O Mundo se encontra em estado de epidemia de ansiedade segundo a Organização Mundial de Saúde (OMS), onde o Brasil se destaca, atualmente os transtornos mentais como Depressão e Ansiedade são a principal causa de incapacidade em que pessoas, com condições graves de saúde mental, morrem prematuramente comparadas a população em geral. O aminoácido L-triptofano (TRP) tem sido amplamente utilizado por indivíduos acometidos por transtornos como depressão e ansiedade. Sendo o TRP, precursor do neurotransmissor serotonina, é um aminoácido essencial, ou seja, sua absorção é obtida somente através da alimentação ou suplementação diária, em concentrações elevadas e aproveitamento baixo, no que se trata da síntese de serotonina. Por essa razão, o TRP foi intercalado em hidróxidos duplos lamelares(HDL/MgAl) via método de coprecipitação, onde o HDL/ MgAl sendo utilizado como nanocarreador, visando o melhor aproveitamento do aminoácido na síntese do neurotransmissor. Esta pesquisa investigou o melhoramento da biodisponibilidade do aminoácido na produção de Serotonina, a fim de potencializar seu efeito ansiolítico e antidepressivo na suplementação alimentar.  Todas as amostras obtidas foram caracterizadas por meio de difração de raio-x (DRX), onde os padrões demonstram se o HDL puro e o composto híbrido (HDL-TRP) exibem alto grau de cristalinidade, o que confere uma liberação mais controlada e contínua, Microscopia Eletrônica de Varredura (MEV) e Espectroscopia por Dispersão de Raios- X (EDS) os quais podem predizer o arranjo morfológico dos cristais gerados e sua composição específica e quantificação no Espectrofotômetro de Ultravioleta- Visível(UV-Vis). Os padrões de DRX puderam demonstrar que o HDL puro e o composto híbrido (HDL-TRP) exibiram alto grau de cristalinidade, com tamanhos desejáveis do padrão de partícula. Já a quantificação do TRP na matriz de HDL foi realizada através da espectroscopia no ultravioleta visível (UV-vis), apresentando como valor quantificado a média de 45,88% de TRP intercalado nas lamelas de HDL, essa concentração demonstra uma molécula promissora quanto ao aumento da sua biodisponibilidade.

A Esclerose Lateral Amiotrófica (ELA) também conhecida como Doença de Lou Gherig, é uma doença neurodegenerativa fatal. Caracterizada pela morte celular seletiva de neurônios motores superiores (NMS) e neurônios motores inferiores (NMI) levando a sintomas não motores como depressão e ansiedade e sintomas motores como paralisia irreversível. Pode ser classificada em dois grandes grupos: esporádica e familiar, onde a esporádica é a forma mais comum sendo responsável por 90% dos casos. Sua causa não está totalmente esclarecida, as primeiras hipóteses etiológicas relacionadas a ELA foram a mutação da SOD1 (superóxido dismutase-1) e a neurotoxicidade do glutamato. O diagnóstico é clínico e baseado na história e no exame físico. A morte ocorre por volta de 3 a 5 anos após o início dos sintomas. Atualmente não há cura para a doença e o tratamento medicamentoso é feito com o uso do Riluzol ou Edaravona. Por esse motivo, neste trabalho foi realizado um estudo teórico relacionando a estrutura e atividade antioxidante do riluzol e edaravona. Um estudo teórico comparativo da estrutura e capacidade antioxidante entre edaravona e riluzol foi realizado usando o método TFD (Teoria do Funcional de Densidade) com o conjunto de base B3LYP/6-31+G (d, p). Os cálculos foram realizados em fase gasosa e o método PCM em solventes apolares (clorofórmio e heptano) e solventes polares (água e etanol). Uma análise conformacional mostrou que o amino-exocíclico é o tautômero preferencial do riluzol quando comparado ao amino-endocíclico. Não há diferença entre a fase gasosa e o meio solvente usando o modelo contínuo polarizável (PCM). As propriedades antioxidantes foram calculadas com base nos valores de HOMO, potencial de ionização (PI) e energia de dissociação da ligação (EDL). Os valores de HOMO e PI mostraram que ambos os compostos têm desempenho comparável como nucleófilo e antioxidante por transferência de elétrons e os valores de EDL mostraram que a edaravona possui uma maior capacidade antioxidante por transferência de hidrogênio. As contribuições da densidade de spin explicam a melhor estabilidade química do radical livre catiônico do riluzol em comparação com a edaravona. Por fim, foram avaliados dois derivados de benzotiazol com suas capacidades antioxidantes comparadas com a edaravona. Existe uma forte relação estrutural entre riluzol e edaravona quando comparados com outros análogos de anel relacionados.

The enzyme PcEST, from the fungus Penicillium chrysogenum, has enormous potencial in the pharmaceutical industry, as it acts in the conversion of lovastatin catalysis into monacolin J, the main precursor in the production of simvastatin, a cholesterol-lowering drug. In this work, we seek to evaluate the impacts of mutations on the stability of the PcEST enzyme, through computational methods of molecular dynamics, in order to obtain structural and energetic analysis of the native and mutant PcEST enzymes. According to the results, the native PcEST enzyme and the D106A mutation presented an enzyme-ligand complex (Δ𝐺𝑏𝑖𝑛𝑑) with greater affinity. Molecular dynamics (DM) studies also revealed that the PcEST enzyme and the D106A mutation are more active due to multiple effective interactions with Ser57, Phe129, Tyr170, Ile236, Gly240, Gly241, His253 and Phe309 residues, which play a key role on substrate stability. The W344K and Y127A mutations, on the other hand, exhibited loss of hydrogen interactions during molecular dynamics simulation between the main residues present in the active site of the PcEST enzyme. The W344F and Y127F mutants showed an increase in 𝐾𝑚, thus causing a reduction in their catalytic activity. Therefore, we discuss the main interactions between the native PcEST enzyme and the mutations D106A, D131A, S57A, W344K, W344F, Y127A and Y127F in complex with the lovastatin substrate, in order to add information to increase its resistance and contribute to the production of Monacolin J and, consequently, for the synthesis of simvastatin. The information obtained from its analysis will be of paramount importance for the conjecture of new variants of the PcEST enzyme proposed for future synthesis and biological assays.

