Doutorado em Inovação Farmacêutica em Rede (FF)

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Produção de lacases por Pleurotus ostreatus e o uso da biorremediação e adsorção para tratamento de poluentes via biomassa residual
(Universidade Federal de Goiás, 2022-02-24) Nunes, Elaine Sousa; Santiago, Mariângela Fontes; http://lattes.cnpq.br/7143224488081563; Santiago, Mariângela Fontes; Paula, José Realino de; Morais, Mariana Cristina de; Zang, Warde Antonieta da Fonseca; Faria, Fabrícia Paula de
The contaminants of effluents with domestic and industrial releases have been proven in several regions of the planet. In the face of outbreaks caused by flaviviruses the use of repellents has grown significantly, as well as synthetic dyes, because they are widely used in the textile industry and bisphenol A, because it is found in different commercial polymers, are commonly found in pollutants keeping present in waters generating possible harmful effects. Conventional effluent treatment processes have low chemical removal efficiency and are expensive. In view of this, the objective of this study was the development and evaluation of methodologies for the treatment of effluents contaminated with the active ingredient of repellents, icairidina, red textile dye Drimaren CL-5B and bisphenol A (BPA) by using açaí residue as adsorbent material and/or bioremediation with the lacase produced from the white decomposition fungus Pleurotus ostreatus using as enzymatic inducer the solid residues of acai, pineapple, mexerica and pequi. The enzymatic production with the residues of açaí and pineapple obtained an activity of 1139 UmL-1 and 1031 UmL-1 respectively. Remediation was efficient for BPA, being able to bioremediate up to 100 % of the compound, but it was ineffective for icariride. However, açaí revealed high adsorptive capacity, reaching to fully adsorb bisfinel A, more than 50 % of iridin and more than 70 % of the dye when in a synthetic sample and 40 % in an industrial sample, demonstrating a promising methodology.
Estudo da porosidade de comprimidos de Cloridrato de Propranolol a partir do processamento de imagens de microscopia eletrônica de varredura por elétrons retroespalhados
(Universidade Federal de Goiás, 2021-12-07) Camargo, Henrique Santiago de; Gonçalves, Cristhiane; http://lattes.cnpq.br/3935775322457150; Conceição, Edemilson Cardoso da; http://lattes.cnpq.br/7193007113950510; Conceição, Edemilson Cardoso da; Silva Júnior, Arnóbio Antônio da; Marreto, Ricardo Neves; Soares, Luiz Alberto Lira; Costa, Roseane Maria Ribeiro
The porosity of solid pharmaceutical forms plays a fundamental role in the drug's disintegration the dosage form and consequently in the bioavailability of the active, ensuring its therapeutic action in the desired time, in addition, the porosity influences other aspects such as the mechanical strength of the tablet. Understanding and having methods to study and manipulate the porosity of pills is a crucial factor to have a quality pharmaceutical form. Objectives: Thus, the objective of this work was to study the porosity of Propranolol Hydrochloride tablets from 5 (five) laboratories by processing images obtained in a scanning electron microscope and to correlate these results with dissolution studies and the composition of each tablet. Methodology: The tablets were characterized by thermal techniques, Scanning Differential Calorimetry (DSC) and Thermogravimetry (TGA), and were submitted to hardness, friability and dissolution tests. Electron backscatter SEM images were obtained and processed in order to obtain an estimate of the surface and fracture porosity. Results and discussion: The tablets showed variations in their internal porosity and fracture, all had friability and hardness data that meet current regulatory standards, for the dissolution study, all laboratories presented data within the acceptance criteria of regulatory standards. Conclusions: Through the processing of scanning electron microscopy images obtained from propranolol hydrochloride tablets, it was possible to estimate the surface and fracture porosity of these tablets, thus, this technique is shown as an alternative for the study of the porosity of solid dosage forms (tablets) , being possible to observe the morphology and characteristics of the pores.
