Síntese e avaliação da atividade antibiofilme bacteriano e fitotóxica de γ -alquilideno-γ γ -lactonas análogas aos rubrolídeos e de seus derivados γ -hidroxi-γγ -lactamas, γ -alquilideo-γ γ -lactamas e piridazin-3(2H)-onas

• Autor(a) principal: Pereira, Ulisses Alves
• Data de Publicação: 2014
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: LOCUS Repositório Institucional da UFV
• Texto Completo: http://locus.ufv.br/handle/123456789/228
• topic: Rubrolídeos; Lactama; Piridazinona; Rubrolídeos; Lactam; Pyridazinone; CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA

γ-alkylidenebutenolides are present on the structure of a variety of natural products that bear different biological activities like fungicide, bactericide, anti- inflammatory, cytotoxic and regulation of seed germination. The same is true for γ-hydroxy-γ-lactams and γ-alkylidene-γ-lactams that are present in different natural product scaffold. The pyridazin-3(2H)-ones show a range of biological activities in agrochemical and pharmaceutical fields. In the present work a series of γ-alkylidenebutenolides analogues to rubrolides were synthesized and converted into their corresponding γ-hydroxy-γ-lactams, γ-alkylidene-γ-lactams and pyridazin-3(2H)-ones. In the synthetic route chosen, the mucobromic acid, used as a starting material, was reduced to 3,4-dibromofuran-2(5H)-one that in a later stage reacted with different arylboronic acids by Suzuki cross-coupling to form four 4-aryl-3-bromofuran-2(5H)-ones. The alkylidene reaction between these compounds and aromatic aldehydes resulted in seventeen γ- alkylidenebutenolides analogues to rubrolides. Seven of these compounds were converted through a lactamization with isobutylamine into their corresponding γ- hydroxy-γ-lactams that were posteriorly dehydrated leading to (Z) and (E)-γ- alkylidene-γ-lactams. The others ten analogues to rubrolides were converted into their corresponding pyridazin-3(2H)-ones by reaction with hydrazine. All the compounds prepared were fully characterized by IR, NMR ( 1 H and 13 C), COSY and HETCOR bidimensional experiments, and NOE difference spectroscopy experiments when necessary. The γ-alkylidene-γ-lactones, γ-hydroxy-γ-lactams and γ-alkylidene-γ-lactams were evaluated against Enterecoccus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mutans and Pseudomonas aeruginosa biofilm formation. The results showed that these compounds are more active against E. faecalis, S. epidermidis and P. xviaeruginosa biofilm formation and in some cases they can inhibit by 50% the biofilm formation of P. aeruginosa at 0.6 μg/mL and 0.7 μg/mL, as for 6d and 6f, respectively. It was also observed that between these classes of compounds prepared, the γ-alkylidene-γ-lactams are the most active in most cases. All the compounds synthesized were also evaluated for their ability to inhibit the photosynthetic electron transport chain in isolated spinach (Spinacia oleracea) chloroplasts. The results of this assay showed that the γ-alkylidene-γ-lactones class is the most active and that the compounds that possess electron withdrawing groups like nitro, trifluoromethyl or fluor at the para position of benzylidene group led to a more effective inhibition of photosynthetic electron transport. The mixture of isomers 4i/4i’ that possesses the nitro group on the benzylidene moiety was the most active, inhibiting the rate of ferricyanide reduction by isolated spinach chloroplasts by 62.2% at 10 μM. On another phytotoxic assay the compounds were evaluated for their capacity to inhibit the radicle and the aerial part growth of Sorghum bicolor and Cucumis sativus seedlings. The results showed that some of these compounds are capable of influencing the growth of these seedlings at 100 ppm, besides presenting selectivity, as obtained for some γ-hydroxy-γ-lactams and pyridazin-3(2H)-ones. It occurs for the compounds 8o and 8q that inhibit the root growth of S. bicolor seedlings by 14.2% and 51.5%, respectively, but induce root growth on C. sativus seedlings. The most active compounds in this assay were submitted to the evaluation of their pre-emergency herbicide activity at 100 ppm over Ipomoea grandifolia and Brachiaria decumbens under green house conditions. This assay showed that the pyridazin-3(2H)-ones 8l, 8p and 8q were the most active compounds and that 8q was able to inhibit the root biomass of I. grandifolia by 76.0%, enhancing the use of this class of compounds in the search for new herbicides.