Navegando por Autor "Braga, Saulo Fehelberg Pinto"
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Item Antidepressant-like effect of terpineol in an inflammatory model of depression : involvement of the cannabinoid system and d2 dopamine receptor.(2020) Vieira, Graziela; Cavalli, Juliana; Gonçalves, Elaine Cristina Dalazen; Braga, Saulo Fehelberg Pinto; Ferreira, Rafaela Salgado; Santos, Adair Roberto Soares; Cola, Maíra; Raposo, Nádia Rezende Barbosa; Capasso, Raffaele; Dutra, Rafael CyprianoDepression has a multifactorial etiology that arises from environmental, psychological, genetic, and biological factors. Environmental stress and genetic factors acting through immunological and endocrine responses generate structural and functional changes in the brain, inducing neurogenesis and neurotransmission dysfunction. Terpineol, monoterpenoid alcohol, has shown immunomodulatory and neuroprotective effects, but there is no report about its antidepressant potential. Herein, we used a single lipopolysaccharide (LPS) injection to induce a depressive-like effect in the tail suspension test (TST) and the splash test (ST) for a preventive and therapeutic experimental schedule. Furthermore, we investigated the antidepressant-likemechanism of action of terpineol while usingmolecular and pharmacological approaches. Terpineol showed a coherent predicted binding mode mainly against CB1 and CB2 receptors and also against the D2 receptor during docking modeling analyses. The acute administration of terpineol produced the antidepressant-like effect, since it significantly reduced the immobility time in TST (100–200 mg/kg, p.o.) as compared to the control group. Moreover, terpineol showed an antidepressant-like effect in the preventive treatment that was blocked by a nonselective dopaminergic receptor antagonist (haloperidol), a selective dopamine D2 receptor antagonist (sulpiride), a selective CB1 cannabinoid receptor antagonist/inverse agonist (AM281), and a potent and selective CB2 cannabinoid receptor inverse agonist (AM630), but it was not blocked by a nonselective adenosine receptor antagonist (caffeine) or a β-adrenoceptor antagonist (propranolol). In summary, molecular docking suggests that CB1 and CB2 receptors are the most promising targets of terpineol action. Our data showed terpineol antidepressant-like modulation by CB1 and CB2 cannabinoid receptors and D2-dopaminergic receptors to further corroborate our molecular evidence.Item Brazilian essential oils as source for the discovery of new anti-COVID-19 drug : a review guided by in silico study.(2021) Amparo, Tatiane Roquete; Seibert, Janaína Brandão; Silveira, Benila Maria; Costa, Fernanda Senna Ferreira; Almeida, Tamires Cunha; Braga, Saulo Fehelberg Pinto; Silva, Glenda Nicioli da; Santos, Orlando David Henrique dos; Souza, Gustavo Henrique Bianco deThe emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China and its spread worldwide has become one of the biggest health problem due to the lack of knowledge about an effective chemotherapy. Based on the current reality of the SARS-CoV-2 pandemic, this study aimed to make a review literature about potential anti-coronavirus natural compounds guided by an in silico study. In the first step, essential oils from native species found in the Brazilian herbal medicine market and Brazilian species that have already shown antiviral potential were used as source for the literature search and compounds selection. Among these compounds, 184 showed high antiviral potential against rhinovirus or picornavirus by quantitative structure–activity relationship analysis. (E)-a-atlantone; 14-hydroxy-amuurolene; allo-aromadendrene epoxide; amorpha4,9-dien-2-ol; aristochene; azulenol; germacrene A; guaia-6,9-diene; hedycaryol; humulene epoxide II; aamorphene; a-cadinene; a-calacorene and a-muurolene showed by a molecular docking study the best result for four target proteins that are essential for SARS-CoV-2 lifecycle. In addition, other parameters obtained for the selected compounds indicated low toxicity and showed good probability to achieve cell permeability and be used as a drug. These results guided the second literature search which included other species in addition to native Brazilian plants. The majority presence of any of these compounds was reported for essential oils from 45 species. In view of the few studies relating essential oils and antiviral activity, this review is important for future assays against the new coronavirus.Item Discovery and characterization of trypanocidal cysteine protease inhibitors from the ‘malaria box’.