Estratégia associando métodos substitutivos à experimentação animal para avaliação da toxicidade ocular, categorização e rotulagem de formulações agrotóxicas comercializadas no Brasil
(Universidade Federal de Goiás, 2018-11-20) Andrade, Wanessa Machado; Valadares, Marize Campos; http://lattes.cnpq.br/615775524316701; Valadares, Marize Campos; Costa, Renata Mazaro; Paula, José Realino de; Gomes, Thaisângela Rodrigues Lopes e Silva; Gomes, Marcelo do Nascimento
Introduction: Different strategies for categorization and labeling (C & L) of ingredients and finished products have been considered by the Regulatory Agencies. Regarding agrochemical formulations, the lack of global harmonization for C & L is the main problem for the implementation of substitute methods. On the other hand, in vitro and ex vivo methods are successfully adopted to assess the potential toxicity of chemicals. The standard Bovine Cornea Opacity and Permeability (BCOP) test provides information on permeability and opacity, but histomorphometric analysis of the cornea has been recommended as an additional parameter to better categorize irritant products for the eyes. Objective: To suggest a platform, associating in vitro and ex vivo methods, based on mechanistic parameters of ocular toxicity evaluation for C & L of agrochemical formulations commercialized in Brazil. As well as measuring the depth of bovine corneal injury induced by eye irritants from all categories of the United Nations Globally Harmonized System for Classification and Labeling of Chemicals (UN GHS) and associating it with the severity of the damage. Material and Methods: For the platform, 86 agrochemical formulations of different categories of ocular toxicity were selected in the categorization system of the National Agency of Sanitary Surveillance (ANVISA). First, the potential for ocular toxicity was assessed through the cytotoxicity endpoint using the Short Time Exposure (STE) test. In the second step, the non-classified samples and those classified as non-irritating by the STE were evaluated for the opacity, permeability and histopathological changes of the cornea through the BCOP test. The third step was to evaluate the potential for induction of vascular damage through coagulation and hemorrhage outcomes using the Hen egg Chorion-allantoic Membrane test (HET-CAM). For proficiency, 12 substances belonging to the categories UN GHS (Category 1, 2A and 2B) were selected. The BCOP assay was performed to determine the in vitro irritation index (IVIS). After the fluorescein permeability assay, the corneas used were sectioned in a 5 μm thick cryostat, stained with Hoechst 33342 and analyzed by fluorescence microscopy. Five measurements of depth of permeation of fluorescein were obtained in relation to the total thickness of the epithelium. Results and Discussion: From the palataform, of the 86 formulations of agrochemicals, after the STE test, 68 were highly cytotoxic and were categorized as Category 1 by UN GHS; 13 not classified and 5 non-irritating. These 18 agrochemical formulations were evaluated at the second level of the platform by the BCOP test followed by histopathological analysis, and the irritation profile of these agrochemical formulations was confirmed by the HET-CAM assay. Thus, 7 presented opacity, damage to the cornea in the epithelial portion and in the stroma, coagulation and hemorrhage, and therefore were categorized in Category 2 A of the UN GHS. 11 caused only coagulation and hemorrhage and were categorized into Category 2 B of the UN GHS. In the proficiency, the results showed that the permeation depth of fluorescein was directly proportional to the degree of irritation of the substances tested. Conclusion: Since C&L of agrochemical formulations in Brazil is not based on the UN GHS, this tier platform could be useful to harmonize the categorization of agrochemical formulations in Brazil, providing regulatory subsidies for ANVISA. As well as, refinement of BCOP by analysis of lesion depth through epithelial permeation of fluorescein can be considered a useful quantitative parameter to better categorize eye irritants.
