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- Synthesis of Compounds Containing a 1,3-Diazo Spacer with Potential MTDL Capacity and As-sessment of their Activity on Biological TargetsPublication . Braga, Bernardo Miguel Mendonça de Medeiros; Ferreira, LuísaAlzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder for which the prevailing "One target, one drug" approach has shown limited efficacy. The Multi-Target-Directed-Ligand (MTDL) drug design strategy offers a promising alternative by devel-oping compounds capable of single-handedly modulating multiple pathological pathways. This work explores the synthesis and preliminary biological evaluation of a library of novel compounds designed as potential MTDLs for AD. The main strategy focused on the hydrolysis of bicyclic amidines (DBN and DBU), as well as the monocyclic amidine 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine (DmTHP) to generate a structure with a 1,3-diazo spacer. Using tacrine as the model-drug, these spacers were functionalized with aromatic moieties (e.g., anthracene, acridine, pyridine) through a one-pot reductive amination protocol to yield secondary amines, with an amide group on the second terminal of the 1,3-diazo spacer, which underwent further N-alkylation with propargyl or benzyl bromide to obtain tertiary amines. Building on previous work in our research group, the hydrolysis of DmTHP was monitored by 1HNMR spectroscopy to reveal optimal conditions for ring opening. The structures of all synthesized compounds (BB1-BB9 and their alkylated derivatives) were confirmed by spectroscopic techniques (FTIR, NMR, MS). The synthetic efficiency varied considerably, with the initial reductive amination steps generally returning high yields (47-96%), while the alkylation reactions proved challenging, resulting in low to moderate yields (10-61%) and often failing to reach completion. Preliminary enzymatic assays based on Ellman's method were conducted to assess the inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). De-spite the promising results when testing with BuChE, the assays with AChE reveal that further optimization is necessary for accurate kinetic analysis. Overall, this study successfully estab-lishes a synthetic pathway for obtaining novel 1,3-diazo spacer compounds and provides a foundation for the future development of MTDLs targeting cholinergic dysfunction and other pathologies in Alzheimer's disease.
- ACV de membranas catalíticas porosas aplicadas a processos avançados de biorrefinariaPublication . Botelho, José Marques; Lapa, Nuno; Matos, InêsEste trabalho analisa a sustentabilidade ambiental do uso de carvão ativado com origem em biomassa lenhocelulósica, incorporado em membranas poliméricas, como catalisador heterogéneo em processos típicos de biorrefinaria, nomeadamente na reação de esterificação do ácido levulínico com etanol, com o objetivo de produzir Levulinato de Etilo (LE). O LE é um aditivo renovável para biocombustíveis. A motivação prende-se com a procura de alternativas mais sustentáveis e reutilizáveis aos catalisadores convencionais, como o ácido sulfúrico, para uso em biorrefinarias. A metodologia baseia-se na Avaliação do Ciclo de Vida (ACV), realizada com o software openLCA (v2.1.0) e a base de dados ecoinvent 3.9.1, com aplicação do método ReCiPe (H) 2016, ao nível de indicadores intermédios, para três categorias ambientais: Potencial de Aquecimento Global (PAG), Potencial de Eutrofização de Água Doce (PEA) e Potencial de Acidificação do Solo (PAS). A análise abrange o uso de dois catalisadores: uso de ácido sulfúrico (convencional), carvão ativado em dispersão ou suportado em membrana de álcool polivinílico (PVA). Os resultados mostram que o uso de carvão ativado suportado em membranas de PVA, especialmente quando reutilizado em ciclos sucessivos, reduz significativamente os impactes ambientais comparativa-mente ao cenário convencional. O cenário mais favorável (membrana reutilizada por cinco ciclos) demonstrou reduções superiores a 50% em todas as categorias de impacte analisadas. Conclui-se que o uso de membranas catalíticas com carvão ativado de biomassa local é uma estratégia viável e mais sustentável, com potencial para fortalecer a economia circular e reduzir o impacte ambiental de catalisadores e de biocombustíveis. O estudo sugere aprofundar a avaliação económica e explorar o scale-up desta tecnologia.
