Estudo da relação quantitativa estrutura química-atividade biológica de compostos análogos aos nostoclídeos e síntese de novos γ-alquilidenobutenolídeos

• Ano de defesa: 2009
• Autor(a) principal: Pinheiro, Patrícia Fontes
• Orientador(a): Barbosa, Luiz Claudio de Almeida
• Banca de defesa: Fernandes, Sergio Antônio , Gil, Laurent Frederic , Conceição, Gelson José Andrade da
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Viçosa
• Programa de Pós-Graduação: Doutorado em Agroquímica
• Departamento: Agroquímica analítica; Agroquímica inorgânica e Físico-química; Agroquímica orgânica
• País: BR
• Palavras-chave em Português: Nostoclídeos; QSAR; γ-alquilidenobutenolídeos; Acoplamento de Neguishi; 3,4-dihaloarilidenofuran-2(5H)-onas
• Palavras-chave em Inglês: Nostoclides; QSAR; γ-alkylidenebutenolides; coupling Neguishi; 3,4-dihaloarylidenefuran-2(5H)-one
• Área do conhecimento CNPq: CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA
• Link de acesso: http://locus.ufv.br/handle/123456789/207

Nostoclides are natural substances isolated from blue-green seaweed, Nostoc sp., found in a lichen called Peltigera canina. They belong to the class of compounds known as γ-alkylidenebutenolides. Nostoclides have been used as model compounds aimed the discovery of new herbicides. Compounds 3-benzyl-5-arylidenefuran-2-(5H)-ones, analogues to nostoclides devoid of the isopropyl group were synthesized and phytotoxicity of these compounds was evaluated in vitro for their ability to interfere in electron transport directed by light, water to the non-biological oxidant potassium ferricyanide. For this experiment were used chloroplasts isolated from spinach (Spinacia oleracea). In this study, we look for an understanding of the different parameters involved in the correlation between chemical structure of different analogues nostoclides to those described in the literature and biological activity (ability of analogues to interfere with electron transport in chloroplasts isolated from spinach) of these compounds. For this purpose, we used the software CODESSA (COmprehensive DEscriptors for Structural and Statistical Analysis). We developed two mathematical models, in both models, the descriptor of greater significance was selected 'Image of the Onasager-Kirkwood solvation energy' (SEOK), which relates indirectly to phytotoxicity with the polarity of the molecules. In the present investigation, compounds analogues to nostoclides containing the isopropyl group in position 4 of the lactone ring were synthesized in order to assess the impact of this in the biological activity. For the synthesis of these compounds, compound 3,4-dibromofuran-2(5H)-one was used as starting material. This compound in the presence of isopropyl magnesium bromide, copper iodide and chloride trimethylsilane, led to the synthesis of compound 3-bromo-4-isopropylfuran-2(5H)-one, with 48% yield. The reaction conditions for the synthesis of this compound were optimized. Yields were calculated by the Internal Standard Method using gas chromatography. The compound 3-benzyl-4-isopropylfuran-2(5H)-one, reagent used in the synthesis of analogues to nostoclides, was synthesized from the lactone 3-bromo-4-isopropylfuran-2 (5H)-one by Negishi coupling, using Pd(PPh)4 in DMF:THF/1:1, this compound was obtained with 36% yield. Subsequently, the substance 3-benzyl-4-isopropylfuran-2 (5H)-one was subjected to alkylidenation reactions with differently substituted aromatic aldehydes. Reactions were performed in the presence of diisopropylethylamine (DIPEA) and trifluoromethanesulfonate of tert-butyldimethylsilile (TBDMSOTf), at room temperature. The aldol intermediate obtained were treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under reflux conditions, which resulted in 5 analogues nostoclides substances, with yields ranging from 22-86%. New γ-alkylidenebutenolides belonging to the class of 3,4-dihalo-5-arylidenefuran-2(5H)-ones were prepared from the lactones 3,4-dihalofuran-2(5H)-ones and different aromatic aldehydes by alkylidenation reaction already mentioned. Compounds analogues to nostoclides as 3,4-dihalo-5-arylidenefuran-2(5H)-ones and several lactones precursors were evaluated in vitro for their ability to inhibit the growth of three species of bacteria, E. coli, S. aureus and B. cereus, testing by disk-diffusion. Analogues to nostoclides tested showed no inhibition to none of the bacteria tested. The compounds belonging to the class of 3,4-dihalo-5-arylidenefuran-2 (5H)-ones and lactones 3,4-dibromofuran-2(5H)-one and 3,4-dichlorofuran-2(5H)-one showed inhibition against the different bacteria and they are considered potential antimicrobial agents.