Biossorção de micropoluentes em fibra de sabugo de milho e detecção analítica usando fluorescência de raio x, espectroscopia Raman e análise quimiométrica
(Universidade Federal de Goiás, 2021-04-07) Golveia, Jhéssica Cavalcante de Souza; Schimidt, Fernando; http://lattes.cnpq.br/1884442831412446; Santiago, Mariângela Fontes; http://lattes.cnpq.br/7143224488081563; Col, José Augusto da; Zang, Warde Antonieta da Fonseca; Morais, Mariana Cristina de; Sanches, Renato; Schimidt, Fernando
The presence of micro-pollutants in the waters has led to growing concern due to the impact on human health. Among the most important molecules is Bisphenol-A (BPA), pesticides, hormones and dyes. On the other hand, micro-pollutant removal processes that make use of agro-industrial waste have aroused the interest of researchers. This is because the accumulation of lignocellulosic materials is also an environmental problem. The adsorption capacity was tested using the molecules BPA, diuron, cyproterone acetate, caffeine, erythrosine red and tartrazine yellow. The detection of these pollutants requires the use of sensitive and easy-to-handle techniques. In this context, the X-ray Fluorescence (FRX) and Raman spectroscopic methods are highlighted.The objective of this work is to use corncob agroindustrial residue (CC) as an adsorbent in the removal of micropollutants of aqueous matrix and detect them using FRX and Raman Spectroscopy. The values was treated using Chemoface Software and PLS (Partial Least Square) Model of calibration. The adsorption studies were carried out in reaction media containing the ground vegetable fiber and different concentrations of molecules, as well as at different pHs. Isotherms models and kinetic models were evaluated. The results showed that CC is a potent adsorbent in aqueous solution, leading to about 90% of removal for BPA. The adsorption kinetics followed the pseudo-second order model and isotherm that best suited the Lagmuir model, and the maximum adsorption capacity was 51.25 mg per gram of adsorbent fiber, after 20 minutes of contact. The chemometric analyze showed hat PLS model allows to determine a calibration model capable to reach high values of R2 and low values of error. The thermogravimetric analysis allowed to conclude that it is a material resistant to high temperatures, due to the presence of considerable amount of lignin. Finally, the best results of BPA removal efficiency by CC compared to activated carbon corroborate its high biosorption capacity.
Biotransformação fúngica da hesperetina e sua aplicação na produção de metabólitos ativos
(Universidade Federal de Goiás, 2019-01-11) Cordeiro, Kelly Carolina Frauzino Araújo; Oliveira, Valéria de; http://lattes.cnpq.br/6300240031300604; Oliveira, Valéria de; Silva, Lorena Maione; Silva, Maria do Rosário Rodrigues; Cunha, Carla Rosane Mendanha da; Terezan, Ana Paula
Hesperetin belongs to the flavanone class of flavonoids, its human metabolites (i.e. hesperetin-3’-sulfate, hesperetin-7-sulfate, hesperetin-3’-glucoronide and hesperetin -7-glucoronide), and its glycosylated derivative has potential pharmacological properties. The use of microorganisms, such as filamentous fungi, is an alternative in derivatives production and a useful tool in scale up process. Therefore, the goal of the work was to apply and evaluate different bioprocesses for the production of active metabolites of hesperetin by fungal biotransformation. Application of microbioreactors, use of different carbon sources, substrate concentration, fungal immobilization and monitored reactions by liquid chromatography coupled to high resolution mass spectrometry were some of evaluated bioprocesses. From 15 tested fungi, 12 strains were able to biotransform hesperetin. In silico metabolite prediction modeling with MetaPrint 2D software, indicated positions 7 e 3’ as energetically favored for glycosylation, glucuronidation and sulfation reactions. Mortierella isabellina NRRL 1757 and Beauveria bassiana ATCC 7159 produced only sulfate and glucuronide hesperitins, respectively. Cunninghamella echinulata ATCC 9244 strain produced the glycosylated metabolite. A morphological difference was observed in C. echinulata ATCC 9245 growth using different microbioreactors. Square microwell plates resulted in an amorphous growth whereas round bottom microwell plates favored pellets growth. The latest, with volume well of 2.2 ml led to a higher content of fungi and 48 hours was found to be the ideal time to substract addition. All four strands of Cunninghamella