(2019) Pereira, Glaécia Aparecida do Nascimento; Silva, Elany Barbosa da; Braga, Saulo Fehelberg Pinto; Leite, Paulo Gaio; Martins, Luan Carvalho; Vieira, Rafael Pinto; Soh, Wai Tuck; Villela, Filipe Silva; Costa, Francielly Morais Rodrigues da; Ray, Debalina; Andrade, Saulo Fernandes de; Brandstetter, Hans; Oliveira, Renata Barbosa; Caffrey, Conor R.; Machado, Fabiana Simão; Ferreira, Rafaela SalgadoChagas disease, Human African Trypanosomiasis, and schistosomiasis are neglected parasitic diseases for which new treatments are urgently needed. To identify new chemical leads, we screened the 400 compounds of the Open Access Malaria Box against the cysteine proteases, cruzain (Trypanosoma cruzi), rhodesain (Trypanosoma brucei) and SmCB1 (Schistosoma mansoni), which are therapeutic targets for these diseases. Whereas just three hits were observed for SmCB1, 70 compounds inhibited cruzain or rhodesain by at least 50% at 5 mM. Among those, 15 commercially available compounds were selected for confirmatory assays, given their potency, time-dependent inhibition profile and reported activity against parasites. Additional assays led to the confirmation of four novel classes of cruzain and rhodesain in- hibitors, with potency in the low-to mid-micromolar range against enzymes and T. cruzi. Assays against mammalian cathepsins S and B revealed inhibitor selectivity for parasitic proteases. For the two competitive inhibitors identified (compounds 7 and 12), their binding mode was predicted by docking, providing a basis for structure-based optimization efforts. Compound 12 also acted directly against the trypomastigote and the intracellular amastigote forms of T. cruzi at 3 mM. Therefore, through a combi- nation of experimental and computational approaches, we report promising hits for optimization in the development of new trypanocidal drugs.Item From rational design to serendipity : discovery of novel thiosemicarbazones as potent trypanocidal compounds.(2022) Braga, Saulo Fehelberg Pinto; Santos, Viviane Corrêa; Vieira, Rafael Pinto; Silva, Elany Barbosa da; Monti, Ludovica; Krake, Susann Hannelore; Martinez, Pablo D. G.; Dias, Luiz Carlos; Caffrey, Conor R.; Siqueira Neto, Jair Lage de; Oliveira, Renata Barbosa de; Ferreira, Rafaela SalgadoChagas disease is a major public health problem caused by Trypanosoma cruzi, with an estimated 6–7 million people infected and 70 million at risk of infection. T. brucei gambiense and T. brucei rhodesiense are two subspecies of related parasites that cause human African trypanosomiasis, a neglected tropical disease with also millions of people at risk of infection. Pharmacotherapy for both diseases suffers from low efficacy, side effects, or drug resistance. Recently, we reported a noncovalent competitive inhibitor of cruzain (IC50 26 μM, Ki 3 μM) and TbrCatL (IC50 50 μM), two cysteine proteases considered promising drug targets for trypanosomiasis. Here, we describe the design and synthesis of derivatives of our lead compound. The new thiosemicarbazone derivatives showed potency in the nanomolar concentration range against the two enzymes, but they were later charac- terized as aggregators. Nevertheless, the thiosemicarbazone derivatives showed promising antiparasitic activities against T. b. brucei (EC50 13–49.7 μM) and T. cruzi (EC50 0.027–0.59 μM) under in vitro conditions. The most active thiosemicarbazone was 200-fold more potent than the current anti-chagasic drug, benznidazole, and showed a selectivity index of 370 versus myoblast cells. We have identified an excellent candidate for further optimization and in vivo studies.Item Glucosyl-1,2,3-triazoles derived from eugenol and analogues : synthesis, anti-Candida activity, and molecular modeling studies in CYP-51.