Melanoma is the most aggressive type of skin cancer, accounting for more than 60% of deaths from this type of cancer. One of the main risk factors is high exposure to UV radiation, and it originates in defense cells, melanocytes, which are cells that produce melanin, the brown pigment whose main function is to protect the cell genome against the harmful effects of radiation. UV. The tyrosinase enzyme is of great importance in the melanin synthesis process. Due to the hyperpigmentation present in melanoma, tyrosinase inhibitors are promising in the therapy of this neoplasm. In this context, the objective of this work was to evaluate the cytotoxic effect of Deferiprone (S-04) in an in vitro model of murine melanoma. S-04 has a potential cytotoxic effect on B16F10 melanoma cells after treatment at different concentrations, and this effect is observed from a concentration of 25µM, in addition to demonstrating a high degree of safety at different concentrations tested, through the viability of murine fibroblasts by the assay from MTT. Regarding the mechanism of death, treatment with S-04 showed an increase in annexin marking, indicative of death by apoptosis, thus S-04 was shown to be capable of inducing apoptosis. Drugs with a tyrosinase inhibitor profile may be candidates for the treatment of pigmentation disorders.

The Coronavirus, belonging to the Coronaviridae family and the order Nidovirales, is a nonsegmented virus that acts on the single strands of RNA. A new virus was discovered in December 2019 when an epidemic started out in the city of Wuhan, China. Officially known as severe acute respiratory syndrome (SARS-CoV-2). The infections occur through the interaction of protein S with Angiotensin-converting enzyme 2. Screening studies have been explored to determine potential candidates for the treatment of various diseases. Even with the discovery of vaccines for COVID-19, the virus is still being disseminated. Hydroxychloroquine presents studies showing efficacy for SARS-CoV-2 in vitro. In this study, the planning and identification of ligands with potential activity against the spike protein of SARS-CoV-2 was carried out. Structures of different antiparasitic were used to build the pharmacophoric model. Determined the active region of the crystal structure of the ACE2-linked spike protein (PDB ID: 6M0J). Virtual screening was carried out and 2000 molecules were obtained that went through several stages of filtering their pharmacokinetic and toxicological characteristics. Data obtained from pharmacokinetic, pharmacological and toxicological characteristics were used to separate only those with the best profile for the drug. Applicants who pass the drug profile move on to the binding affinity study. Molecular docking apresented five structures with better binding affinity than hydroxychloroquine. Ligand_003 had a binding affinity of -8,645 kcal.mol-1 , being considered an optimal value for the study. Ligand_003, ligand_033, ligand_013, ligand_044 and ligand_080 have favorable values that fit the profile of new drugs. Synthetic accessibility studies and similarity analysis were performed to select molecules with favorable potential for synthesis. Theoretical IC50 values demonstrate that the candidates are promising for in vitro testing. Chemical descriptors demonstrated good molecular stability for candidates. The theoretical studies here demonstrate that these structures have the potential to be studied as antivirals for SARS-CoV-2.

Stroke is a neural disorder that affects millions of people worldwide, being the second leading cause of death among all other global diseases. After an ischemic injury caused by the interruption of blood flow in the vessels that supply the brain (EVAi), functional deficits are generally disabling and permanent for the patient. And with the exception of the use of thrombolytics, there are no other pharmacological treatments or cell therapy available for this pathological condition. Due to its epidemiological, clinical, and economic-social relevance, it is essential to search for new treatments, such as the development of neuroprotective agents. There are several natural products with antioxidant action, but their therapeutic actions for central nervous system (CNS) diseases are poorly investigated. In the present work, we used an experimental model of focal IVA to evaluate the neuroprotective actions of the bioactive compound present in mango, Mangiferin (Mng). Adult Wistar rats underwent focal ischemic injury through microinjections (40pMol/µl) of endothelin-1 (ET-1) in the primary sensorimotor cortex (S1/M1) and treated with intraperitoneal injections of Mangiferin (30 mg/kg). Animals were perfused 4 days after injury. Histological analysis was performed by staining with Cresilla violet. The results obtained indicate that mangiferin has a protective activity for nerve cells against damage caused by ischemic injury.

