Planejamento e s?ntese de compostos ftalazoilidraz?nicos como agentes anti-TNF-?

• Ano de defesa: 2013
• Autor(a) principal: Teixeira, F?bio Barbosa
• Orientador(a): K?mmerle, Arthur Eugen
• Banca de defesa: Graebin, Cedric Stephan, Miranda, Leandro S. M.
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal Rural do Rio de Janeiro
• Programa de Pós-Graduação: Programa de P?s-Gradua??o em Qu?mica
• Departamento: Instituto de Ci?ncias Exatas
• País: Brasil
• Palavras-chave em Português: Ftalimidas; atividade anti-TNF-?; inflama??o
• Palavras-chave em Inglês: Phthalimides; anti-TNF-? activity; inflammation
• Área do conhecimento CNPq: Qu?mica
• Link de acesso: https://tede.ufrrj.br/jspui/handle/jspui/3428

Many classes of organic compounds have shown promising biological effects, and among them are the cyclic imides, compounds that have on their structure the fragment CO-N(R)-CO-, in which R is a hydrogen atom, an alkyl or an aryl group. The phthalimides,that have recognized biological activity, are compounds related to thalidomide, a molecule with structure derived from phthalimide, but also presents a glutarim?dic group, being considered the most relevant molecule that belongs to this class of compounds. The phthalimidic ring is related as an interesting biophore, constituting a subunity structure of pharmacophore character for a series of compounds with different pharmacological activities, including the anti-inflammatory, according to a mechanism of inhibition of tumor necrosis factor alpha (TNF-?), a pro-inflammatory cytokine. Due to the side effects associated to current medications anti-TNF-?, that belong exclusively to the class of biotech drugs, and the high cost of treatment, the discovery of new anti-inflammatory micromolecules that act inhibiting the production of TNF-? is important. In this context, one of the first described molecules with this activity was thalidomide, whose pharmacological action is attributed to the phthalimidic group. in this work N-hydrazil substituted phthalimides, the phthalazoylidrazides were synthesized, charatered and tested for biological activity. These compounds were synthesized from benzoic acids and corresponding aldehydes, that were transformed into methyl esters. Subsequent hydrazinolysis reaction, with hydrazine hydrate, provided the corresponding hydrazides that, after, reacted with phthalic anhydride in order to form the phthalimidic ring. This initial series was still methylated by reaction with methyl iodide in basic medium. The synthesis of phthalazoylidrazides N-methylated and non-methylated intent to analyze the effect of the presence of the methyl group on the possible biological activity of the compounds, because it is known that the methyl group exerts estereoeletr?nic effects over biomolecules that can lead to significant changes in biological effects of molecules. 22 final compounds were synthesized with yields between 58% and 96%. The pharmacological analysis showed that some methylated derivatives were able to inhibit the production of TNF-? in experiments with macrophages stimulated by LPS. The activity presented shows the biological importance of phthalimides and N-methylation in this series. Furthermore, the synthesis proposal proved adequate and practical using microwave irradiation.