tested for biotransformation in a microscale were able to produce the glycosylated metabolite. Analyzes of the biotransformation kinetics by HPLC-HRMS showed that Cunninghamella echinulata ATCC 9244 produced four microplate derivatives: eriodictiol, sulfated hesperetin, glycosylated hesperetin and glucuronidated hesperetin. Such analyzes have also shown that high concentrations of hesperetin inhibit these derivatives formation. Stainless steel sponge proved to be efficient for Cunninghamella echinulata and Cunninghamella elegans strains immobilization. The immobilization process achieved biofilm in 48 hours. ESI-IT-MS and ESI-IT-MS/MS analysis indicated production of a glycosylated and a hydroxylated-sulfonated derivative. Thus, studies demonstrated that different bioprocesses can be applied to optimize scale up reactions and produce hesperetin derivatives using filamentous fungi
Estudo ecotoxicológico de corante têxtil e remediação por Fenton e Fenton-like
(Universidade Federal de Goiás, 2018-06-18) Fernandes, Neemias Cintra; Marreto, Ricardo Neves; http://lattes.cnpq.br/6127043775208484; Marreto, Ricardo Neves; Costa, Orlene Silva da; Oliveira, Gisele Augusto Rodrigues de; Cunha Filho, Marcílio Sérgio Soares da; Brito, Núbia Natália de
Azo dyes represent the most important class of textile dyes, being widely used in the pharmaceutical and food industry. These molecules are present in domestic and industrial wastewater, and are resistant to conventional effluent treatment eventually producing more toxic products than the original dyes. Advanced oxidative processes (AOPs) have been implemented in order to decompose or mineralize substances that are difficult to treat, reducing their toxicity and the inherent risks of releasing pollutants into the environment. Objective: To study the ecotoxicity and optimize the operational conditions in the decomposition of textile azo dye DR343 using Fenton and Fenton-like reactions. Method: Oxidative processes were studied using the factorial design Box-Behnken Design (BBD), and the optimization of the reaction conditions was performed by applying the desirability function. The pH of the medium, the reaction time, the concentrations of iron [Fe 2+ ] (Fenton) and [Fe 3+ ] (Fenton-like) as well as the oxidizing agent [H 2 O 2 ] were used as independent variables in the planning. The responses studied were the removal of DR343, the concentration of residual hydrogen peroxide [H 2 O 2residual ] and the mortality of Artemia salina. The toxicity of the untreated dye was evaluated in different organisms (lettuce seeds, Artemia salina and zebrafish embryos). Samples treated under optimal conditions were submitted to the same protocols. Results: The dye removal was in the range of 5.8% to 100%, being affected only by the concentration of catalyst [Fe 2+ /Fe 3+ ] in both processes. On the other hand, the process time had a significant effect on the mortality of A. salina in samples submitted to the Fenton process, which suggests formation of toxic oxidation byproducts at the beginning of the process, followed by the mineralization of the samples. Optimum conditions for the Fenton reaction included [Fe 2+ ] of 0.33 mmol.L -1 and [H 2 O 2 ] of 4.50 mmol.L -1 . Under these conditions, 100% of the dye decomposition was observed in 16.1 minutes. On the other hand, the optimal conditions of the Fenton-like process included [Fe 3 + ] of 0.25 mmol.L -1 and [H 2 O 2 ] of 0.54 mmol.L -1 . Under these conditions total dye decomposition was observed in only 9.2 minutes. No [H 2 O 2residual ] was detected in both optimized processes. No significant phytotoxic effects were observed on the untreated dye dispersions, nor after treatment in both procedures. In the case of the A. salina assays, differences between the two processes were observed. Samples treated by Fenton-like did not show significant toxicity, whereas the Fenton process induced significant mortality for this organism. Samples treated under optimal conditions, from both methods, did not induce lethal or sublethal effects on zebrafish embryos. Total organic carbon reduction of 52.0% and 34.8% was observed for Fenton and Fenton-like, respectively. Conclusion: Both the studied processes can be successfully used to decompose the DR343 dye in water, however, the Fenton reaction, despite obtaining better mineralization rates, produced more toxic by-products when compared to the Fenton-like process. The untreated dye did not show phytotoxicity, nor did it generate significant effects on zebrafish embryos.
