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Concerned about weed infestation, a major threat to food production and herbicide resistance that interferes in the mechanism of action of the main herbicides, we have synthesized eight isatin derivatives using the "Click Chemistry" approach through copper-catalyzed azide-alkyne cycloadditions (CuAAC). Sixteen isatin derivatives were evaluated for their phytotoxic activity against the seed culture of the model plants

A transição escolar é um momento muito importante no desenvolvimento biopsicossocial de toda criança, pois ao sair da pré-escola se depara com uma nova maneira de aprendizagem, de socialização e desenvolvimento, o qual colabora integralmente no processo educacional de toda criança, quando esta transição é realizada de forma positiva e saudável, consequentemente haverá de ter resultados satisfatórios diante da transição, quando ocorre de forma negativa, inevitavelmente haverá problemas que certamente afetarão sua aprendizagem e seu desenvolvimento. Por conta da Pandemia da covid-19, o ensino se tornou remoto e híbrido, o ensino educacional teve que ressignificar sua metodologia de ensino, trazendo consigo diversas mudanças. Desta forma, o presente trabalho teve por objetivo observar como os professores das escolas públicas de Agudos/SP estão lidando com a transição em tempos de pandemia da covid-19. A metodologia utilizada foi através do método estatístico, com abordagem indutiva que obteve resultados através de dados coletados, feitos por um questionário online. O resultado alcançado deixou evidente que possivelmente todas as escolas municipais do ensino fundamental de Agudos estão trabalhando de acordo com a BNCC (Base Nacional Comum Curricular) e juntamente com a OMS (Organização Mundial da Saúde), a fim de favorecer esta transição de forma correta no processo de transição da pré-escola para o 1º do Ensino fundamental na cidade de Agudos, em tempos de pandemia da covid-19.

Este artigo tem como objetivo geral a intenção de contribuir com a gestão do conhecimento na Marinha do Brasil (MB). A questão principal que norteou o presente estudo foi: Quais os desafios encontrados pelos usuários do Sistema de Gerência de Documentos Eletrônicos da Marinha (SiGDEM) para a aplicação do processo de plena operacionalização da gestão documental na MB por meio do sistema? O mérito norteador do estudo está na apresentação de um breve histórico do processo de digitalização na Administração Pública até a criação do SiGDEM; na realização de entrevistas semiestruturadas com militares usuários do SiGDEM; e na tentativa de equiparar as funcionalidades do SiGDEM com outros dois sistemas digitais (SEI - Sistema Eletrônico de Informações e SAPIENS - Sistema AGU de Inteligência Jurídica) utilizados em outros órgãos da Administração Pública. A metodologia escolhida foi a pesquisa qualitativa de natureza bibliográfica e entrevista semiestruturada. Esta obra desenvolveu-se em seções: Seção 1 - Traços evolutivos do processo de digitalização na Administração Pública até a criação do SiGDEM, a saber a fundamentação teórica deste estudo; Seção 2 - Entrevistas com atores envolvidos no uso do SiGDEM de Organizações Militares diferentes, que demonstra a contribuição dos resultados das entrevistas realizadas com os sujeitos da pesquisa e Seção 3 - Considerações Finais. Acredita-se que este trabalho coopere com novas pesquisas que se debrucem sobre implicações do efeito digital no processo de ampla digitalização na Administração Pública tendo como fator exemplificativo o ciclo de processamento e gerenciamento de documentos eletrônicos em ambientes organizacionais da MB.

Aim: Glioblastoma multiforme (GBM) is an aggressive cancer with very limited clinical therapies. Herein, we have designed novel mercaptobenzimidazole derivatives (1–7) as multitarget antineoplastic drugs and assessed their antiproliferative profiles on an experimental model for GBM, the C6 glioma line. Results: The target compounds were synthesized in few steps with reasonable yields (33–90%). Compounds 1 (∼18 μM) and 4 (∼20 μM) showed dose-dependent antiproliferative effects on C6 glioma and significantly increased early apoptosis, but only 4 disrupted the cell cycle progression and did not induce autophagy. Docking simulations suggested these compounds as dual kinase and colchicine binding site inhibitors. Conclusion: In spite of the limited selective toxicity, 4 hold the potential to be further optimized for the treatment of GBM.