Ferulic acid (FA), is one of the most abundant phenolic acids in nature - present in plants and food that are part of the Brazilian diet - has certain properties, mainly to stop chains of radical reactions by resonance, followed by their polymerization and, therefore, provides protection against the ultraviolet radiation, but the instability that leads to the oxidation of this molecule, still, is a challenge. The present work, therefore, sought to synthesize, characterize and the controlled release of the ferulic acid (FA), intercalated in double hydroxides lamellar (HDL) and behaved in chitosan (QUI). In this work, the ferulic acid (FA) was intercalated in ZnAl-HDL (molar ratio 2: 1) and QUI through the coprecipitation method. In this way, the synthesized nanohybrids were characterized by X-ray diffraction (XRD), visible ultraviolet absorption spectroscopy (UV-vis), infrared (IR) spectroscopy, thermogravimetric analysis (TGA), differential thermal analysis (DTA), and, finally, scanning electron microscopy (SEM); the quantification and kinetics of AF in the matrix was determined by UV-Vis absorption spectroscopy. Confirmation of synthesis was demonstrated by XRD analysis with the basal planes of type (003), (006), (110), characteristic of HDL and the peak (100) typical of QUI found in hybrids. In the IR, the regions considered the “fingerprint” of HDL, in 604 and 425 cm -1 were present in the hybrids. In the SEM readings, it was possible to observe the structures of HDL and hybrids with evident changes, as well as the hybrid (HDL-AF-QUI). In TGA it was possible to observe in HDL-AF and HDL-AF-QUI the thermal stability that the lamellar double hydroxides and chitosan provide. In UV-vis, the release kinetics were read, proving that the hybrids do have a controlled release. The main conclusion that nanohybrids showed the presence of HDL and chitosan in their structure through DRX, proving thermal stability through TG, biocompatibility, protection to photosensitivity; and finally, through UV-Vis it was possible to monitor the controlled release, until the present moment it is through which it suggests having excellent drug potential.

Chronic Myeloid Leukemia (CML) is a chronic clonal myeloproliferative disease, characterized by leukocytosis with left shift, splenomegaly and the presence of the Philadelphia (Ph) chromosome, which results from the reciprocal and balanced translocation between the advanced states of chromosomes 9q34 and 22q11, generating a hybrid protein BCR-ABL, with increased activity of tyrosine kinase. Thus, it carried out a virtual screening study based on the ligand Imatinib, with a defined crystallographic pose, deposited under the code PDB ID 1IEP. Six databases of merchants were used to select molecules, using the software ROCS (shape similarity) and EON (electrostatic similarity), followed by pharmacokinetic and toxicological predictions in silicon, resulting in 9 methods with satisfactory values, compared with Imatinib , which were submitted to a study of biological activity prediction via PASS Prediction online server, resulting in two structures with Probability of being "active" (Pa) values for protein kinase inhibition activity, such as LMQC01 molecules (Pa = 0.457) and LMQC04 (Pa = 0.658), selected for the study of molecular docking. Use a Pyrx 0.8 graphical interface, to evaluate as likely interactions with amino acid residues and binding affinity as structures with the BCR-ABL active site, resulting in -8.6Kcal /
mol-1 for structure LMQC01 and -12.2Kcal / mol -1 for LMQC04, with the LMQC04 structure reaching a value higher than the experimental binding affinity of imatinib (- 11.18Kcal / mol-1), being the one selected as a drug promoter for further studies.

Adenoid cystic carcinoma (ACC) is a rare neoplasm that mainly affects the head and neck regions, especially salivary glands. Growth is slow, but with but with a propensity to perineural invasion, local postoperative recurrence and metastasis. The most used treatment for this type of tumor is surgery followed by postoperative radiotherapy. The molecular characteristics of ACC are unclear, and unfortunately, the rarity of this type tumor limits to obtain in vitro and in vivo models that contribute in the investigation of pathogenesis and more efficient treatments. In the present study, a cell line was established and characterized for the evaluation of anticancer molecules. For this, it was obtained tissue samples of ACC off the tubular histological subtype from the retromolar trigone and a blood sample from a 59-year-old female patient. Array Comparative Genomic Hybridization (aCGH) performed molecular cytogenetic characterization in tumor tissue and cell line, while blood was genotyped for ancestry. Cell culture established from the collected tumor tissue showed rapid growth of tumor colonies from passage 18, stabilizing at passage 30. Blood genotyping revealed an ancestral contribution of 19% Amerindians, 31.5% Europeans and 49.5% of blacks. In cytogenetic analysis, gains were observed in loci harboring important genes such as EGFR (7p22.1-p11.2), BRAF (7q32.3-q34), HER2 (17q12-q21.2) and SMARCA1 (xq25-q27.1). Also in the lineage, loss (6q23.3-q25.1, PLAGL1 gene locus) and deletion (9p21.3-p21.1, CDKN2A/B gene locus) were observed; In tissue, only gains were observed (9q34.3, NOTCH1 locus and 5q32, PDGFRβ locus). The loss in 19p13.3-p12, locus of the CDKN2D gene, stands out as a common event in both samples. These findings corroborate other studies in the literature and make the established lineage a good in vitro model that can assist in the investigation of the pathogenesis of CAC and the basic research for new therapeutic modalities.