Potencial antioxidante e atividade vasodilatadora de cervejas comerciais
(Universidade Federal de Goiás, 2017-05-05) Oliveira Neto, Jerônimo Raimundo de; Vaz, Boniek Gontijo; http://lattes.cnpq.br/7814534710550639; Gil, Eric de Souza; http://lattes.cnpq.br/3218622824233303; Gil, Eric de Souza; Paula, José Realino de; Guedini, Paulo César; Cunha, Luiz Carlos da; Ferreira, Rafael de Queiroz
Beer is one of the oldest and most popular beverages consumed by mankind, the main classification of beers is the type of fermentation, divided into ale or lager, high and low fermentation, respectively. In this study, beer samples were divided into two portions, the first one for the spectrophotometric and electrochemical tests, which was used in natura form. And the second part was lyophilized, aiming at the concentration use standardization, alcohol withdrawal and guaranteeing an increase of durability, and then used in the pharmacological and chromatographic tests. The aim of this study was to investigate the antioxidant potential and vasodilator activity and correlate them with the phenolic profiles of twenty-two commercial beers. In addition, the antioxidant activity and the phenolic profile of hops and malts from different origins were also verified. From the raw materials, hops samples showed better antioxidant activity when compared to malt samples (p <0.05). The correlation between electrochemical index (EI) and total phenols (TPC), and radical scavenging methods, 1,1-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis (3-ethylbenzthiazoline -6-sulphonic acid) (ABTS) was 0.86, 0.77 and 0.85 respectively for the hop samples. From the beers, ale group showed better antioxidant activity and TPC values when compared to the lager group. However, according to the Pearson correlation matrix, the correlation between IE with TPC, DPPH and ABTS was 0.86, 0.89 and 0.96 respectively for the lager group. While for the ale group, the correlations were not statistically significant (p> 0.05), mainly due to the turbidity interference of the samples during spectrophotometric assays. This fact reiterates the use of electrochemical methods, which minimize this type of problem besides being more sensitive and quick. Following the proposed electrochemical methodology, using the IE calculation, LB10 and AB1 samples obtained the highest indices. In the results of the principal components analysis (PCA) three groups were observed, where group III confirms LB10 and AB1 as the best antioxidants potential. LB10, AB1 and AB6 showed a maximal vasodilator effect of 92 ± 4, 88 ± 3 and 79 ± 3%, respectively. Both the vasodilator effect and the lipid peroxidation inhibition capacity may be associated with the presence of phenolic compounds in the beer samples, identified by mass spectrometry. This study, therefore, verified that the proposed IE methodology is an important tool to evaluate antioxidant properties and showed a good correlation with radical scavenging assays. Moreover, the study showed that beers may have a beneficial effect on the cardiovascular system, showing a good correlation of the vasodilator effect and antioxidant potential, which may be useful for future research on health, sensorial properties and quality parameters. Still from the standpoint of the quality of the beers, hop extracts as well as malt exhibited statistically results, corroborating to the applicability of these tools in the choice of these major ingredients improve the quality of the final product.
Desenvolvimento e avaliação de sistemas automicroemusionáveis contendo carvedilol pela técnica de termoextrusão
(Universidade Federal de Goiás, 2017-04-07) Silva, Luís Antônio Dantas; Marreto, Ricardo Neves; http://lattes.cnpq.br/6127043775208484; Marreto, Ricardo Neves; Freitas, Luís Alexandre Pedro de; Taveira, Stephânia Fleury; Cunha-Filho, Marcílio Sérgio Soares da; Zampieri, Ana Lúcia Teixeira de Carvalho
Introduction: Self-emulsifying drug delivery systems (SMEDDS) have been successfully used as carriers for poorly water-soluble drugs, because they can effectively solubilize them, as well as stimulate their intestinal lymphatic transport, reduce first-pass metabolism, and inhibit efflux proteins present in intestinal cells. All these effects together contribute to the improvement in the oral bioavailability of the incorporated drugs. The preparation of solid self-emulsifying systems is associated with additional advantages, such as increased stability, ease of transport, storage, and administration. Hot-melt extrusion is a technique that has attracted great interest in the pharmaceutical industry in recent years for enabling continuous production of solid dosage forms, with high productivity and low cost. In addition, it can be performed without the use of solvents. Despite this, there are no reports in the literature about the use of this technique in the production of solid self-emulsifying systems. Objectives: The objective of the present work was to perform preformulation studies and to develop solid self-microemulsifying systems containing carvedilol by hot-melt extrusion, aiming at improving the dissolution of this drug. Methods: Initially, carvedilol solubility and compatibility in different lipid excipients were determined, respectively, by the equilibrium solubility method and thermoanalytical, spectroscopic and isothermal stress techniques. An analytical method was developed and validated to carvedilol quantitation by high performance liquid chromatography. Next, the selected excipients were used in the construction of a ternary phase diagram, in order to determine the best ratio for SMEDDS production. Finally, the selected liquid formulation was mixed with a polymeric system consisting of an enteric polymer (hydroxypropylmethylcellulose acetate succinate) and other excipients. The resulting mixture was extruded in a twin screw hot-melt extruder. Box-Behnken factorial design was used to evaluate the effects of formulation (carvedilol concentration) and process variables (temperature and recirculation time) on the release of the drug (in 0.1 M HCl and phosphate buffer pH 6.8) and redispersion of the microemulsion from the solid system. The extrudates’ morphology was evaluated by light microscopy and scanning electron microscopy and the physical state of the drug in the preparation was investigated by differential scanning calorimetry and X-ray powder diffraction. Results: Preformulation studies showed that carvedilol is incompatible with the lauric acid, oleic acid, Gelucire® 44/14, Capmul® MCM, canola oil, castor oil, polyethoxylated castor oil, corn oil, soybean oil, sunflower oil and safflower oil. On the other hand, carvedilol was stable in mixtures with sesame oil, Plurol® Isostearique, Transcutol HP®, stearic acid, palmitic acid, Compritol® 888 ATO, Emulium® 22 and with the mixture of capric/caprilic triglycerides (CCT). The CCT showed to be the best solvent for carvedilol (3.93 ± 0.20 mg mL-1), among the compatible lipid excipients. Thus, the mixture of CCT, Plurol® and Transcutol HP® was selected for preparation of the self-emulsifying systems containing carvedilol. The phase diagram showed that the ratio of 50/37.5/12.5 (oil/surfactant/cosurfactant) resulted in the best parameters of self-emulsification (time, clarity and stability) average size (140.04 ± 7.22 nm) and size distribution (0.219 ± 0.011). These values were not significantly altered by the inclusion of carvedilol in the mixture (139.06 ± 7.28 nm and 0.221 ± 0.015). This self-microemulsifying concentrate with polymeric carriers were then extruded and the resulting product was a compact matrix. Factorial design showed that the drug concentration, temperature and recirculation time significantly influenced the drug release in different media, as well as the reconstitution efficiency of the microemulsion. Carvedilol release in acid medium was in the range of 12 to 25% and it was significantly affected by the temperature and recirculation time. The polymeric matrix was able to prevent redispersion of the system in acid. In turn, drug released was significantly affected by drug concentration in pH 6.8, ranging from 43 to 85%. Drug release in this medium was primarily affected by the concentration of the drug in the formulation. The reconstitution efficiency was significantly affected by the circulation time and process temperature, ranging from 55 to 100% in pH 6.8. Average size (145 to 164 nm) and PdI (0.209 to 0.262) were not significantly affected by the studied variables Conclusion: Self-microemulsifying extrudates were prepared from the lipid concentrate selected from the preformulation studies. The solid systems allowed a site-specific microemulsion redispersion, thus presenting potential for lymphatic absorption of carvedilol. The experimental results presented here are the first report about the production of solid self-microemulsifying systems containing carvedilol by hot-melt extrusion.
Estratégias computacionais como métodos alternativos para avaliação da sensibilização cutânea
(Universidade Federal de Goiás, 2017-05-12) Alves, Vinícius de Medeiros; Tropsha, Alexander; Muratov, Eugene; http://lattes.cnpq.br/9372290911831306; Andrade, Carolina Horta; http://lattes.cnpq.br/2018317447324228; Andrade, Carolina Horta; Oliveira, Gisele Augusto Rodrigues de; Ferreira, Márcia Miguel Castro; Costa, Fernando Batista da; Nascimento, Paulo Gustavo Barboni Dantas
Introduction: Skin sensitization is a major environmental and human health hazard. Although many chemicals have been evaluated in humans, there have been no efforts to model these data to date. Skin sensitization is commonly evaluated using structural alerts. However, there has been a growing concern that alerts disproportionally flag too many chemicals as toxic, which questions their reliability as toxicity markers. The main goal of this thesis was to develop and apply new cheminformatics methods to predict skin sensitization of chemical compounds that lack experimental data. Methodology: It has been compiled, curated, analyzed, and compared the available human data and the murine (performed in mice) animal model data, named LLNA (local lymph node assay). Using these data, it was developed reliable computational models and applied them for virtual screening of chemical libraries to identify putative skin sensitizers. It was developed a freely accessible web-based application for the identification of potential skin sensitizers. In addition, it was demonstrated that contrary to the common perception of QSAR models as “black boxes” they can be used to identify statistically significant chemical substructures (QSAR-based alerts) that influence toxicity. Results and discussion: The overall concordance between murine LLNA and human skin sensitization responses for a set of 135 unique chemicals was low (R = 28-43%), although several chemical classes had high concordance. We have succeeded to develop predictive QSAR models of all available human data with the external correct classification rate of 71%. A consensus model integrating concordant QSAR predictions and LLNA results afforded a higher correct classification rate of 82% but at the expense of the reduced external dataset coverage (52 %). We used the developed QSAR models for virtual screening of CosIng database and identified 1,061 putative skin sensitizers; for seventeen of these compounds, we found published evidence of their skin sensitization effects. The developed Pred-Skin web app (http://www.labmol.com.br/predskin/) is based on binary QSAR models of human (109 compounds) and LLNA (515 compounds) data with good external correct classification rate (70-81% and 72-84%, respectively). It is also included a multiclass potency model based on LLNA data (accuracy ranging between 73-76%). Conclusions: Models reported herein provide more accurate alternative to LLNA testing for human skin sensitization assessment across diverse chemical data. In addition, they can also be used to guide the structural optimization of toxic compounds to reduce their skin sensitization potential. The Pred-Skin web app is a fast, reliable, and user-friendly tool for early assessment of chemically-induced skin sensitization. A new approach that synergistically integrates structural alerts and rigorously validated QSAR models for a more transparent and accurate safety assessment of new chemicals was also proposed.