(2021) Magalhães, Lorena Severiano de; Reis, Adriana Cotta Cardoso; Nakao, Izadora Amaral; Péret, Vinícius Augusto Campos; Reis, Rúbia Castro Fernandes Melo; Silva, Naiara Chaves; Dias, Amanda Latercia Tranches; Carvalho, Diogo Teixeira; Dias, Danielle Ferreira; Brandão, Geraldo Célio; Braga, Saulo Fehelberg Pinto; Souza, Thiago Belarmino deThis work describes the synthesis, anti-Candida, and molecular modeling stud- ies of eighteen new glucosyl-1,2,3-triazoles derived from eugenol and corre- lated phenols. The new compounds were characterized by combined Fourier Transform Infrared, 1 H and 13C nuclear magnetic resonance and spectroscopy of high-resolution mass spectrometry. The synthesized compounds did not show significant cytotoxicity against healthy fibroblast human cells (MCR-5) providing interesting selectivity indexes (SI) to active compounds. Considering the antifun- gal activity, nine compounds showed anti-Candida potential and the peracety- lated triazoles 17 and 18 were the most promising ones. Eugenol derivative 17 was active against three species of Candida at 26.1–52.1 μM. This compound was four times more potent than fluconazole against Candida krusei and less toxic (SI > 6.6) against the MCR-5 cells than fluconazole (SI > 3.3) considering this strain. Dihydroeugenol derivative 18 showed similar activity to 17 and was four times more potent and less toxic than fluconazole against C. krusei. The deacety- lated glucosides and non-glucosylated corresponding derivatives did not show considerable antifungal action, suggesting that the acetyl groups are essential for their anti-Candida activity. Molecular docking coupled with molecular dynam- ics showed that 14α-lanosterol demethylase is a feasible molecular target, since 17 and 18 could bind to this enzyme once deacetylated in vivo, thereby acting as prodrugs. Also, these studies demonstrated the importance of hydrophobic sub- stituents at the phenyl ring.Item New miconazole-based azoles derived from eugenol show activity against Candida spp. and Cryptococcus gattii by inhibiting the fungal ergosterol biosynthesis.(2023) Péret, Vinícius Augusto Campos; Reis, Rúbia Castro Fernandes Melo; Braga, Saulo Fehelberg Pinto; Benedetti, Monique Dias; Caldas, Ivo Santana; Carvalho, Diogo Teixeira; Santana, Luiz Felipe de Andrade; Johann, Susana; Souza, Thiago Belarmino deThis work describes the design, synthesis and antifungal activity of new imidazoles and 1,2,4-triazoles derived from eugenol and dihydroeugenol. These new compounds were fully characterized by spectroscopy/spectro- metric analyses and the imidazoles 9, 10, 13 e 14 showed relevant antifungal activity against Candida sp. and Cryptococcus gattii in the range of 4.6–75.3 μM. Although no compound has shown a broad spectrum of antifungal activity against all evaluated strains, some azoles were more active than either reference drugs employed against specific strains. Eugenol-imidazole 13 was the most promising azole (MIC: 4.6 μM) against Candida albicans being 32 times more potent than miconazole (MIC: 150.2 μM) with no relevant cytotoxicity (selectivity index >28). Notably, dihydroeugenol-imidazole 14 was twice as potent (MIC: 36.4 μM) as miconazole (MIC: 74.9 μM) and more than 5 times more active than fluconazole (MIC: 209.0 μM) against alarming multi-resistant Candida auris. Furthermore, in vitro assays showed that most active compounds 10 and 13 altered the fungal ergosterol biosynthesis, reducing its content as fluconazole does, suggesting the enzyme lanosterol 14α-demethylase (CYP51) as a possible target for these new compounds. Docking studies with CYP51 revealed an interaction between the imidazole ring of the active substances with the heme group, as well as insertion of the chlorinated ring into a hydrophobic cavity at the binding site, consistent with the behavior observed with control drugs miconazole and fluconazole. The increase of azoles-resistant isolates of Candida species and the impact that C. auris has had on hospitals around the world reinforces the importance of discovery of azoles 9, 10, 13 e 14 as new bioactive compounds for further chemical optimization to afford new clinically antifungal agents.Item Otimização de derivado triazólico do 2-metoxi-4-propilfenol (di-hidroeugenol) : síntese de novas substâncias, avaliação biológica e estudos de modelagem molecular.(2022) Reis, Rúbia Castro Fernandes Melo; Souza, Thiago Belarmino de; Braga, Saulo Fehelberg Pinto; Souza, Thiago Belarmino de; Bernardes, Lílian Sibelle Campos; Mosqueira, Vanessa Carla FurtadoA doença de Chagas ainda afeta cerca de 6 milhões de pessoas no mundo, sendo considerada uma doença endêmica em muitos países, sobretudo na América Latina. O tratamento para essa doença no Brasil é restrito a dois fármacos, benznidazol e nifurtimox, ambos com limitações tanto no que diz respeito à toxicidade quanto à sua ineficácia na fase crônica da doença. Os produtos naturais, dentre eles o eugenol e seus derivados, ganham destaque por apresentarem diversas atividades biológicas, incluindo atividade antiparasitária. Além disso, relatos na literatura relacionam derivados contendo um núcleo 1,2,3-triazólico