The enzymatic synthesis of oligosaccharides depends on the availability of suitable enzymes, which remains a limitation. Without recourse to enzyme engineering or evolution approaches, herein we demonstrate the ability of wild‐type cellodextrin phosphorylase (CDP: β‐1,4‐glucan linkage‐dependent) and laminaridextrin phosphorylase (Pro_7066: β‐1,3‐glucan linkage‐dependent) to tolerate a number of sugar‐1‐ phosphate substrates, albeit with reduced kinetic efficiency. In spite of catalytic efficiencies of, Milking phosphorylases: We demonstrate the ability of wild‐type cellodextrin phosphorylase (CDP: β‐1,4‐glucan linkage‐dependent) and laminaridextrin phosphorylase (Pro_7066: β‐1,3‐glucan linkage‐dependent) to tolerate a number of sugar‐1‐phosphate substrates, thereby enabling the construction of new‐to‐nature analogues of human milk oligosaccharides.

Sialic acid is the natural substrate for sialidases and its chemical modification has been a useful approach to generate potent and selective inhibitors. Aiming at advancing the discovery of selective

The design of new functional materials and devices substantially relies on self-assembly of hierarchical structures. Formation of 2D platelets is known in the enzymatic synthesis of cellulose-like polymers. Here we demonstrate the feasibility of postsynthesis assembly of novel fluorinated cellodextrins. Highly ordered 2D structures of large lateral dimensions, unattainable in the polymerization process, can be formed because of postsynthesis assembly of the cellodextrins. These cellodextrins were also involved in coassembly with cellulose nanocrystals (CNCs) leading to hybrid systems. The hybrid architectures obtained depend on the content of fluorine atoms in the fluorinated cellodextrins. Monofluorinated cellodextrins coassemble with CNCs into a nanoweb, while multifluorinated cellodextrins assemble around the CNCs.

Understanding the fine details of the self‐assembly of building blocks into complex hierarchical structures represents a major challenge en route to the design and preparation of soft‐matter materials with specific properties. Enzymatically synthesised cellodextrins are known to have limited water solubility beyond DP9, a point at which they self‐assemble into particles resembling the antiparallel cellulose II crystalline packing. We have prepared and characterised a series of site‐selectively fluorinated cellodextrins with different degrees of fluorination and substitution patterns by chemoenzymatic synthesis. Bearing in mind the potential disruption of the hydrogen‐bond network of cellulose II, we have prepared and characterised a multiply 6‐fluorinated cellodextrin. In addition, a series of single site‐selectively fluorinated cellodextrins was synthesised to assess the structural impact upon the addition of one fluorine atom per chain. The structural characterisation of these materials at different length scales, combining advanced NMR spectroscopy and microscopy methods, showed that a 6‐fluorinated donor substrate yielded multiply 6‐fluorinated cellodextrin chains that assembled into particles presenting morphological and crystallinity features, and intermolecular interactions, that are unprecedented for cellulose‐like materials., Generating glycomaterials: Enzymatic incorporation of singly and multiply fluorinated glucose residues into cellodextrin chains produces selectively fluorinated cellodextrins that self‐assemble into crystalline materials. Multiply 6‐fluorinated cellodextrin gave rise to an allomorph not previously reported for celluloses or cellulose‐like materials. Our findings highlight the potential of chemoenzymatic synthesis for generating novel glycomaterials of controlled molecular structure and morphology.