- Study of ionic effects in polyelectrolytes by multinuclear NMRPublication . Cardoso, Isabel Filomena de Carvalho Ramos; Martinho, Ricardo; Corvo, MartaPolieletrólitos são polímeros compostos por unidades repetidas de um tipo de elétrodo. Eles são aplicáveis na área de biomedicina na entrega de fármacos, na indústria cosmética, em engenharia de tecidos, e no fabrico de materiais devido ao comportamento eletrostático. São classificados como poliácidos e polibásicos. Este trabalho foca nos polieletrólitos polibásicos, compostos por grupos que contêm carga positiva nos monómeros. A natureza policatiónica dos polieletrólitos como as polietilenoimina (PEI) e polialimina (PAH), torna estes compostos eficientes para sistemas de entrega de fármacos e entrega de genes. O comportamento electrostático desses polieletrólitos é dependente do pH, influenciando o estado de protonação. Assim, este trabalho tem como objetivo investigar o potencial electrostático dessas polieletrólitos a partir da titulação potenciométrica, e da ressonância magnética nuclear (RMN), complementando com a dinâmica molecular. Este trabalho estudou a teoria de Manning na condensação dos contra iões entre as poliaminas com diferente contra iões, os contra iões foram selecionados a partir da série de Hof- meister. Além disso, foi analisado um caso de aplicação da capacidade do PEI para regulação de pH – a adsorção e libertação do azul metileno (MB) como fármaco modelo usando um criogel de PEI. Este estudo demonstrou que as curvas de titulações de PEI linear e PAH são diferentes, a PEI linear apresenta elevada densidade de carga e capacidade tampão útil para entrega de fármacos. A PAH apresenta também elevada densidade de carga, mas baixa capacidade tam- pão sendo assim menos promissora para aplicações biomédicas. Com os resultados obtidos em RMN de alto campo e por Time Domain NMR (TD-NMR) concluiu-se que PEI linear tende a agregar-se quando os grupos aminas estão protonados, mas PAH mostrou um comportamento diferente agregando-se quando os grupos aminas estão desprotonados, e este resultado é sustentado pela dinâmica molecular. A RMN multinuclear dos contra iões revelou interações intermoleculares dos iões halogenados com PEI linear e PAH. A dinâmica molecular confirmou condensação dos contra iões entre os iões halogenados, apesar que nem todos parâmetros experimentais foram reprodutivos. Por fim, o criogel de PEI mostrou eficiência na regulação de pH para adsorção de azul metileno, mas fraca libertação.
- PHOTOCATALYTIC METHODS FOR THE SYNTHESIS OF INDOLE DERIVATIVESPublication . Vilela, Gonçalo Higino; Vale, João; Branco, PaulaThe indole moiety is one of the most extensively studied heterocycles in organic chem- istry due to its prevalence in natural products, pharmaceuticals, agrochemicals, and a wide range of bioactive compounds. Despite this, traditional methods for the synthesis of indoles, such as the Fischer, Bartoli, and Leimgruber-Batcho reactions as well as many other estab- lished approaches, suffer from major drawbacks, including the need for harsh conditions, the use of expensive, toxic, and difficult-to-handle reagents, and limited functional group toler- ance. Therefore, the development of more sustainable, efficient, and versatile methodologies for the preparation of these scaffolds remains a key objective in synthetic chemistry. In this work, a novel visible light-mediated strategy was developed for the synthesis of 1,2,3,4-tetrahydrocyclopent[b]indoles starting from furfural, a widely available and easily pro- duced industrial chemical. Furfural can be directly obtained from biomass waste, and its con- version into value-added products has been extensively investigated by our research group. The synthetic route begins with the conversion of furfural into trans-4,5-diamino-cyclo- pent-2-enones (DCPs) via a Nazarov-type electrocyclization. Subsequent catalytic hydrogena- tion and β-amine elimination afford α-enaminones, which serve as key intermediates for the photochemical step. Unpon blue light irradiation and in the presence of 3DPAFIPN photocata- lyst, these α-enaminones undergo oxidative photocyclization, yielding the indole derivatives. The scope study shows consistent isolated yields around 38–53% across diverse substit- uents, while strong electron-withdrawing groups (–CF₃, –CN) give lower yields (20% and 27%) with incomplete conversion. Enaminones with secondary amines did not work under these conditions and attempts to use protection or alkylation to broaden the scope were also unsuc- cessful. Optimization studies evaluated the impact of photocatalyst type, solvent, atmospheric conditions, reaction concentration, and the presence of different additives on reaction perfor- mance. The reaction required molecular oxygen for efficient conversion, as yields decreased significantly under inert atmospheres. Preliminary mechanistic studies combined cyclic voltammetry data with literature elec- tronic potentials, pointing toward energy transfer (EnT) as the most likely pathway.