Muscimole is a psychoactive izoxazole compound extracted from mushrooms of the genus Amanita muscaria has been studied as a GABA inhibitor due to behavioral genes, since its structural structure is based on mammalian neurotransmitters GABA and glutamic acid. Due to its high selectivity and its own potential for neural activity, it is able to act as a drug, since it has a higher affinity for the GABAA receptor than GABA. Since the 1980s studies suggesting that GABA and muscimol are related to serotonin concentration, where increased GABA concentration or muscimol injection increases serotonin concentration and decreases inactive product after serotonin. oxidation, 5-HIAA. For this reason, this work aimed to plan and develop muscimol derivatives as an alternative for increase the serotonin using antioxidant activity. For this reason, this work aimed to plan and develop muscimole derivatives as an alternative for the treatment of anxiety and depression. For this, was used the drug planning method known as bioisosterism, which is characterized by being compounds or subunits of bioactive substances with similar structural characteristics, as well as similar physical and chemical properties with the ability to present analogous biological properties, can be agonists or antagonists. Firstly, a study was made of the groups that are responsible for the biological activity through the muscimole pharmacophores, where the groups that interact with the GABAA receptor are the -NH2 groupings, the isoxazole ring, as well as the oxygen present in the carbonyl. Then molecular modeling was performed, which was performed using the DFT B3LYP 6-311G (2d, 2p) method to verify the values of HOMO, LUMO, GAP, ionization potential (IP), bond energy dissociation, hydrogen atom transfer and single electron transfer, where it was found that the derivative S1 presented values equal -7.61 eV, -1.36 eV, -6.25 eV, 205.87.85 kcal/mol, 80.81 kcal/mol, -15.45 kcal/mol e -6.99 kcal/mol, respectively. The derivative S2 presented values of -6.80 eV, -1.08 eV, 5.72 eV, 198.41 kcal/mol, 77.73 kcal/mol, -18.53 kcal/mol e -0.47 kcal/mol, respectively. When compared with GABA, it was found that they are reactive, among which derivative S2 is more reactive, presenting lower GAP value compared to S1, and with PI values, it was found that derivative S1 has a lower electron donor capacity than derivative S2, highlighting that the best route is through the hydrogen donation mechanism. Then, the regioisomers derivatives were synthesized with a yield for S1 and S2 of 74,08% and 60,42%, respectively, as well as characterization through the melting point, where the derivative S1 had equal melting point. at 114,5 ° C - 115 ° C and S2, 182,5 ° C, showing that the synthesized molecules are pure, since they were compared with the data in the literature. With these data it is possible to say that muscimol derivatives have high antioxidant activity.

Natural products are sources of secondary metabolites with wide pharmacological applicability, including anticancer. Biflorin, a prenylated ortho-naphthoquinone that has been isolated from the roots of the Capraria biflora L. plant, has stood out as a potent prototype antitumor drug. However, despite promising potential, its antineoplastic capacity is incipiently applied to gastric cancer, one of the most incidente, aggressive and lethal cancers, nationally and globally. In this context, this study aimed to analyze the structure-toxicity relationship of biflorin by the redox in silico mechanism, as well as the in vitro cytotoxic and anti-invasive potential, using as a model strains of intestinal-type gastric adenocarcinoma   metastatic (AGP01) and isolated from primary tumor (ACP03). In silico analysis showed that biflorin has a differentiated reactivity characteristic and can act as electron donor or acceptor in nucleophilic and electrophilic reactions, respectively. Moreover, when compared to other natural naphthoquinones such as β-lapachone and lapachol, it presented better redox properties and reactivity conditions, but with less toxic effect due to their ability to form more stable intermediates. The molecular simplification of biflorin also allowed to infer that the ortho-naphthoquinone functional group is probably the most related to naphthoquinones toxicity. Additionally, biflorin showed cytotoxic activity at considerably low concentrations for both strains, however, cytotoxicity was more pronounced for AGP01 (IC₅₀ 3.1 μM) compared to ACP03 (IC₅₀ 4.5 μM) at 48h treatment. Regarding antimetastatic activity, biflorin reduced the cell invasion capacity of the AGP01 strain only (p <0.0001). The results indicate that biflorin has cytotoxic activity for both gastric cancer strains AGP01 and ACP03, as well as anti-invasive specifically for metastatic cells AGP01. In addition, it was 

Bacteria can be distinguished in two groups through the Gram technique, where Grampositive and Gram negative bacteria can be differentiated, the main differences between these organisms being the structure of the cell wall, its components and its functions. More evidence has emerged of bacteria resistant to antibiotics, the case of Gram-negative bacteria is more worrisome due to the emergence of strains resistant to various antibiotics. Lipopolysaccharide (LPS) is a component of the outer membrane of Gram-negative bacteria responsible for toxic manifestations such as inflammation. 3-Deoxy-D-manno-octulosonate (KDO) is a site component of the inner core of LPS essential for its formation. The reaction for KDO production requires two substrates, phosphoenolpyruvate (PEP) and D-arabinose 5-phosphate (A5P), catalyzed by 8phosphate synthase 3-Deoxy-D-mannoocobluconate (KDO8PS). This reaction is important because it plays a crucial role in the assembly of LPS. This enzyme is in two distinct forms as the dependence of the presence or absence of divalent metal ion in the active site. There are several inhibitors of KDO8P synthase, two were selected based on their inhibition constants (Ki), with BPH1, the most active among them with a value of 0.37 μM in KDO8P metal synthase independent in E. coli and BPH2 with value of 7.9 ± 1.6 μM for metal-independent KDO8P synthase in N. meningitidis, these K i values are approximately 2 to 3 times higher than the Km values for PEP that were also used in this work, in addition to a third hypothetical inhibitor that combines the main characteristics of the inhibitors already described in the literature. Molecular Dynamics, Molecular Dynamics and Free Energy of bonding with the methods MMGBA, MMPBSA, SIE and Energy decomposition by residue to analyze the coupling mode of these ligands and the PEP substrate were used. With the results obtained, we analyzed the main interactions of these ligands and the molecular behavior of both the ligands and the protein. Therefore, more favorable binding-free energy values were obtained for the complexes formed with the BPH1 linker with the three methods -96.07 Kcal / mol with MMGBSA, -107.09 Kcal / mol with MMPBSA and -13.53 with SIE and observed these complexes perform a greater number of effective interactions. Thus, it is suggested that the BPH1 linker has an excellent potential for inhibiting the catalytic activity of the enzyme KDO8P synthase responsible for the production of KDO, essential component of LPS for the formation of the outer membrane of Gram-negative bacteria.