β-1→4-Glucan polysaccharides like cellulose, derivatives and analogues, are attracting attention due to their unique physicochemical properties, as ideal candidates for many different applications in biotechnology. Access to these polysaccharides with a high level of purity at scale is still challenging, and eco-friendly alternatives by using enzymes in vitro are highly desirable. One prominent candidate enzyme is cellodextrin phosphorylase (CDP) from Ruminiclostridium thermocellum, which is able to yield cellulose oligomers from short cellodextrins and α-d-glucose 1-phosphate (Glc-1-P) as substrates. Remarkably, its broad specificity towards donors and acceptors allows the generation of highly diverse cellulose-based structures to produce novel materials. However, to fully exploit this CDP broad specificity, a detailed understanding of the molecular recognition of substrates by this enzyme in solution is needed. Herein, we provide a detailed investigation of the molecular recognition of ligands by CDP in solution by saturation transfer difference (STD) NMR spectroscopy, tr-NOESY and protein-ligand docking. Our results, discussed in the context of previous reaction kinetics data in the literature, allow a better understanding of the structural basis of the broad binding specificity of this biotechnologically relevant enzyme.

ERK1/2 inhibitors have attracted special attention concerning the ability of circumventing cases of innate or log-term acquired resistance to RAF and MEK kinase inhibitors. Based on the 4-aminoquinazoline pharmacophore of kinases, herein we describe the synthesis of 4-aminoquinazoline derivatives bearing a 1,2,3-triazole stable core to bridge different aromatic and heterocyclic rings using copper-catalysed azide-alkyne cycloaddition reaction (CuAAC) as a Click Chemistry strategy. The initial screening of twelve derivatives in tumoral cells (CAL-27, HN13, HGC-27, and BT-20) revealed that the most active in BT-20 cells (25a, IC50 24.6 μM and a SI of 3.25) contains a more polar side chain (sulfone). Furthermore, compound 25a promoted a significant release of lactate dehydrogenase (LDH), suggesting the induction of cell death by necrosis. In addition, this compound induced G0/G1 stalling in BT-20 cells, which was accompanied by a decrease in the S phase. Western blot analysis of the levels of p-STAT3, p-ERK, PARP, p53 and cleaved caspase-3 revealed p-ERK1/2 and p-STA3 were drastically decreased in BT-20 cells under 25a incubation, suggesting the involvement of these two kinases in the mechanisms underlying 25a-induced cell cycle arrest, besides loss of proliferation and viability of the breast cancer cell. Molecular docking simulations using the ERK-ulixertinib crystallographic complex showed compound 25a could potentially compete with ATP for binding to ERK in a slightly higher affinity than the reference ERK1/2 inhibitor. Further in silico analyses showed comparable toxicity and pharmacokinetic profiles for compound 25a in relation to ulixertinib.

Understanding the fine details of self-assembly of building blocks into complex hierarchical structures represents a major challenge en route to the design and preparation of soft matter materials with specific properties. Enzymatically-synthesised cellodextrins are known to have limited water solubility beyond DP9, a point at which they self-assemble into particles resembling the anti-parallel cellulose II crystalline packing. We have prepared and characterized a series of site-selectively fluorinated cellodextrins of different degrees of fluorination and substitution patterns by chemoenzymatic synthesis. The structural characterization of these materials at different length scales, combining advanced NMR and microscopy methods, showed that multiply 6-fluorinated cellodextrin chains assembled into particles presenting morphological and crystallinity features that are unprecedented for cellulose-like materials. In contrast, the introduction of a single fluorine atom per cellodextrin chain had a minor impact on materials structure. Our work emphasizes the strength of combining chemoenzymatic synthesis, fluorinated building blocks and advanced NMR and microscopy methods for the thorough characterization of hierarchical structures, leading to the controlled design of new biomaterials with specific properties.