Planejamento, síntese guiada por QSAR, avaliação biológica e modelagem molecular de chalconas com atividade antituberculose
(Universidade Federal de Goiás, 2017-04-06) Gomes, Marcelo do Nascimento; Oliveira, Guilherme Roberto de; http://lattes.cnpq.br/8239498431579015; Andrade, Carolina Horta; http://lattes.cnpq.br/2018317447324228; Andrade, Carolina Horta; Emery, Flávio da Silva; Lião, Luciano Morais; Romeiro, Luiz Antônio Soares; Oliveira, Valéria de
In view of the current panorama of tuberculosis (TB) pandemic in the world, aggravated by co-infection with the HIV virus and the emergence of resistant strains of Mycobacterium tuberculosis (M. tb.), The research and discovery of new Anti-TB drugs. The present work aimed at the planning, synthesis and biological evaluation of new compounds with anti-TB activity, candidates for TB drugs. Structure and activity relationship (SAR) studies were developed using Matched Pair Molecular Analysis (MMPA) and binary models of quantitative relations between structure and activity (QSAR) using a combination of molecular fingerprints and machine learning methods. Bioisosteric replacement were proposed to plan new aryl and heteroaryl chalcones using the information obtained from SAR and QSAR analyses. Thirty-three compounds were selected by the consensus QSAR model for the synthesis. These compounds were synthesized and their structures confirmed by infrared (IR), hydrogen nuclear magnetic resonance (1H NMR) and carbon (13C NMR) spectroscopic methods and mass spectrometry (MS). Compounds which showed high purity (≥95% in HPLC) were tested against strains of M. tb. H37Rv (sensitive) and resistant to rifampicin (RMP) or isoniazid (INH). In addition, they were also tested in mammalian cell cytotoxicity assays and activity spectrum. We identified 22 hits with anti-TB activity, with minimum inhibitory concentration (MIC) in M. tb. H37Rv in aerobic conditions (MABA) <10 μM. Of these, 12 compounds exhibited potent M. tb. replication activity on nanomolar scale, with MIC values in MABA <1 μM and in micromolar under anaerobic conditions (LORA) with MIC <10 μM. In addition, these compounds also showed potent inhibitory activity against monoresistant strains at RMP or INH (MIC <1 μM and MIC <10 μM, respectively). Hits also demonstrated low cytotoxicity in mammalian cells (Vero cells) and selectivity index between 11 and 545 for M. tb. The same selectivity was verified in the activity spectrum assay against four commensal strains and six strains of non-tuberculosis mycobacteria (NTMs), in which the compounds presented broad spectrum against the NTMs strains. These results demonstrated that the combination of in silico strategies for the design of aryl and heteroaryl chalcones was efficient in identifying new compounds that proved to be potent, selective and promising candidates for prototypes of anti-TB drugs.