The black pepper (Piper nigrum L.), member of Piperaceae family, presents the alkaloid piperine traditionally used as antidepressant, neuroprotective, anti-inflammatory, antioxidant, antibacterial, antifungal and larvicidal and bioavailability of several drugs with concomitant use. This natural amide has motivated several scientific studies due to chemical composition. Thus, the procedures for extracting, isolating and characterizing the piperine component from the Piper nigrum L. species were developed. The extraction was fulfilled in Soxhlet (40 g black pepper ground, 250 ml of absolute ethyl alcohol) to obtain solid piperine, followed by analytical procedures for substance characterization, such as: Thermogravimetry (TG), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (DR-X), infrared (IR) spectroscopy, Raman and 13C and 1H nuclear magnetic resonance (NMR). As well as the combined use of molecular modeling techniques in the spectral identification via NMR, Raman and infrared of the piperine molecule to corroborate with experimental data obtained. A second method for extraction by maceration (200 g ground pepper / 1L of absolute ethyl alcohol) was applied for 30 days. The components in the macerated extract (EEPM), the pepper extracts from the soxhlet (EEPS) and purification stages (RP and SR) were evaluated by phytochemical prospection. Also, biological tests were performed with the samples (EEPM, EEPS, RP, CP and SR) for proof antimicrobial, fungal and larvicidal bioactivities. All characterization analyzes for piperine crystals (MEV, DSC, XRD, IR-ATR, Raman and NMR) were effective in confirming the component. With the use of molecular modeling the theoretical data (IV, Raman and 13C and 1H NMR) obtained showed promising correspondence in comparison with experimental data. The theoretical and experimental compared, through Simple Linear Regression, reached statistically satisfactory results (R2, Q2) values above 94%. Alkaloids, Catechins, Anthocyanins and Anthocyanidins, Leucoantocyanidins, Catheter tannins, Flavonones and Phenols were detected in the samples (EEPM, EEPS, RP and SR). In the microbiological analyzes, the EEPM sample showed high efficiency of the extract in the inhibition of Salmonella sp. (MIC) <100 μg/mL. The EEPS sample presented promising inhibitory activity for almost all microorganisms, with no inhibition relevant to Pseudomonas aeruginosa. Also showed potent inhibition coefficients against Staphylococcus aureus and Salmonella sp. (MIC) <100 μg / mL) for the RP sample. The CP sample showed a great inhibition coefficient in most of microorganisms occurring inactivity in Pseudomonas aeruginosa. In the analysis of larvicidal activity, the percentage of larval mortality did not reach 50% in any of the samples submitted to 24 hours of exposure and at 48 hours, the concentration of 100 μg.mL-1 of the EEPM sample was the most significant with a mortality rate of 85.7%.

Paracetamol is a clinically proven analgesic and antipyretic, which promotes analgesia by
elevating the pain threshold and antipyretic through action in the hypothalamic center that
regulates the temperature. Currently paracetamol is one of the medicines that is available in all
the countries of the world in places related to health and can be acquired without prescription.
Considered one of the most widely used drugs in the world as it is cheap and easy to access, it
can also be used from birth to the elderly. Like non-steroidal anti-inflammatory drugs (NSAIDs)
paracetamol is able to inhibit the synthesis of prostaglandins from arachidonic acid under
specific conditions by inhibiting cyclooxygenase (COX). Although it is considered safe at
therapeutic doses, Paracetamol has a toxicity attributed to one of its metabolic intermediates
called N-acetyl-p-imine-benzoquinone (NAPQI), produced through enzymes present in
cytochrome P450 (CYPE21). Thus, the objective of this present work is to plan, synthesize and
evaluate possible antinociceptive and antipyretic activities of paracetamol analogues,
ortacetamol and its derivatives in order to obtain a less toxic derivative. The calculations of
electronic properties such as higher energy occupied molecular orbital (HOMO), lower energy
unoccupied molecular orbital (LUMO), ionization potential (PI), phenolic bond dissociation
energy (BDEOH) and spin densities were performed using the Gaussview and Gaussian 2009
packages. The values of the average values of BDENH, among others, are those that are observed
with the quality of a heating cycle for the high speed with the possibility of a chelation defined
by a hydrogen bond of the amide with the phenoxyl radical. Given the results it is possible that
BDENH energy compounds may be less potent than hindering the action of CYP on oxidation
to form toxic intermediates. A proposed chlorinated derivative was proposed and synthesized.
It is in biological evaluation phase. Orthacetamol was more potent antioxidant than
paracetamol. Experimental results are in aggrement with theoretical values. We conclude that
ortcetamol may be a potentially safer bioactive candidate than paracetamol.