The synthesis of the O-3 triazole-linked galactosyl arylsulfonamides 1–7 as potential inhibitors of Trypanosoma cruzi cell invasion is described. These target compounds were synthesized by Cu(I)-catalysed azide-alkyne cycloaddition reaction (‘click chemistry’) between different azide arylsulfonamides and the alkyne-based sugar 3-O-propynyl-βGalOMe. Inhibition assays of T. cruzi cell invasion with compounds 1–7 showed reduced values of infection index (∼20) for compounds 3 and 5, bearing the corresponding 5-methylisoxazole and 2,4-dimethoxypyrimidine groups, which also presented higher binding affinities to galectin-3 (EC50 17–18 μM) in Corning Epic label-free assays. In agreement with experimental results, the assessment of the theoretical binding of compounds 1–7 to galectin-3 by MM/PBSA method displayed higher affinities for compounds 3 (−9.7 kcal/mol) and 5 (−11.1 kcal/mol). Overall, these achievements highlight compounds 3 and 5 as potential T. cruzi cell invasion blockers by means of a galectin-3 binding-related mechanism, revealing galectin-3 as an important host target for design of novel anti-trypanosomal agents.

The multivalent effect of carbohydrates (glycoclusters) has been explored to study important biological targets and processes involving Trypanosoma cruzi (T. cruzi) infection. Likewise, CuAAC cycloaddition reactions (click chemistry) have been applied as useful strategy in the discovery of bioactive molecules. Hence, we describe the synthesis of 1,2,3-triazole-based tetravalent homoglycoclusters (1–3) and heteroglycoclusters (4 and 5) of d-galactopyranose (C-1 and C-6 positions) and sialic acid (C-2 position) to assess their potential to inhibit T. cruzi cell invasion and also its cell surface trans-sialidase (TcTS). The target compounds were synthesised in good yields (52–75 %) via click chemistry by coupling azidosugars galactopyranose and sialic acid with alkynylated pentaerythritol or tris(hydroxymethyl)-aminomethane (TRIS) scaffolds. T. cruzi cell invasion inhibition assays showed expressive low parasite infection index values (5.3–6.8) for most compounds. However, most glycoclusters proved to be weak TcTS inhibitors at 1 mM (3 (99 % at 1 mM, IC50 450 μM). Therefore, we assume that T. cruzi cell invasion blockage is not due to TcTS inhibition by itself, but rather by other mechanisms involved in this process. In addition, all glycoclusters were not cytotoxic and had significant trypanocidal activity upon parasite survival of amastigote forms.

Human T cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that infects approximately 10-20 million people worldwide and causes an aggressive neoplasia (adult T-cell leukemia/lymphoma - ATL). Therapeutic approaches for the treatment of ATL have variable effectiveness and poor prognosis, thus requiring strategies to identify novel compounds with activity on infected cells. In this sense, we initially screened a small series of 25 1,2,3-triazole derivatives to discover cell proliferation inhibitors and apoptosis inducers in HTLV-1-infected T-cell line (MT-2) for further assessment of their effect on viral tax activity through inducible-tax reporter cell line (Jurkat LTR-GFP). Eight promising compounds (02, 05, 06, 13, 15, 21, 22 and 25) with activity ≥70% were initially selected, based on a suitable cell-based assay using resazurin reduction method, and evaluated towards cell cycle, apoptosis and Tax/GFP expression analyses through flow cytometry. Compound 02 induced S phase cell cycle arrest and compounds 05, 06, 22 and 25 promoted apoptosis. Remarkably, compounds 22 and 25 also reduced GFP expression in an inducible-tax reporter cell, which suggests an effect on Tax viral protein. More importantly, compounds 02, 22 and 25 were not cytotoxic in human hepatoma cell line (Huh-7). Therefore, the discovery of 3 active and non-cytotoxic compounds against HTLV-1-infected cells can potentially contribute, as an initial promising strategy, to the development process of new drugs against ATL.

