeloperoxidase enzyme activity. Thus, our study provides that the new pyrazole derivative, LQFM219, demonstrated low toxicity, antinociceptive and anti-inflammatory potential in vitro and in vivo.Item Anti-inflammatory effect of a new piperazine derivative: (4-methylpiperazin-1-yl)(1-phenyl-1H-pyrazol-4-yl)methanone(2017) Batista, Daniel da Costa; Silva, Daiany Priscilla Bueno da; Florentino, Iziara Ferreira; Cardoso, Carina Sofia; Gonçalves, Merita Pereira; Valadares, Marize Campos; Liao, Luciano Morais; Sanz Lobón, Germán; Vaz, Boniek Gontijo; Costa, Elson Alves; Menegatti, RicardoAims This study investigates the anti-nociceptive and anti-inflammatory effects of new piperazine compound (LQFM182) as well as the toxicity acute in vitro. Main methods To evaluate the anti-nociceptive activity, the acetic acid-induced abdominal writhing test, tail flick test and formalin-induced pain test were used. The anti-inflammatory activity was evaluated using the models of paw oedema and pleurisy induced by carrageenan and some inflammatory parameters were evaluated, including cell migration, myeloperoxidase enzyme activity and the levels of TNF-α and IL-1β cytokines in pleural exudate. The acute oral systemic toxicity of LQFM182 in mice was evaluated through the neutral red uptake (nru) assay. Key findings LQFM182 (50, 100 or 200 mg/kg, p.o.) decreased the number of writhings induced by acetic acid in a dose-dependent manner, and an intermediate dose (100 mg/kg, p.o.) reduced the paw licking time of animals in the second phase of the formalin test. Furthermore, LQFM182 (100 mg/kg, p.o.) reduced oedema formation at all hours of the paw oedema induced by carrageenan test and in pleurisy test reduced cell migration from the reduction of polymorphonuclear cells, myeloperoxidase enzyme activity and the levels of pro-inflammatory cytokines IL-1β and TNF-α. Therefore, it was classified in GHS category 300 < LD50 < 2000 mg/kg.Item Anti-inflammatory, antinociceptive, and vasorelaxant effects of a new pyrazole compound 5-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)-1H-tetrazole: role of NO/cGMP pathway and calcium channels(2023) Oliveira, Lanussy Porfiro de; Florentino, Iziara Ferreira; Silva, Daiany Priscilla Bueno da; Pazini, Francine; Carvalho, Flávio Silva de; Sanz Lobón, Germán; Vaz, Boniek Gontijo; Rocha, Fabio Fagundes da; Fajemiroye, James Oluwagbamigbe; Ghedini, Paulo César; Liao, Luciano Morais; Menegatti, Ricardo; Costa, Elson Alves; Oliveira, Thiago Sardinha deMolecular modification of compounds remains important strategy towards the discovery of new drugs. In this sense, this study presents a new pyrazole derivative 5-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)-1H-tetrazole (LQFM039) and evaluated the anti-inflammatory, analgesic, and vasorelaxant effects of this compound as well the mechanisms of action involved in the pharmacological effects. For this, mice were orally treated with LQFM039 (17.5, 35, or 70 mg/kg) prior acetic acid-induced abdominal writhing, formalin, tail flick, and carrageenan-induced paw edema protocols. In addition, vascular reactivity protocols were made with aortic rings contraction with phenylephrine and stimulated with graded concentrations of LQFM039. Abdominal writhing and licking time in both neurogenic and inflammatory phases of formalin were reduced with LQFM039 without altering latency to nociceptive response in the tail flick test. Carrageenan-induced paw edema showed that LQFM039 reduces edema and cell migration. In addition, the mechanism of action of LQFM039 involves NO/cGMP pathway and calcium channels, since this new pyrazole derivate elicited concentration-dependent relaxation attenuated by Nω-nitro-l-arginine methyl ester and 1H-[1,2,4] oxadiazolo [4,3-alpha]quinoxalin-1-one, and blockade of CaCl2-induced contraction. Altogether, our finding suggests anti-inflammatory, antinociceptive, and vasorelaxant effect of this new pyrazole derivative with involvement of NO/cGMP pathway and calcium channels.Item Antiangiogenic and antitumoral activity of LQFM126 prototype against B16F10 melanoma cells(2020) Silva, Artur Christian Garcia da; Rodrigues, Bruna dos Santos; Andrade, Wanessa Machado; Santos, Thaís Rosa Marques dos; Flávio Silva de Carvalho; Sanz Lobón, Germán; Vaz, Boniek Gontijo; Liao, Luciano Morais; Menegatti, Ricardo; Valadares, Marize CamposInhibition of mouse double minute 2 homolog (MDM2)-p53 interaction and reactivation of p53 signaling have been explored as effective anticancer therapeutic strategy. The potent and specific antitumor activity shown by Nutlins, first class of MDM2-p53 inhibitors discovered, has made these compounds potential antitumor candidates. To this end, we synthesized Nutlin-1 and Nutlin-2 analogs through