Planejamento, síntese, caracterização e avaliação toxicológica de um novo composto candidato a protótipo de fotoprotetor orgânico – LQFM184
(Universidade Federal de Goiás, 2016-09-30) Vinhal, Daniela Cristina; Menegatti, Ricardo; http://lattes.cnpq.br/8354030864254626; Cunha, Luiz Carlos da; http://lattes.cnpq.br/6349547031976679; Cunha, Luiz Carlos da; Romeiro, Luiz Antônio Soares; Gonçalves, Pablo José; Diniz, Danielle Guimarães Almeida; Fajemiroye, James Oluwagbamigbe
In Brazil, the estimates for the year 2016 point to approximately 596,000 new cases of skin cancer, being mostly related to exposure to ultraviolet radiation. According to current consensus, such damage can be minimized by prophylactic use of sunscreens. This way, this study proposes the planning, synthesis, structural characterization and toxicological assessment of a new candidate compound to organic sunscreen, LQFM184 (20). The structural planning was based both on molecular similarity in chemical action triazine derivatives (10, 11 and 13), cinnamic (4) and LQFM048 (14), with the starting compound (E)-2-cyano-3-(4-hydroxy-3-methoxyphenyl)acrylamide (18) which was produced from vanillin. In addition, LQFM184 (20) compound has molecular weight 729.65 Daltons and the synthetic route proposal consisted of two stages, 53% overall yield, which were performed under the scope of green chemistry. All the synthesized compounds were characterized by techniques of nuclear magnetic resonance, infrared, mass, ultraviolet and fluorescence. From the spectrophotometric absorption technique it was identified that LQFM184 (20) compound had two peaks of maximum absorption (λmax.) 306 nm in the region of UVB and 344 nm for UVA and molar absorptivity (ε) whose values were above 104 M-1 cm-1. As to the technique of cyclic voltammetry LQFM184 (20) compound was stable considering the applied potential and when under an atmosphere of synthetic air showed a weight loss of ~14% in the range of 250°C, characterized as a stable compound at high temperatures. From the in vitro evaluation by the spectrophotometric method described by Mansur it presented Solar Protection Factor (SPF) equal to 3.69 for the UVB. Moreover, the compound does not promote irritation or serious damage when in contact with rabbit cornea cells SIRC and was classified in category 4 of the GHS system as OECD 423, low toxicity. At the end of this work it is possible to observe that the proposed synthetic route to obtain the LQFM184 (20) compound was effective, given the obtained high yields, laborious and low cost steps as well as promising profile sunscreen.
Desenvolvimento de métodos eletroanalíticos para avaliação da capacidade antioxidante
(Universidade Federal de Goiás, 2016-03-28) Benjamin, Stephen Rathinaraj; Gil, Eric de Souza; http://lattes.cnpq.br/3218622824233303; Gil, Eric de Souza; Marreto, Ricardo Neves; Ghedini, Paulo César; Colmati Junior, Flavio; Oliveira, Severino Carlos Bezerra de
This study investigated the antioxidant activity using biosensors based on carbon paste electrode (CPE) modified with crude extract of laccase (Pycnoporus sanguineus, activity 2019 U L-1) in different compositions. The biosensor consists of carbon nanotubes activated with DNA (CPEL-DNA: CN) showed the best sensitivity level, 0.0549 μA / μM and 1.2 uM detection limit (LOD) in the concentration range of 20-140 μM of rutin. This biosensor showed excellent stability over 10 days and reproducibility (RSD <5%). This biosensor was used to determine the total amount of phenol in coffee samples (expressed by the equivalent rutin) using electroanalytical technique. For the evaluation of its detection capability, the results were compared with other electroanalytical techniques using analytical basis as samples of commercial coffee from different countries. The CPL-DNA: CN was used to determine the total amount of phenol in coffee samples (expressed by the equivalent rutin). Thus, it was possible to propose the CPL as an analytical tool for the detection of phenols. In this research, we developed several studies using different CPE to investigate the antioxidant natural product profile such as coffee samples, dry extracts of acerola, obtained by cyclic voltammetry (CV),) differential pulse voltammetry (DPV) and square wave voltammetry (SWV), which allowed to conclude classes of antioxidants present in the samples. The quantitative determination of these compounds was performed using the standard addition method by differential pulse voltammetry and electrochemical index (EI) has been proposed for estimating the oxidizing potential between different samples. Carbon paste electrode was also investigated using the different quality control samples commercialized produced from acerola employing DPV for the quantification of ascorbic acid (AA) in all samples, where the limit of detection (LOD) and limit of quantification (LOQ) was 0.31 and 0.96 μM and with excellent recovery between 97.4 to 102.2% The DPPH tests were used to compare the antioxidant activity in coffee and acerola samples. The Folin-Ciocalteu method was used to estimate the antioxidant activity of rutin from coffee samples. These methods proposed had advantages such as simplicity of sample preparation and the speed of the analysis of antioxidant capacity.

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