34 p.-9 fig.-1 tab.-1 graph. abst., Acetylcholinesterase (AChE) is the key enzyme targeted in Alzheimer's disease (AD) therapy, nevertheless butyrylcholinesterase (BuChE) has been drawing attention due to its role in the disease progression. Thus, we aimed to synthesize novel cholinesterases inhibitors considering structural differences in their peripheral site, exploiting a moiety replacement approach based on the potent and selective hAChE drug donepezil. Hence, two small series of N-benzylpiperidine based compounds have successfully been synthesized as novel potent and selective hBuChE inhibitors. The most promising compounds (9 and 11) were not cytotoxic and their kinetic study accounted for dual binding site mode of interaction, which is in agreement with further docking and molecular dynamics studies. Therefore, this study demonstrates how our strategy enabled the discovery of novel promising and privileged structures. Remarkably, compound 11 proved to be one of the most potent (0.17 nM) and selective (>58,000-fold) hBuChE inhibitor ever reported., This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP (grant 2012/14114-5, 2013/50788-3, 2014/04868-8), Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Consejo Superior de Investigaciones Científicas – CSIC (grant i-Link0801) and MINECO (CTQ2015-66313-R).

Peptide stapling is a strategy for constraining short peptides typically in an alpha-helical conformation. Stapling is carried out by covalently linking the side-chains of two amino acids, thereby forming a peptide macrocycle. There is an expanding repertoire of stapling techniques based on different macrocyclisation chemistries. In this tutorial review, we categorise and analyse key examples of peptide stapling in terms of their synthesis and applicability to biological systems.

Submitted by PETERSON DE SANTIS SILVA null (pssilva@eei.com.br) on 2017-07-24T21:38:51Z No. of bitstreams: 1 Dissertação Versão Final (Repostório).pdf: 1996967 bytes, checksum: d4353fea9aeab28308e59bd2a461e1a6 (MD5) Approved for entry into archive by Luiz Galeffi (luizgaleffi@gmail.com) on 2017-07-26T16:27:12Z (GMT) No. of bitstreams: 1 silva_ps_me_bauru.pdf: 1996967 bytes, checksum: d4353fea9aeab28308e59bd2a461e1a6 (MD5) Made available in DSpace on 2017-07-26T16:27:12Z (GMT). No. of bitstreams: 1 silva_ps_me_bauru.pdf: 1996967 bytes, checksum: d4353fea9aeab28308e59bd2a461e1a6 (MD5) Previous issue date: 2017-05-24 O presente estudo visa analisar e apontar a TV híbrida como oportunidade de negócios para as emissoras regionais de televisão aberta no Brasil. O advento da TV Digital e das SmartTVs, entre outras, que permitem o acesso de conteúdos broadband (sinal por IP – internet protocol), em conjunto com a tradicional transmissão broadcast (sinal por ar) apresentam uma tendência de convergência tecnológica e comportamental que une o broadcast e o broadband, a que pode-se denominar “TV híbrida”. A TV híbrida surge não apenas como uma possível convergência natural da cultura da sociedade atual, mas também como oportunidade para uma nova maneira de fazer e ver televisão. Este estudo, por meio de uma metodologia que combina a pesquisa exploratória e o modelo de reconhecimento de oportunidade, identificou a TV híbrida como uma oportunidade de negócios para emissoras regionais de televisão aberta no Brasil, e encontrou no uso da segunda tela oportunidades de negócios para mensuração da audiência, publicidade estratégica, conteúdos extras, ensino à distância (EaD) e edutretenimento, e relacionamento e fidelização da audiência. The present study aims to analyze and point out the Hybrid TV as a business opportunity for regional broadcasters in Brazil. The advent of Digital TV and SmartTVs, among others, which allow the access of broadband content (using a signal enabled by IP - internet protocol), together with the traditional broadcast transmission (signal enabled by air) present a trend of technological and behavioral convergence that unites the broadcast and the broadband, which can be called "Hybrid TV". This said Hybrid TV arises not only as a possible natural convergence of the culture in today's society, but also as an opportunity for a new way of making and watching television. This study, using a methodology that combines exploratory research and the opportunity recognition model, has identified hybrid TV as a business opportunity for regional open television broadcasters in Brazil, and found in the use of the second screen business opportunities for Audience measurement, strategic advertising, extra content, distance learning (EaD) and edutainment, but also to enhance audience relationship and loyalty.