- Development of fluorescent receptors to detect and bind bacterial peptidoglycanPublication . Petriccione, Giovanna Due Mesquita; Filipe, SérgioStaphylococcus aureus is a pathogenic Gram-positive bacterium responsible for a wide range of infections, from mild skin infections to more severe conditions such as pneumonia and endocarditis. Due to its ability to develop resistance to multiple antibiotics, S. aureus poses a significant medical challenge, particularly in hospital settings. Peptidoglycan (PGN), a key component of its cell wall, plays a critical role in its survival and pathogenicity, making it a promising target for new therapeutic and diagnostic approaches. This thesis focused on the development of fluorescent receptors that through the pres- ence of LysM domains can detect and bind to the PGN macromolecule at the surface of S. aureus bacteria. With the goal of optimizing these interactions for diagnostic and biomedical applications, this study explored how variations in the number, in the particular sequence and identity of the domain, and the spacing between different LysM domains may influence the binding efficiency to PGN. The receptors were produced carrying His-tags to facilitate their purification via Immobilized Metal Affinity Chromatography (IMAC). Mutant strains of S. aureus with distinct envelope composition were further used to eval- uate the binding capacity of the receptors to the PGN accessible at the bacterial cell envelope. The results suggest that variations in LysM domain configurations significantly affect PGN recognition, highlighting the potential of these proteins in novel bacterial diagnostic strategies and the development of antimicrobial agents.
- Aumento do Rendimento da Extração de Óleo de ColzaPublication . Festas, António Saldanha Sardinha Tavares; Carvalho, Renato; Eusébio, MárioA presente dissertação teve como principal objetivo o estudo do processo de preparação e extração de óleo em meio industrial por forma a determinar e analisar quais as soluções que conduzem a um aumento do rendimento num processo de extração de óleo de colza na Iberol. Da pesquisa bibliográfica realizada e do know-how existente na Iberol concluiu-se que o aumento do rendimento da extração de óleo de colza seria possível através da instalação de uma ou duas prensas, bem como, através da otimização das condições do processo. Da pesquisa bibliográfica realizada resultou uma árvore de decisões, a partir da qual se elaboraram os vários cenários que se adequam ao caso prático da Iberol. Conjuntamente ao estudo do processo, realizou-se uma pesquisa de fornecedores de prensas com o objetivo de decidir qual o fornecedor e modelo a adquirir, bem como, quais os layouts e necessidades técnicas para a alteração tecnológica à unidade de preparação e extração. Foi então realizada uma análise económica dos quatro layouts possíveis com base nos custos, proveitos e investimento requerido em cada um dos casos. Posteriormente, realizou-se uma hierarquização dos mesmos com base em critérios económicos e em critérios técnicos, por forma a decidir qual o melhor layout. O estudo técnico-económico para o layout selecionado prevê um VAL (valor atual líquido) de 5,3 milhões de euros, uma TIR (taxa interna de rentabilidade) de 94% e um payback de aproximadamente 14 meses. De referir que, esta melhoria tecnológica está associada a um aumento do rendimento de 95,66% para 97,63%.
- Defining package plant moving bed biofilm reactor for nitrogen and phosphorus removalPublication . Parsotamo, Anita; Soares, Ana; Reis, Maria AscensãoThis project investigated existing package plants for decentralized domestic wastewater treatment, focusing on the state-of-the-art technologies and proposing a new design using moving bed biofilm reactors (MBBR) for total nitrogen removal and absorbents for phosphorus removal. A detailed design and mass balance were performed for both an existing package plant and a newly designed MBBR- based plant. Additionally, lab-scale experiments were conducted to evaluate phosphorus removal using an aluminum-based granular adsorbent and to establish the correlation between carbon-to-nitrogen (C/N) ratios and denitrification efficiency in MBBR systems. Phosphorus removal experiments showed an adsorption capacity of 4.3 mg P/g of adsorbent, following a Langmuir isotherm model, with a regen- eration efficiency of 57.3% using 4% NaOH. Denitrification tests using MBBR technology at a C/N ratio of 14 demonstrated a maximum removal rate of 12.67 mg NO₃/h under low dissolved oxygen levels. Results indicated that nitrate removal increased with lower C/N ratios and higher recirculation ratios, while the denitrification rate per gram of volatile suspended solids (VSS) decreased as the C/N ratio increased. The existing package plant, designed for the removal of TSS, COD, and ammonia, had a working volume of 3.82 m³ and a hydraulic retention time (HRT) of 72 hours. Hydrolysis in the pri- mary sedimentation tank (PST) increased soluble COD, ammonia, and phosphorus levels before biolog- ical treatment, which achieved 96% BOD, 90% COD, and 97% ammonia removal. Denitrification oc- curred in the final sedimentation tank (FST) with 25% efficiency, alongside a 43% removal of TSS. The new MBBR design incorporated pre-denitrification, with a denitrification tank positioned after the PST and before BOD/COD removal. This setup had an HRT of 4 hours and a recirculation ratio of 600%, achieving a C/N ratio of 13.