The Chagas disease, caused by protozoan Trypanosoma cruzi, still has high rates of
contagion in the present days, especially in the Amazon region, being orally the most
common type of transmission. After contagion, the disease has two phases: acute and
chronic. The acute phase is, in most cases, asymptomatic and treated with greater
efficiency, the chronic phase, despite being symptomatic, has not efficient treatment. To
treat the disease, there is only one available medicine, benznidazole or Rochagan®,
distributed free of charge, and it must be administered during, approximately, 60 days.
However, benznidazole has low efficiency, being effective only on acute phase
(asymptomatic). Besides that, the medicine use to cause severe side effects in patients
treated, causing many times the abandonment of treatment. The molecular modeling has
become an important tool on new drugs design, using theoretical study to evaluate of the
new molecules potency. Thereby, the goal of this work was to design new derivatives using
molecular modifications of benznidazole and metronidazole aiming to reduce their redox
capacity. With this purpose, a theoretical study was performed of two benznidazole
derivatives, using molecular association and methylation. The molecular association was
accomplished with the union of benznidazole and metronidazole molecules, another
medicine with antiprotozoal activity, but with less toxicity than benznidazole. Both
designed derivatives were synthesized on laboratory using the classics methodologies of
electrophilic and nucleophilic substitution, esterification, alkylation and nitration. From the
theoretical study, it was possible observe that the nibendazole 1 and nibendazole 2
compounds have lower redox capacity than benznidazole, according to its results of
HOMO, LUMO, ionization potential and electron affinity.The GAP values showed that the
derivatives are less reactive than benznidazole. The HOMO and LUMO graphics, showed
that the nitroimidazoles rings have high electron-donation capacity as well as benzyl radical
has high electron-aception capacity, on benznidazole and on derivatives compounds.

Edaravone is a commercial drug released on the Japanese Market, indicated in the treatment and prevention of ischemic stroke. Its action is due to its scavenger properties of free radical released in the ischemia. However, its use may lead to a kidney toxic effect. Therefore, in this work, a new bioisostere derivative from Edaravone was proposed, by the change of a pyrazolone ring for an indolone. Antioxidant properties was determined through computational methods. Calculations were undertaken in the software Gaussian, through the B3LYP method, with the set of bases 6-31G (d, p). Antioxidant activity was predicted from HOMO, LUMO, Gap, Ionization potential (IP) and Bond dissociation energy (BDE). Results indicate analogous compounds showed higher ClogP values compared to Edaravone, which means higher facility to pass through biological barriers, with higher liposoluble properties. Edaravone derivative, called Imidazone, also showed higher antioxidant potential than Edaravone. Methyl group in second position of heterocyclic ring was essential to more stable resonance structures formation to semiquinone form. All new derivatives proposed were extremely promising with antioxidant capacity superior to Edaravone.

It is a plant popularly found in the North and Northeast of Brazil, being called taperebazeiro or cajazeiro, belongs to the family of Anarcadiaceae, whose scientific name is Spondias Mombin L., is considered a high plant, being able to reach up to 15 meters of height, its leaves are considered glabrous and unequal in the base, their bark presents a whitish and rough coloration. In addition, it has in its chemical composition alkaloids, resin, tannins and saponins. It has several biological effects, such as: antimicrobial, anti-inflammatory and antipsychotic effect. The Amazon has one of the world's largest reserves of biodiversity, however, there are few researches on plant species with potential to be used as natural sunscreens. In recent years cases of skin cancer have grown, in 2016, the National Cancer Institute estimated that 175,760 people would contract the disease. In the cosmetic market there is a great demand for products of natural origin, especially those that have proven scientific studies. Therefore, the objective of this work was to analyze extraction methods and parameters for In Vitro evaluation: Photoprotective Activity, Antioxidant Activity and Total Flavonoid Dosage for the preparation of photoprotector from extracts of Spondias Mombin L.

Leishmaniasis is protozoan caused by different species of the parasite of the genus Leishmania that present themselves in the promastigote form, when they are infecting the insect vector or amatisgota, when they are infecting a vertebrate host. The chemotherapy treatment is still the main means of fighting the disease, however due to the high cost and some unwanted side effects, it makes treatment difficult. Several proteins with enzymatic and structural functions have been identified as possible pharmacological targets against the parasite species in question due to their specific functions, cellular location and considerable phylogenetic distance. Glucosomal proteins are pharmacological targets that meet these requirements and have been targets of different studies. The glycosomal enzyme Glycerol 3-phosphate dehydrogenase (GPDH) from Leishmania mexicana has its crystallographic structure attached to the NAD+-DHAP bissubstrat (NDE), available in the Protein Data Bank (PDB). 10 residues in the active site are noted which are highly conserved and conformational changes in their structure. From this, in the present study, molecular dynamics (DM) simulations were combined with Principal Component Analysis (PCA) to verify the conformational activity in the non-bounded form (apo) and in the bound form (holo). A total of 100 ns of DM for each system were generated, as well as free energy calculations that estimated the structural mechanism by observing that the C-terminal domain moved considerably while the N-terminal remained conservated and stable. The results also show that the closed state after NDE formation is favorable for the enzymatic action process.

Chagas’ disease is an infection caused by the Trypanosoma Cruzi flagellated protozoan
transmittedbyinsects(gnat)knowninBrazilas“barbeiro”(barber).IntheAmazonregion,
studies have shown that oral contamination has been frequent. The only available drugs
for the treatment of Chagas’ disease - Benzonidazole (RochaganR, Roche) and Nifurtimox
(LampitR, Bayer) - have shown limited efficiency and severe side effects. Cruzain is an
enzyme present at all stages of the life cycle of T. cruzi and is the most abundant of the
family of papain cysteine proteases found in the parasite, being a promising enzymatic
target for the design and development of inhibitors against the disease. Non-peptidic noncovalently
bound to the enzyme were synthesized and evaluated biologicallyin vitro andin
vivo byFerreiraetal.(2014)analogsofthe8D(orB95)leadercompound(crystallographic),
yielding a series of active compounds, of which the most powerful are: 8K, 8L and 8R.
This work investigated the potential interactions and energies of the cruzain (PDB code:
3KKU) complexed with these four ligands by means of computational tools in order to help
elucidate their potential inhibition activity in this enzyme. The computational protocol
(parameters, topologies, coordinates, minimizations, thermalizations and productions) was
the same for each system. In the final stage of molecular dynamics (MD) production,
each system was simulated for a period of 100 ns, to which the mean square deviation
(RMSD) stability values of the enzyme and the marked change in 8L ligand conformation
were analyzed. The quality of the simulation was also evaluated through potential, kinetic
and total energy, volume and temperature graphs. Interactions of hydrogen bonds of
the ligands with some amino acid residues belonging to the catalytic site were analyzed.
The interaction between the ASP161 and the 8R ligand is emphasized, being ratified by
the energy decomposition by residue showing that ASP161 has the best contribution.
In terms of binding free energy, the ∆Gtotal follows the experimental trend, pointing
the 8R ligand as the most favorable to the reaction having a theoretical value of -30.04
kcal.mol−1. This spontaneity is ratified by means of the values obtained with the SIE
method, whose theoretical value was -7.54 kcal.mol−1. The results of this work should favor
the optimization of compound 8R or development of a series of analogs of this molecule in
order to be used as a possible drug for the treatment of Chagas’ disease.