Neglected Diseases (NDs) affect million of people, especially the poorest population around the world. Several efforts to an effective treatment have proved insufficient at the moment. In this context, triazole derivatives have shown great relevance in medicinal chemistry due to a wide range of biological activities. This review aims to describe some of the most relevant and recent research focused on 1,2,3- and 1,2,4-triazolebased molecules targeting four expressive NDs: Chagas disease, Malaria, Tuberculosis and Leishmaniasis.

The trans-sialidase of Trypanosoma cruzi (TcTS) is a surface enzyme that modifies the parasite glycocalyx covering it with sialic acid. This process is essential to adhesion and invasion mechanisms in life cycle of the protozoan in the human host, making TcTS a very attractive molecular target for drug design. Using the TcTS substrate 3'-sialyllactose as prototype, D-galactose-derived potential inhibitors of TcTS were designed using strategies of molecular modification. Ten new aryl galactosides modified at carbon-3 were synthesized employing classical carbohydrate chemistry and dibutyltin oxide method for regioselective 3-O-alkylations and evaluated against TcTS by spectrofluorimetry. The 4-methoxycarbonyl-2-nitrophenyl 3-O-carboxymethyl-β-D-galactopyranoside was the most active compound inhibiting 21% of TcTS enzymatic activity at 1 mM.

Stapling peptides for inhibiting the p53/MDM2 interaction is a promising strategy for developing anti-cancer therapeutic leads. We evaluate double-click stapled peptides formed from p53-based diazidopeptides with different staple positions and azido amino acid side-chain lengths, determining the impact of these variations on MDM2 binding and cellular activity. We also demonstrate a K24R mutation, necessary for cellular activity in hydrocarbon-stapled p53 peptides, is not required for analogous ‘double-click’ peptides. ASTAR (Agency for Sci., Tech. and Research, S’pore)