molecular simplification and selected the compound with the most efficient antitumoral activity. Cytotoxicity of Nutlin-2 analog LQFM126 on B16F10 melanoma cells induced intense cytoplasmic vacuolization, reduction of cell size, chromatin condensation, cytoplasmic degeneration and nuclear fragmentation. LQFM126 antiproliferative effects mediated cell cycle retention in G0/G1 phase and increased the levels of cell cycle regulatory proteins p21 and p27. This Nutlin analog increased mitochondrial membrane potential, activated caspase-8, -9 and -3/7 and reduced VEGF levels in B16F10 cells. Therefore, LQFM126 promoted alterations suggestive of apoptosis, G0/G1 cell cycle arrest and suppression of angiogenesis through modulation of VEGF expression in B16F10 cells. Additionally, LQFM126 was classified as UN GHS category 4 (LD50 > 300–2000 mg/kg), suggesting it has low acute systemic toxicity. LQFM126 can be a promising prototype for anticancer therapy.Item Antiangiogenic and antitumoral activity of LQFM126 prototype against B16F10 melanoma cells(2020) Alonso, Lais; Menegatti, Ricardo; Gomes, Rodrigo Saar; Dorta, Miriam Cristina Leandro; Luzin, Rangel Magalhães; Liao, Luciano Morais; Alonso, AntonioItem Antimicrobial alumina nanobiostructures of disulfide- and triazole-linked peptides: synthesis, characterization, membrane interactions and biological activity(2019) Torres, Lívia Mara Fontes Costa; Almeida, Mainara Trindade de; Santos, Talita Lopes dos; Marinho, Luiz Eduardo Silva; Mesquita, João Paulo de; Silva, Leonardo Morais da; Santos, Wallans Torres Pio dos; Martins, Helen Rodrigues; Kato, Kelly Cristina; Alves, Eliane Santana Fernandes; Liao, Luciano Morais; Magalhães, Mariana Torquato; Mendonça, Fernanda Gomes de Quezado de; Pereira, Fabiano Vargas; Resende, Jarbas Magalhães; Bemquerer, Marcelo Porto; Rodrigues, Magali Aparecida; Verly , Rodrigo MoreiraDue to the its physical-chemical properties, alumina nanoparticles have potential applications in several areas, such as nanobiomaterials for medicinal or orthodontic implants, although the introduction of these devices poses a serious risk of microbial infection. One convenient strategy to circumvent this problem is to associate the nanomaterials to antimicrobial peptides with broad-spectrum of activities. In this study we present two novel synthesis approaches to obtain fibrous type alumina nanoparticles covalently bound to antimicrobial peptides. In the first strategy, thiol functionalized alumina nanoparticles were linked via disulfide bond formation to a cysteine residue of an analog of the peptide BP100 containing a four amino acid spacer (Cys-Ala-Ala-Ala). In the second strategy, alumina nanoparticles were functionalized with azide groups and then bound to alkyne-decorated analogs of the peptides BP100 and DD K through a triazole linkage obtained via a copper(I)-catalyzed cycloaddition reaction. The complete physical-chemical characterization of the intermediates and final materials is presented along with in vitro biological assays and membrane interaction studies, which confirmed the activity of the obtained nanobiostructures against both bacteria and fungi. To our knowledge, this is the first report of aluminum nanoparticles covalently bound to triazole-peptides and to a disulfide bound antimicrobial peptide with high potential for biotechnological applications.Item Antinociceptive effects of new pyrazoles compounds mediated by the ASIC-1α channel, TRPV-1 and μMOR receptors(2019) Florentino, Iziara Ferreira; Silva, Daiany Priscilla Bueno da; Cardoso, Carina Sofia; Menegatti, Ricardo; Carvalho, Flávio Silva de; Liao, Luciano Morais; Pinto, Paulo Marcos; Peigneur, Steve; Costa, Elson Alves; Tytgat, JanPyrazoles are potent medicinal scaffolds and exhibit a wide spectrum of biological activities, such as analgesic, anti-inflammatory and antipyretic. In this paper we report on research we have performed with the aim of continuing the biological evaluation of the regio-isomeric pyrazole compounds, LQFM-020 (fluorine, para position), LQFM-021 (fluorine, meta position), and LQFM-039 (fluorine, ortho position) in models of pain induced by acidified saline, capsaicin, and formalin. We also investigated the mechanisms of action of these compounds via electrophysiological analyses using the two-electrode voltage-clamp technique and heterologous expression in Xenopus laevis oocytes. This enabled us to study different potassium channel subtypes: the ASIC-1α channel, TRPV-1, and μMOR receptors. Our results indicate that LQFM-020, LQFM-021, and LQFM-039 (15, 30 or 60 mg.kg−1) compounds inhibited the nociceptive response induced by acidified saline in a dose-dependent manner. The dose of 30 mg.kg−1 inhibited the nociceptive response induced by capsaicin