Dissertações em Química Medicinal e Modelagem Molecular (Mestrado) - PPGQMMM/ICS
URI Permanente para esta coleçãohttps://repositorio.ufpa.br/handle/2011/14431
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Dissertação Acesso aberto (Open Access) Investigação teórica da síntese de mdma a partir do safrol e estudo da atividade de anfetaminas via qsar(Universidade Federal do Pará, 2018-03-28) COSTA, Miony Carolina Cardoso; MACEDO, Luiz Guilherme Machado de; http://lattes.cnpq.br/3809730482457606; https://orcid.org/ 0000-0002-8257-5662Amphetamine are drugs that stimulate the central nervous system. They cause increase of physical and psychic capacities, and they are sympathomimetic substances that have the basic chemical structure of beta phenethylamine. It is also a drug that can be produced from easily accessible reagents. Its synthesis is most often done in low cost clandestine laboratories and its consumption is a public health problem. In the present work the MDMA synthesis reaction from Safrol was investigated. This that occurs in two steps: first a halogenhydride addition, followed by a nucleophilic substitution. The thermodynamic properties of the Safrol reaction were investigated, and the NMR, UV-visible, IR spectra of the reagent, intermediate and product are shown. An high yield alternative route of synthesis is also suggested. For the electronic structure calculations, the DFT method was used with different functionals and basis sets in order to obtain results with chemical accuracy (CBS-QB3) and minimal deviation with respect to the experimental values. Finally, a study of the QSAR of 30 amphetamine derivatives and the MDMA molecule was carried out, since according to the literature it has biological activity, and a R2 (correlation coefficient square) of 0.886 and Q2 (of the cross-validation correlation coefficient) near 0.74, these two values confirm the high variability and predictability of the model.Dissertação Acesso aberto (Open Access) Planejamento de inibidores da enzima 3-deoxy-D manooctulosonato 8-fosfato Sintase (KDO8PS): um novo alvo para tratamento de infecção bacteriana(Universidade Federal do Pará, 2019-07-23) ARAÚJO, Jessica de Oliveira; SILVA, Jerônimo Lameira; http://lattes.cnpq.br/7711489635465954; https://orcid.org/0000-0001-7270-1517; LIMA, Anderson Henrique Lima e; http://lattes.cnpq.br/2589872959709848; https://orcid.org/0000-0002-8451-9912Bacteria can be distinguished in two groups through the Gram technique, where Gram positive 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 8-phosphate 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.Dissertação Acesso aberto (Open Access) Planejamento e síntese de novos derivados da associação molecular benzonidazol e metronidazol(Universidade Federal do Pará, 2018-09-25) COSTA, Fernanda Menezes; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/0000-0003-4072-7573Chagas disease is caused by protozoan Trypanosoma cruzi, still has high contagion rates in present days, especially in the Amazon region. After contamination, the infective cycle of Chagas disease has two phases: acute and chronic. The acute phase is, in majority of cases, asymptomatic and efficiently treated, however the chronic phase is symptomatic and has proved not efficient treatment. There is only one available medicine, the generic benznidazole or Rochagan®, distributed free of charge, and it must be administered for 60 days, approximately. However, benznidazole has low efficiency, being effective only on acute phase (asymptomatic). Besides that, the medicine use to cause severe side effects in clinical patients, producing in many times the treatment rejection. The molecular modeling has become an important tool on new drugs design, using the DFT method to evaluate of the new potent molecules. Thereby, the main goal of this work was to design new derivatives by 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 through molecular association and chain increase. From the theoretical study, this molecular association between benznidazole and metronidazole molecules can develop a less toxic new derivative of than benznidazole. Both designed derivatives were synthesized on laboratory using the classics methodologies of electrophilic and nucleophilic substitution, esterification, alkylation and nitration. According to their HOMO, LUMO, ionization potential, and electron affinity values, it was possible observe that the nibendazole 1 and nibendazole 2 compounds have a lower redox capacity when compared to benznidazole. 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-withdrawing capacity as well as benzyl group has high electron-donating capacity. These properties change in accordance to methyl moiety or nitrogen positions on azolic ring of derivatives compounds.Dissertação Acesso aberto (Open Access) Planejamento, Síntese, Avaliação das Propriedades Teóricas de orto-Regioisômeros Substituídos do Paracetamol(Universidade Federal do Pará, 2018-12-28) MORAIS, Roberto Barbosa de; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/0000-0003-4072-7573Paracetamol 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.