SÃntese e avaliaÃÃo do potencial biolÃgico de novos derivados N-fenacilados do aza-biciclo pirrolidino [3,2-d] isoxazolina

AUTOR(ES)
DATA DE PUBLICAÇÃO

2005

RESUMO

Recently, our group of research had been gotten N-(benzoyl)-pyrrolidine[3,2-d]-2- isoxazolines derivatives 40, by 1,3-dipolar cycloaddition of five membered endociclic enecarbamates and enamides, with excellent biological activities. Due to this fact, we intended the obtention of the derivatives N-(fenacyl)-pyrrolidine[3,2-d]-2-isoxazolines 41, using the aza-bicycle isoxazoline as starting material. Initially, we was tried the synthesis of endociclic N-fenacyl-enamine, that should act as dipolarofile in the cycloaddition reaction, however, the only isolated product and in low yield, was N-fenacyl-pyrrol, with products of degradation, fact this, attributed to the high reactivity of the formed enamine, when compared with the respective enecarbamate. So then, we used the enecarbamate N-(benzyloxycarbonyl)- 2-pyrroline in the reactions of this work. The respective isoxazoline cycloadduct 43 (with protecting group Cbz) was obtained. This cycloaddut, after hydrogenolysis of the CBz group, supplied quantitatively the deprotected cycloaddut, which was submitted to the reaction of Nfenacylation with the respective fenacyl halides, being produced new N-(fenacyl)-aza-bicycleisoxazolines 46, 47 and 48, with the peculiarity of they will possess in nitrogen (N6) a tertiary amine function, conferring to the molecule, different chemical properties, when compared with the isoxazoline derivatives (with amide function), already gotten in the group. These derivatives 46, 47 and 48, duly had been characterized by espectromtric methods, where, 47 and 48 had been submitted to one qualitative antimicrobials screening and had shown activity against lutea Sarcina, Staphylococcus aureus, M. luteus, Bacillus subtilis, Mycobacterium tuberculosis, Mycobacterium smegmatis and against M. luteus, S. lutea and Mycobacterium tuberculosis, respectively. Later, esters 46, 47 and 48, had been submitted to the reaction with hydrazine 25% in ethanolic media, but only one, the hydrazone/acid derivative 49, was duly isolated and identified. With hydrazone/acid 49, an evaluation of the acute toxicity was become through preliminary assays in mice, showing a very high activity of this coumpoud in the PNS and, mainly, at level of CNS, where effect depressors and stimulants had been observed, predominating the stimulants ones in agreement the increase of the managed dose. Hydrazone/acid 49, could be used for future non-natural amino acid attainment, after reductive split of the isoxazoline nucleus and this, in turn, can be precursory of its respective alkyl-iminio, serving as important intermediary in the synthesis of a series of potentially bioactive pirrolidine derivatives

ASSUNTO(S)

screening microbiolÃgico substÃncias sintetizadas novos derivados â n-fenacilados do azabiciclo pirrolidino [3,2-d] isoxazolina reaÃÃes de cicloadiÃÃo 1,3- dipolar teste de toxicidade aguda (efeitos gerais) elucidaÃÃo estrutural e avaliaÃÃo biolÃgica farmacia

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