catalase-peroxidase, KatG, which produces an isonicotinoyl-NADH adduct, INNADH, whichtargets the M tuberculosis Enoyl-ACP reductase protein, InhA, in order to disrupt thesynthesis chain of mycolic acidsResistance to isoniazid alone or in combination with otherdrugs is one of the most common forms of resistant tuberculosis and poses a threat to thecontrol of this disease. In this context, triclosan (TCL) appears as an alternative inhibitor ofthe synthesis of mycolic acids, since it is also specific to InhA. This study aims to evaluate theinteractions of inhibitors of InhA through Molecular Dynamics Simulation (DM) and proposepossible new inhibitors for this enzyme. The system used in this work was captured from thedatabase PDB, code 4TRO. Eight ligands, NADH, INNADH, and the TCL, P31, P41, P52,P61, P72 and P80 derivatives were evaluated. In the lower region of the active site of InhAwere more frequent π charge stacks made by PHE41 and PHE97 with the ligands NADH,INADH, P80, P31, P72, however P41 made a hydrogen bond (LH) with PHE41. In the centralregion of the active site, residues such as A GLY96, SER20 and ILE21 did LH with NADH,INNADH, P31, P41 and P80. In relation to the upper region of the InhA site. The PHE149performed EC-π with the INNADH and P41. Already in P31 was an LH with this residue andin P80 the energies are favorable for interaction. The free energies of each system presentedin descending order are INNADH (-72,038 kcal / mol), P80 (-45,841 kcal / mol), NADH (41,463kcal / mol), P41 (-40,178 kcal / mol), P31 (-30.614 kcal / mol), p52 (-19.475 kcal /mol) and P61 (-12.297 kcal / mol). These results highlight P80 and P41 as promisingcandidates for M. tuberculosis mycolic acid synthesis inhibitors, since being an energy profileis competitive with the values shown by NADH.

The pharmacological research has been aimed at the knowledge of regional folk medicine, in order to establish the scientific bases of their respective pharmaceutical products’ effectiveness. Among the many natural sources used in our region are the species Conocarpus erectus L, popularly known as the "mangrove bud", belonging to the Combretaceae family. Different parts of the plant such as leaves, stems, fruits and flowers have their biological activity studied, among them the anticancer and antimicrobial effects. Ethnopharmacological reports obtained in the region of Salinópolis - PA also described a potential use in digestive disorders. Although a great advance in the drug therapy used in the cases of gastric ulcerationhas been made, it is important to carry out studies that prove its validity. This work aims to verify the cytoprotective activity and cicatrizing activity of the lyophilisatebark teaobtained by decoction of the species Conocarpus erectus L (LCE) in acute and chronic gastric lesions. The methodologies for evaluating the cytoprotective effect were acute lesions inducted by indomethacin and ethanol, while the cicatrization effect was evaluated by chronic acetic acid-induced lesions in adult Wistar rats. The intragastric pH variation was measured by the pylorus ligament assay. The lyophilizate’santioxidant activity was evaluated by the DPPH assay, as well as the lipid perioxide levels’ that were evaluated by the TBA-RS method in chronic lesions induced by acetic acid 5 and 10%. The results showed cytoprotective activity of LCE by the indomethacin induction model reduced the ulceration index (IU) in the treated group by 51,49%, omeprazole group by 51,33% and sucralfate group by 71,28%, all of them when compared to the controlled group. On the model of ethanol LCE’s induction, the area affected was reduced by 90.94%, and in the sucralfate’s induction group, by 75.88% when compared with the controlled group. The LCE’s healing effect reduced gastric lesions to 5% in 80.11%, while the on omeprazole group to 52.75% and the sucralfate group reduced to 66.33%, whereas in the 10%gastric lesionsthe LCE group reduced 72.11%, the omeprazole 57.47%, and the sucralfate group 43.77% (p>0,05Anova, post test Dunnett's and Turkey). The LCE treatment showed an increase of 39% onintragastric pH when compared to control (p>0,05Anova, post test Dunnett's e Turkey’s) and did not statistically showed any different from the omeprazol e group by themodel of pylorus ligation. The LCE antioxidant effect was confirmed by the DPPH assay, as it was diluted in 10x, 50x and 100x with a percentage of 67.65% ± 0.52, 73.22% ± 0.17 and 72.70% ± 1.39, respectively, when compared to the ascorbic acid antioxidant of 33,74% (AA) like this (p <0.05, Anova post test Dunnett). A lipid peroxidation evaluated in the lesions obtained by the 5%-acetic-acid-induction model showed that the average MDA levels in the nave group, controlled group and treated group LCE were 0.492 ± 0.0849, 1.579 ± 0.219, and 0.399 ± 0.092, respectively, showing that the LCE-treated group was able to reduce lipid peroxidation by 74.73% in comparison to the controlled group (p<0,05 Anova post test Dunnet) and it did not statisticallydiffer from the nave group. On the 10%-acetic-acid-model the average level of malonaldehyde in the nave group, controlled group and the LCE-treated group was 0.628 ± 0.042, 1.567 ± 0.234 and 0.441 ± 0.12, respectively.  The LCE treated group managed to reduce by 71.85% the lipid peroxidation caused by acetic acid induced lesions when compared to the control group (p <0.05 Anova post test Dunnet).These results confirm the cytoprotective and cicatrizing effects of LCE and suggest possible action mechanisms associated with its antioxidant potential, as well as possible acid secretioninhibition.