A doença de Chagas, também conhecida como tripanossomíase americana, é uma das doenças tropicais mais devastadoras e é causada pelo protozoário Trypanosoma cruzi. O parasita expressa uma enzima de superfície, Trypanosoma cruzi trans-sialidase (TcTS), responsável pela transferência de ácidos siálicos de células do hospedeiro para moléculas de -galactose terminais presentes em glicoproteínas de sua superfície. As moléculas de glicoproteína sialiladas estão envolvidas na adesão e subsequente penetração do parasita em células hospedeiras. Logo, TcTS desempenha papel fundamental no reconhecimento e na invasão de células do hospedeiro. Além disso, a ausência de trans-sialidase em seres humanos faz de TcTS um alvo potencial a ser explorado, no entanto nenhum inibidor desta enzima (em concentração nanomolar) é conhecido até o momento. Considerando a importância da unidade de galactose e da função carboxila do ácido siálico para interações no sítio activo de TcTS, focamos na síntese de derivados de galactose com ácido succínico em diferentes posições do anel de açúcar e sua avaliação biológica em TcTS. Além disso, foi proposta uma busca por novos inibidores de TcTS através de técnicas de modelagem molecular, como triagem virtual baseada no sítio ativo da enzima. -D-galactose e -Dgalactopiranosídeo de metila, disponíveis comercialmente, foram tratados com reagentes adequados para fornecer alguns intermediários com apenas uma hidroxila livre em poucas etapas. O tratamento destes compostos com anidrido succínico em piridina levou à formação dos respectivos derivados com ácido succínico em todas as posições do anel galactosídico. Após etapa de desproteção foi obtido apenas o derivado com ácido succínico na posição 4 (85), que foi testado em TcTS por ensaio fluorimétrico in vitro para avaliação de sua atividade inibitória. Adicionalmente, 85 foi testado em ensaios in vitro para avaliação de sua atividade tripanocida e citotóxica. De acordo com os ensaios biológicos, o composto 85 apresentou atividade inibitória promissora (56%) na concentração de 1,0 mM. Esse resultado preliminar foi importante para mostrar que esse tipo de derivado pode atuar como inibidor de TcTS e para orientar a síntese de novos derivados de galactose. O valor da atividade tripanocida foi inferior a 40% (0,5 mM) e não foi observada citotoxicidade na concentração de 0,5 mM. Os estudos de triagem virtual realizados neste trabalho através de simulações de \"docking\" resultaram na seleção das 50 melhores moléculas, baseada na orientação de maior pontuação, dentre 50.000 encontradas na base de dados diverset. O próximo passo envolve novos estudos para filtrar as moléculas mais promissoras para serem testadas em TcTS. Chagas\' disease, also known as American trypanosomiasis, is one of the most devastating tropical diseases and it is caused by the protozoan Trypanosoma cruzi. The parasite expresses a cell surface enzyme, Trypanosoma cruzi trans-sialidase (TcTS), responsible for the transference of sialic acids from host cells to terminal -galactose molecules present on its glycoprotein surface. The sialylated glycoprotein molecules are involved in the attachment and subsequent penetration of the parasite into host cells. As a result, TcTS plays a key role in the recognition and invasion of host cells. Moreover, the lack of trans-sialidase in humans makes TcTS a potential drug target to be explored, however no strong inhibitors (at nanomolar range) of this enzyme are known to date. Considering the importance of galactose unit and the carboxyl function in sialic acid for interactions in the active site of TcTS, we have focused on the synthesis of galactose derivatives containing succinic acid in different positions of the sugar ring and on their biological evaluation against TcTS. In addition, we have proposed the search for new TcTS inhibitors applying molecular modeling techniques, like virtual screening based on the enzyme´s active site. Commercially available ,-D-galactose and methyl--D-galactopyranoside were treated with suitable reagents to afford some intermediates with just one free hydroxyl group in few steps. Treatment of these compounds with succinic anhydride in pyridine afforded derivatives thereof with succinic acid in all galactosidic ring positions. After deprotection step it was only obtained the derivative containing succinic acid at position 4 (85), which was tested in in vitro TcTS fluorimetric assay for evaluation of its inhibitory activity. In Addition, 85 was tested in in vitro assays for assessment of their trypanocidal activity and cytotoxic. According to the biological assays, compound 85 showed promising inhibitory activity (56%) at 1.0 mM concentration. This preliminary result was important both to show that this type of derivative can act as an inhibitor of TcTS and to guide the synthesis of new derivatives of galactose. The trypanocidal activity value was lower than 40% (0.5 mM) and there was no cytotoxicity at 0.5 mM concentration. The virtual screening studies performed in this work through docking simulations resulted in the selection of the 50 top-ranked molecules, based in the highest score orientation, among 50.000 found at diverset data base. The next step involves new studies to filter the most promising molecules to be tested against TcTS.