a uma promissora atividade tripanocida, dentre eles um derivado 1,2,3-triazólico do di-hidroeugenol recentemente descoberto por nosso grupo de pesquisas, que apresentou resultados tripanocidas promissores in vitro e in vivo. Estudos de docking molecular realizados no trabalho mostraram uma afinidade desse derivado pela cruzaína, uma enzima lisossomal importante para a sobrevivência do Trypanosoma cruzi no hospedeiro. Somados, esses resultados tornam o derivado citado acima um hit para possíveis modificações moleculares e apontam a enzima cruzaína como um importante alvo molecular do T. cruzi. Diante disso, no presente trabalho foi proposta a otimização deste derivado 1,2,3-triazólico a partir de uma síntese convergente entre diferentes alquilazidas derivadas do eugenol (e seus análogos) com alquilfenóis contendo um alcino terminal, via reação click, além de outras modificações em sua estrutura, que originaram 20 substâncias puras inéditas. Os resultados de docking molecular apontaram, novamente, a enzima cruzaína como um forte candidato a alvo molecular de ação dessas substâncias, principalmente por apresentarem melhores pontuações quando comparadas a dois outros alvos avaliados, tripanotiona redutase e CYP51. Quanto aos resultados da avaliação do potencial tripanocida e citotóxico das substâncias sintetizadas, destacam-se os triazóis 21, 26, 27 e 28, com valores de CI50 abaixo de 53 M (resultado apresentado pela substância protótipo). Dentre elas, a substância 27, derivada do di-hidroeugenol e contendo um grupo nitro, apresentou CI50= 7,32 M e índice de seletividade de 77,62, superior aos valores encontrados para o protótipo e para o benznidazol, neste ensaio.Item Planejamento, síntese e avaliação citotóxica de novas chalconas derivadas do 2-METOXI-4-PROPILFENOL, a partir da otimização estrutural de um composto hit.(2023) Nakao, Izadora Amaral; Souza, Thiago Belarmino de; Souza, Thiago Belarmino de; Dias, Danielle Ferreira; Braga, Saulo Fehelberg PintoO câncer representa a segunda maior causa de mortes no Brasil e no mundo e a busca por novas terapias para esta doença é um desafio constante, em vista da agressividade e toxicidade associadas aos tratamentos disponíveis. Atualmente existem diversos fármacos disponíveis para o tratamento do câncer porém, apesar do seu objetivo principal consistir na destruição das células neoplásicas, estes atuam de forma não seletiva, o que consiste na principal limitação do tratamento, justificando a busca por novas substâncias mais potentes e seletivas. No âmbito das substâncias naturais biologicamente ativas, as chalconas, flavonoides de cadeia aberta contendo dois anéis aromáticos unidos por um sistema α,β-insaturado, são amplamente distribuídas no reino vegetal, e exibem um diversificado espectro de atividades biológicas, dentre elas, potencial antitumoral. Recentemente nosso grupo relatou a síntese de uma série de chalconas inéditas derivadas do eugenol e análogos, dentre as quais uma delas (substância I, derivada do 2-metoxi-4-propil-fenol), se destacou quanto ao seu potencial citotóxico, sendo mais de duas vezes mais potente e três vezes menos tóxica que a doxorrubicina contra células de hepatocarcinoma humano (HepG2). Considerando estratégias de modificações moleculares, como hibridação molecular e bioisosterismo, realizou-se neste trabalho o planejamento e síntese de novas chalconas derivadas da chalcona I e a avaliação do seu potencial citotóxico contra diferentes linhagens de células tumorais. Todas as substâncias sintetizadas foram devidamente caracterizadas por espectroscopia de ressonância magnética nuclear (RMN) de 1H e 13C e sua atividade citotóxica avaliada contra as linhagens tumorais HeLa, HepG2, T24 e TOV-21G, além da linhagem humana sadia MRC-5. Dentre os derivados ativos, a chalcona 19 apresentou a atividade mais promissora, sendo ativa contra todas as linhagens tumorais avaliadas, com valores de CC50 de 7,05 μM (HeLa), 5,61 μM (HepG2), 6,60 μM (TOV-21G) e 2,08 μM (T24), e índice de seletividade até 250 vezes maior que a doxorrubicina, fármaco utilizado como controle positivo nos testes realizados, para a linhagem TOV-21G.Item Purity determination of a new antifungal drug candidate using quantitative 1H NMR spectroscopy : method validation and comparison of calibration approaches.