Inflammation is a ubiquitous homeostatic mechanism generated to protect the body's integrity against endogenous or exogenous harmful agents. Inflammatory diseases constitute a complex and heterogeneous group of diseases, being an important cause of morbidity and mortality. Adenosine A2A receptor (A2AAR) has a considerable importance in the anti-inflammatory process. For the search of agonists with anti-inflammatory activity, the (6-(2,2-diphenylethylamino)-9-((2R,3R,4S,5S) -5-(ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-yl)-N-(2-(3-(1-(pyridin-2-yl)piperidin-4-yl)ureido)ethyl)-9H-purine-2-carboxamide) (UK-432097) and a set of 20 compounds found in the BindingDB database was analized. These compounds were used to generate several pharmacophore models. The predicted molecular properties were used for the construction of QSAR models (bi-, tri-, tetra-, penta-, hex-parametric) via Multiple Linear Regression Model for the prediction of biological activity. In addition, the PASS webserver was also used to predict activity. The best pharmacophoric model was used for commercial compounds in databases and the resulting compounds from the virtual screening were applied to the QSAR models. Following the methodological sequence, the results of the virtual screening were possible to select two compounds with promising activity to present specific characteristics delineated in the work, besides presenting satisfactory pharmacokinetic and toxicological profiles, being able to be used in future biological assays to confirm its activity and anti- inflammatory response to the A2AAR receptor.

Salicylate derivatives are successfully used as analgesic, antipyretic, anti-inflammatory agents and in prevention of cancer, mainly rectal colon. They reduce the risks of many diseases associated with old age. However, adverse effects related to gastrointestinal events are always associated to its main constituent (ASA). These aspects are linked to their chemical stability and affinity for biological receptors. The aim of this work are the design, synthesis and applications of naphthalene-salicylic derivatives as antioxidants. Thus, a theoretical study of the twelve studied compounds was carried out. The calculations of electronic properties such as frontier orbitals HOMO-LUMO, ionization potential (IP), bond dissociation energy of phenolic moiety (BDE_OH), and spin density contributions were performed by using density functional theory (DFT) at the B3LYP/6-31G (d, p) level of theory on Gaussview and Gaussian computational packages. Some of these compounds were synthesized by using classical methods. The theoretical results showed that both additional hydroxyl or substitution on benzene ring for naphthalene increase the antioxidant capacity in the same values with small dissimilarities among acid, ester, and amide derivatives. A synergistic effect was observed when both are used together, producing the most potent molecules. In addition, spin density calculations have indicated a regioselective pathway can be gotten from monohydroxylated derivatives, with high possibility of generating of in vivo dihydroxy derivatives mainly at the para position relative to the phenolic group, through enzymatic or non-enzymatic reactions. Finally, the replacement of the naphthalene ring instead of the benzene ring increases both reactivity and chemical stability for the quinone-type intermediates, explaining how these compounds may play a role in the preventive mechanisms and way treatment of cancer. Some synthesized compounds are in anticancer and anti-inflammatory tests.

C

O melanoma maligno é resistente à maioria dos medicamentos disponíveis. A mortalidade causada pelo melanoma vem crescendo durante as últimas décadas, chegando a aproximadamente 150.000 novos pacientes por ano no mundo. Assim, neste trabalho foram investigadas a ação antoproliferativa e citotóxica de três novas moléculas derivados do ácido kójico (AK) em linhagem celular de melanoma B16F10 in vitro. O efeito da citotoxicidade in vitro foi avaliado pela redução do MTT. Além do mais, o modo de ligação e os efeitos inibitórios, na enzima Tirosinase (TYR), foram analisados por simulação computacional através da técnica de docagem molecular. Os resultados mostraram que as moléculas Mol 01 e Mol 03 já possuem potencial efeito antiproliferativo contra as células B16F10 de melanoma após um tratamento de 24h, a partir da concentração de 10 µM, com uma queda na viabilidade de aproximadamente 75%. Já nas concentrações de 75 µM e 100 µM a viabilidade já era de 0% em relação ao controle, para ambos os compostos. No entanto observou-se que o grupo de células tratadas com a Mol 02 em todas as concentrações e em todos os tempos, não apresentaram diferenças significativas quando comparadas ao grupo controle de 100%.   Por fim, os resultados de docagem sugerem que os inibidores exibem comportamentos semelhantes aos inibidores TRO (tropolone) e AK, o que enfatiza seu modo competitivo de inibição, bem como suas interações como os íons Cu²⁺ presentes no sítio catalítico da enzima TYR.