- Development of Screen-Printed Electrocatalysts for a Green Hydrogen EconomyPublication . Silva, Marta Sofia Nunes da; Ribeiro, Rui; Cordas, CristinaThe transition from fossil fuels to cleaner and sustainable sources is urgent due to climate change and finite resources. Hydrogen (H2) offers a versatile energy carrier that can support this transition. Green H2 is obtained through water electrolysis which relies on noble metal catalysts valued for their high activity but limited by scarcity and high cost. To replace them, research has focused on developing efficient low-cost non-noble metal-based electrocatalysts, from which nickel (Ni) and cobalt (Co) stand out as highly catalytic active. This work investigates the performance of carbon-based catalysts incorporating Ni and Co prepared through screen-printing, a simple and cost-effective fabrication method. Metal con- taining - Ni, Co, and Ni:Co/1:1 were prepared as well as a metal-free reference. To assess their performance, the redox behavior of metals must be characterized through electrochemical techniques. Linear sweep voltammetry showed the Ni:Co/1:1 layer achieved the highest hy- drogen evolution reaction performance, reaching -3.2 mA and producing visible hydrogen bubbles, while also exhibiting effective oxygen evolution reaction activity. Scanning electron microscopy and elemental mapping confirmed uniform carbon distribution. The metal disper- sion was less homogeneous, highlighting opportunities for further optimization. In sum, this study explores screen-printing as a method to produce high-performance electrodes for water electrolysis.
- Saliva Biofluid Screening of Potential Stress Biomarkers for Health DiagnosisPublication . Vieira, Rute Alexandra Abrantes; Nunes, Maria João; Cordas, CristinaNowadays, biomarkers are widely used for diagnosis, allowing information about human health and well-being. In addition to blood, other fluids have been the subject of interest, such as sweat, tears and saliva, as they are less invasive and more practical methods. For biochemical evaluations, saliva represents an attractive medium, but still relatively little explored, and therefore time should be devoted to its study. The main objective of the project is to identify potential non-protein salivary biomarkers useful for the assessment of human health, more specifically with regard to stress monitoring. A set of 11 small molecules (acetylcholine, dopamine, epinephrine, norepinephrine, glutamic acid, serotonin, tyrosine, tryptophan, ascorbic acid, lactic acid, and cortisol) was selected for their potential as relevant biomarkers for identifying stress in humans. These molecules were analysed using analytical chromatographic tools, specifically the liquid chromatography coupled with TANDEM mass spectrometry. To determine which of these molecules could be identified in saliva, samples were collected from 24 healthy individuals, comprising 12 men and 12 women under the age of 30. The samples were analysed using LC-MS/MS, successfully identifying and quantifying acetylcholine, dopamine, epinephrine, norepinephrine, glutamic acid, tyrosine, tryptophan, ascorbic acid, and cortisol in saliva. Lactic acid could not be quantified due to sampling limitations. Electrochemical analysis of the saliva samples was also performed using screen-printed elec- trodes (SPEs) and the techniques of cyclic voltammetry (CV) and differential pulse voltammetry (DPV), allowing the identification of three regions where the biomarkers under study could be detected. The pH of the samples was also measured.
- Novel regeneration approaches of saturated porous carbons based on Advanced Oxidation ProcessesPublication . Bandinha, Guilherme Afonso; Ania, Maria Concepcion; Bernardo, MariaWastewater pollution has long been an issue in society, receiving increasing attention in recent years. Activated carbon (AC) has been widely used in wastewater treatment plants (WWTPs); however, its progressive saturation requires its replacement or regeneration. The regeneration of activated carbons is considered a suitable solution, both from an economic and environmental point of view, as it reduces waste production and contributes to in-line material recycling. Nevertheless, current regeneration technologies are energy-intensive and environ- mentally demanding, which has motivated research initiatives on the development of alterna- tive technologies. This study investigates the feasibility of a Fenton-like process for regenerating AC satu- rated with emerging pollutants such as methylparaben (MP) and butylparaben (BP). The ap- proach is based on the generation of radical species in the presence of hydrogen peroxide ca- pable of degrading the pollutant retained inside the porosity of the activated carbon. The regeneration assays were only conducted on a commercial activated carbon widely used in water treatment. Two saturation levels (10% and 100%) were explored, and two con- centrations (30 and 300 ppm) of the radical-producing agent. The regeneration extent of the AC was evaluated in terms of the recovery of the porosity (specific surface area, pore vol- umes), evaluated by N2 and CO2 gas adsorption. In all conditions, more than 97% of the pol- lutant was degraded from the AC. For the AC 10% saturated and exposed to 300 ppm of H2O2, about 98% of the specific surface area (SBET), ~99% of the total pore volume (VTotal pores) and ~86% of the micropore volume (Wo) were recovered. In contrast, a lower regeneration was obtained for the AC saturated at 100% and regenerated by exposure to 300 ppm of H2O2; the recoveries were ~59%, ~64% and ~66% of SBET, VTotal.pores and Wo, respectively. As a conclusion, this study demonstrates the efficiency of the applied advanced oxidation process (AOP) in regenerating the AC and degrading the target pollutant.