Planejamento, síntese e avaliação farmacológica de novos protótipos de fármacos vasorelaxantes

• Ano de defesa: 2012
• Autor(a) principal: Pazini, Francine
• Orientador(a): Lião, Luciano Morais
• Banca de defesa: Barreiro, Eliezer de Jesus, Pinto, Angelo da Cunha, Ghedini, Paulo César, Oliveira, Cecília Maria Alves de, Queiroz Junior, Luiz Henrique Keng
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Goiás
• Programa de Pós-Graduação: Programa de Pós-graduação em Química (IQ)
• Departamento: Instituto de Química - IQ (RG)
• País: Brasil
• Palavras-chave em Português: Pirazóis; Ressonância magnética nuclear; Anéis heterocíclicos; Tetrazóis
• Palavras-chave em Inglês: Pyrazoles; Tetrazoles; Nuclear magnetic resonance; Heterocycles
• Área do conhecimento CNPq: QUIMICA ORGANICA::FOTOQUIMICA ORGANICA
• Link de acesso: http://repositorio.bc.ufg.br/tede/handle/tede/4350

Cardiovascular diseases are the leading cause of death worldwide, so the search for cardiotonic drugs more effective, safer and with lower side effects compared to currently available therapy, is of fundamental importance. Thus, we used in our design the phosphodiesterase 3 inhibitors, milrinone (13) and cilostazol (4), which show positive inotropic activity, relaxation effect and vasodilators. The new heterocyclic compounds (20a-20o) were originally designed by applying molecular hybridization strategy from these lead-compounds. The synthetic route to obtain the compounds 20a-20o resulted in overall yields ranging from 16.2 and 73.4%. During the synthesis, we used the Duff reaction conditions to formylation of N-phenylpyrazoles (1-phenyl-1H-pyrazole) (9a-o), which was an alternative synthetic methodology to classic Vilsmeier-Haack conditions. All the synthesized compounds were characterized by infrared and NMR spectroscopy combining the 1H, 13C, HSQC and HMBC correlation spectra. The compounds 20c, 20d, 20e, 20f and 20g, were evaluated for their relaxation profile of vascular smooth muscle. From this preliminary test, the 20d compound was selected to be further evaluated in pharmacological models, as provided better relaxation among this series of compounds in order to investigate the action mechanism. In these assays, 20d compound showed a relaxing activity in isolated arteries, potentiate by the presence of endothelium, with the participation of routes GCs/GMPc and AC/AMPc and where the flows of K+ and Ca2+through the membrane and the uptake of Ca2+ by the sarcoplasmic reticulum are important. Given the promising pharmacological profile of 20d compound, it was subjected to safety testing in preclinical in vitro model of the neutral red incorporation by cultures of 3T3 cells and acute oral toxicity tests. According to the International Organization for Economic Cooperation and Development (OECD) 423, the 20d compound was classified in 4 class, which shows that the compound was tolerated at a dose of 2000mg/kg orally. At the end of this work, we conclude that the design strategy employed has been validated, as the 20d compound showed a similar pharmacological profile to lead-compounds milrinone (13) and cilostazol (4). The pharmacological evaluation of all synthesized compounds in this work, will serve as a guide to establish the structure activity relationship of the series, and in turn, lead future changes on the chemical structures of the compounds for the activity cardiotonic optimization.