(2019) Franco, Pedro Henrique Cavalcanti; Braga, Saulo Fehelberg Pinto; Oliveira, Renata Barbosa de; César, Isabela da CostaQuantitative nuclear magnetic resonance (qNMR) is an analytical technique that offers numerous advantages in pharmaceutical applications including minimum sample preparation and rapid data collection times with no need for response factor corrections, being a powerful tool for assaying drug content in both drug discovery and early drug development. In the present work, we have applied qNMR, using both the internal standard and the electronic refer- ence to access in vivo concentrations 2 calibration methods, to assess the purity of RI76, a novel antifungal drug candidate. NMR acquisition and processing parameters were optimized in order to obtain spectra with intense, well‐ resolved signals of completely relaxed nuclei. The analytical method was vali- dated following current guidelines, demonstrating selectivity, linearity, accu- racy, precision, and robustness. The calibration approaches were statistically compared, and no significant difference was observed when comparing the obtained results and their dispersion in terms of relative standard deviation. The proposed qNMR method may, therefore, be used for both qualitative and quantitative assessments of RI76 in early drug development and for character- ization of this compound.Item Synthesis and structural characterization of new benzylidene glycosides, cytotoxicity against cancer cell lines and molecular modeling studies.(2021) Péret, Vinícius Augusto Campos; Reis, Adriana Cotta Cardoso; Silva, Naiara Chaves; Dias, Amanda Latercia Tranches; Carvalho, Diogo Teixeira; Dias, Danielle Ferreira; Braga, Saulo Fehelberg Pinto; Brandão, Geraldo Célio; Souza, Thiago Belarmino deThis work describes the synthesis, structural characterization (by combined Fourier Transform Infrared - FTIR, 1H and 13C Nuclear Magnetic Resonance - NMR spectroscopy and High Resolution Mass Spectrometry - HRMS) and biological evaluation of a new series of glycosides designed from a benzylidene glucoside derived from eugenol (23) active against Candida glabrata. The mass accuracy between the calculated and found values observed in HRMS analyses were lower than 5 ppm, which are acceptable for proposing a molecular formula using this technique. We decided to keep the benzylidene group of 23, while changing either the saccharide unit (glucose or galactose) or the natural aglycone (eugenol, isoeugenol, dihydroeugenol or guaiacol) to check their influence in antifungal activity. Since the chemical modifications performed did not contribute to enhance the antifungal activity, the synthesized compounds (23– 30) were further screened against four cancer cell lines (HeLa: cervix carcinoma; MDA-MB-231: breast carcinoma; T-24: urinary bladder carcinoma; and TOV-21G: ovarian carcinoma). The glucoside 27 showed promising activities (IC50 10.08–59.91 μM) against all the assayed cancer cell lines and higher values of selectivity index than doxorubicin, the control drug. The galactoside 28 demonstrated interesting results against HeLa, MDA-MB-231 and T-24 cells. This compound was active at 17.41 μM with a selectivity index greater than 13.7 against the HeLa cells, while doxorubicin was active at 10.01 μM with a selectivity index close to 1.5 considering this cell line. Further, we performed docking studies of these compounds with type II topoisomerase-DNA complex (TOP2) in order to try to explain their mechanism of action.Item Synthesis, trypanocidal and cytotoxic activities of α,β-unsaturated ketones derived from eugenol and analogues.(2022) Reis, Rúbia Castro Fernandes Melo; Reis, Adriana Cotta Cardoso; Torchelsen, Fernanda Karoline Vieira da Silva; Lana, Marta de; Sales Júnior, Policarpo Ademar; Brandão, Geraldo Célio; Braga, Saulo Fehelberg Pinto; Souza, Thiago Belarmino deThis work describes the synthesis, structural characterization, trypanocide and cytotoxic evaluation of α,β-unsaturated ketones derived from eugenol and analogues. Among the synthesized compounds, the cyclopentanonic/dihydroeugenol derivative 12 was active against amastigote forms of Trypanosoma cruzi at 5.2 nM (700 times more potent than benznidazole) and represents a potential hit for future structural optimizations to reduce its toxicity. All the compounds were also evaluated against a healthy human and four cancer cell lines and the derivative 10 was more active than doxorubicin against three cancer cells (IC50 values between 2.03–23.51 μM) and showed the higher selectivity index considering the human cells. Derivative 14 was also more potent and selective than doxorubicin against two cancer cells (IC50 values between 4.71–8.86 μM).