by 53.3%, 51.4%, and 52.1%, respectively. In addition, we found that naloxone reverses the antinociceptive effect produced by the compounds in both phases of the formalin test. In electrophysiological analyses, we observed that the LQFM-020, LQFM-021, and LQFM-039 compounds did not modulate voltage-gated K + channel subtypes. In contrast, all the compounds tested inhibited the ASIC-1α channel at pH 4.5, with IC50-values of 96.1, 91.6, and 235.2 μM, respectively. All compounds also inhibited the TRPV-1 channel with IC50-values of 139.1, 212.5, and 159.1 μM, respectively. In contrast to the ASIC-1α and TRPV-1 targets, all compounds showed agonist activity on the μMOR receptor with an EC50-value of 117.4, 98.9, and 86.3 μM, respectively. We thus conclude that the ASIC-1α, TRPV-1, and μMOR channels are targets that are directly involved in the antinociceptive effect of LQFM-020, LQFM-021, and LQFM-039. Furthermore, the modifications of the fluorine positions in the phenyl analogs do not change the analgesic effect. However, LQFM-039 showed lower interaction with ASIC-1α channel.Item Anxiolytic- and antidepressant-like effects of new phenylpiperazine derivative LQFM005 and its hydroxylated metabolite in mice(2022) Moreira, Lorrane Kelle da Silva; Silva, Rafaela Ribeiro; Silva, Dayane Moreira da; Silva, Mirella Andrade; Brito, Adriane Ferreira de; Sanz Lobón, Germán; Silva, Artur Christian Garcia da; Oliveira, Valéria de; Vaz, Boniek Gontijo; Liao, Luciano Morais; Costa, Elson Alves; Menegatti, RicardoThe current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)−4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)− 1H-pyrazol-1-yl)phenol (LQFM235). The production of the metabolite was initially performed by in vitro biotransformation of LQFM005 using Aspergillus candidus and then by chemical synthesis. Oral administration of either 12 or 24 µmol/kg LQFM005 to mice did not affect spontaneous locomotor activity but increased the time spent in the center of the open field. Both LQFM005 and LQFM235 (24 µmol/kg) increased the time spent by the mice in the open arms of the elevated plus maze (EPM), a good indication of anxiolytic-like effect, and decreased the immobility time in the forced swimming test (FST), suggesting an antidepressant-like effect. The previous administration of WAY-100635 (a 5-HT1A antagonist) abolished the effects of LQFM005 in both EPM and FST. Binding experiments showed that LQFM005 and its metabolite bind to the 5-HT1A receptor with a moderate affinity (Ki around 5–9 µM). The two compounds are relatively safe, as indicated by cytotoxic assessment using the 3T3 fibroblast cell line and estimated LD50 around 600 mg/kg. In conclusion, oral administration of the newly synthesized phenylpiperazines produced anxiolytic- and antidepressant-like effects in behavioral tests, putatively in part through the activation of 5-HT1A receptors.Item Anxiolytic-like effect of 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol is mediated through the benzodiazepine and nicotinic pathways(2017) Brito, Adriane Ferreira de; Fajemiroye, James Oluwagbamigbe; Neri, Hiasmin Franciely da Silva; Silva, Dayane Moreira da; Silva, Daiany Priscilla Bueno da; Sanz Lobón, Germán; Vaz, Boniek Gontijo; Carvalho, Flávio Silva de; Ghedini, Paulo César; Liao, Luciano Morais; Menegatti, Ricardo; Costa, Elson AlvesIn this study, we proposed the design, synthesis of a new compound 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032), and pharmacological evaluation of its anxiolytic-like effect. This new compound was subjected to pharmacological screening referred to as Irwin test, prior to sodium pentobarbital-induced sleep, open-field and wire tests. The anxiolytic-like effect of this compound was evaluated using elevated plus maze and light–dark box tests. In addition, the mnemonic activity was evaluated through step-down test. In sodium pentobarbital-induced sleep test, LQFM032 decreased latency and increased duration of sleep. In the open-field test, LQFM032 altered behavioral parameter, that suggested anxiolytic-like activity, as increased in crossings and time spent at the center of open field. In the plus maze test and light–dark box test, the LQFM032 showed anxiolytic-like activity, increased entries and time spent on open arms, and increased in number of transitions and time spent on light area, respectively. Those effects was antagonized by flumazenil but not with 1-(2-Methoxyphenyl)-4-(4-phthalimidobutyl)piperazine (NAN-190). The LQFM032 did not alter mnemonic activity. Moreover, the anxiolytic-like activity of LQFM032 was antagonized by mecamylamine. In summary, LQFM032 showed benzodiazepine and nicotinic pathways mediated anxiolytic-like activity without altering the mnemonic activity.