Alzheimer’s disease is a complex neurodegenerative disorder of the central nervous system, characterized by amyloid-β deposits, τ-protein aggregation, oxidative stress and reduced levels of acetylcholine in the brain. One pharmacological approach is to restore acetylcholine level by inhibiting acetylcholinesterase (AChE) with reversible inhibitors, such as galanthamine, thus helping to improve the cognitive symptoms of the disease. In order to design new galanthamine derivatives and search for novel, potential inhibitors with improved interactions, as well as a suitable pharmacokinetic profile and low toxicity, several molecular modeling techniques were applied. These techniques included the investigation of AChE–drug complexes (1QT1 and 1ACJ Protein Data Bank codes), ligand-binding sites calculation within the active site of the enzyme, pharmacophore perception of galanthamine derivatives, virtual screening, toxicophorical analysis and estimation of pharmacokinetics properties. A total of four galanthamine derivatives having a N-alkyl-phenyl chain were designed, since the tertiary amine substituents could reach the peripheral anionic site that is not occupied by galanthamine. In addition, 12 drug-like compounds from the Ilibdiverse database were selected by virtual screening as novel, hypothetical AChE inhibitors. The toxicophorical analysis revealed that only four proposed inhibitors have chemical groups able to develop mutagenicity and chromosome damage. The remaining compounds showed only mild or none toxicophorical alerts. At least three screened compounds presented theoric parameters consistent with good oral bioavailability. The designed molecules have the potential to become new lead compounds that might guide the design of drugs with optimized pharmacodynamic and pharmacokinetic properties in order to improve the treatment of Alzheimer’s disease by creating new pharmacotherapeutic options.

Trypanosoma cruzi trans-sialidase (TcTS) plays a key role in the recognition and invasion of host cells and in enabling the parasite to escape the human immune response. To explore this potential drug target, we have synthesized a small library of substrate analogues based on 1,4-disubstituted 1,2,3-triazole derivatives of galactose modified at either the C-1 or C-6 positions. This was achieved by coupling the appropriate azido-sugars with a panel of 23 structurally diverse terminal alkynes by using the copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction, giving a library of 46 derivatives in good to excellent yield and with complete regioselectivity. The sugar triazoles showed weak inhibition towards TcTS-catalyzed hydrolysis of 2'-(4-methylumbelliferyl)-alpha-d-N-acetylneuraminic acid in vitro (

A reconstrução esofágica é uma das mais complexas cirurgias do aparelho digestivo, principalmente quando realizada por técnicas minimamente invasivas. Esse procedimento está associado a inúmeras complicações, como deiscência de anastomose, quilotórax, necrose do tubo gástrico e fistulas. Relatamos o caso de um paciente com o diagnóstico de carcinoma epidermoide no terço distal do esôfago que foi submetido à uma esofagectomia por videotoracoscopia e laparoscopia. Durante o ato operatório, houve lesão do brônquio principal esquerdo, sendo necessária a correção cirúrgica imediata da lesão. No pós-operatório, o paciente evoluiu com insuficiência respiratória aguda e grande escape aéreo pelos drenos de tórax e pela ferida operatória cervical. Foi submetido à nova intervenção cirúrgica, através da qual se observou uma grande lesão na parede membranosa da traqueia, que foi corrigida com um retalho de músculo intercostal.Esophageal reconstruction is one of the most complex types of gastrointestinal surgery, principally when it is performed using minimally invasive techniques. The procedure is associated with various complications, such as anastomotic dehiscence, chylothorax, esophageal necrosis and fistulae. We report the case of a patient diagnosed with epidermoid carcinoma in the distal third of the esophagus. The patient was submitted to esophagectomy by video-assisted thoracoscopy and laparoscopy. During the operation, the left main bronchus was injured, and this required immediate surgical correction. In the postoperative period, the patient presented with acute respiratory failure and profuse air leak through the thoracic drains and through the cervical surgical wound. The patient underwent a second surgical procedure, during which a large lesion was discovered in the membranous wall of the trachea. The lesion was corrected with an intercostal muscle pedicle flap.

Chagas, or American trypanosomiasis, remains an important public health problem in developing countries. In the last decade, trans-sialidase has become a pharmacological target for new anti-Chagas drugs. In this work, the aims were to design and find a new series of benzoic acid derivatives as trans-sialidase (TS) inhibitors and anti-trypanosomal agents. Three compounds (14, 18, and 19) sharing a para-aminobenzoic acid moiety showed more potent trypanocidal activity than the commercially available drugs nifurtimox and benznidazole in both strains: the lysis concentration of 50% of the population (LC50) was