Master of Science / Department of Chemistry / Mark Hollingsworth / The crystal structures of the inclusion compounds 1,6-diisocyanohexane/urea and 1,6-dicyanohexane/urea were refined at several temperatures from X-ray data. These urea inclusion compounds are commensurate structures with host:guest ratios of 6:1. In contrast with the ordinary helical topology of the urea host, these structures have stacked loop topologies of the host hydrogen bonds and crystallize in space group P21/n. At room temperature, both structures are distorted along [001] from hexagonal metric symmetry. As in earlier studies of 1-chloro-6-cyanohexane/urea, cooling 1,6-diisocyanohexane/urea gives rise to an exothermic phase transition (Hº = -856 cal mol 1, Sº = -5 cal mol-1 K-1) at 175 K that results in the cooperative translation of guest molecules by 5.5 Å along the channel axis. In the low temperature form, 1,6-diisocyanohexane/urea is distorted along [100], much like X(CH2)6Y, where X, Y = Br, Cl. Although the crystal structure of 1,6-dicyanohexane/urea is essentially isomorphous with that of the high temperature form of 1,6-diisocyanohexane/urea, it does not undergo an equivalent phase transition at low temperatures. Both of these systems exhibit dynamic disorder between two gauche conformers of the guest, which have mean planes of the alkyl chains lying within 1º of [100] (major conformer) and approximately 14º from [001] (minor conformer). The temperature dependence of site occupancy factors for the disordered sites yielded enthalpy differences between major and minor sites in 1,6-diisocyanohexane/urea and 1,6-dicyanohexane/urea of 216 and 127 cal mol 1, respectively. Since the low temperature form of 1,6-diisocyanohexane/urea is distorted along [100], this is favored at low temperatures by an increased concentration of the major conformer, which predominates in 1,6-dibromohexane/urea and congeners. In 1,6-diisocyanohexane/urea, the phase transition to the low temperature form occurs at a threshold concentration for the major conformer of 67%. With its shallower temperature dependence, 1,6-dicyanohexane/urea should not reach this threshold population until approximately 92 K, at which temperature the system cannot overcome the barrier for cooperative translation of guests along the channel axis.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-10-25T16:53:43Z No. of bitstreams: 1 vanessacristinaestevambittencourt.pdf: 4643233 bytes, checksum: f4c1b1d214125b1ed5e1cc2be806cd22 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-11-09T13:53:22Z (GMT) No. of bitstreams: 1 vanessacristinaestevambittencourt.pdf: 4643233 bytes, checksum: f4c1b1d214125b1ed5e1cc2be806cd22 (MD5) / Made available in DSpace on 2017-11-09T13:53:22Z (GMT). No. of bitstreams: 1 vanessacristinaestevambittencourt.pdf: 4643233 bytes, checksum: f4c1b1d214125b1ed5e1cc2be806cd22 (MD5) Previous issue date: 2016-09-29 / Neste trabalho foram preparados, caracterizados e avaliadas as atividades larvicida e citotóxica dos compostos de inclusão formados entre as benzoilfeniluréias (novaluron - NOV e diflubenzuron - DIF) e avermectina (abamectina - ABA) com β-ciclodextrina (βCD). A presença de alterações nos espectros na região do infravermelho e nos perfis térmicos dos compostos de inclusão em relação aos seus precursores e misturas mecânicas sugeriram a ocorrência de interação entre esses compostos e a βCD. Os dados termodinâmicos obtidos por titulação calorimétrica isotérmica permitiram verificar a formação de compostos de inclusão com estequiometria 1:1, sendo os processos espontâneos e com valores bem distintos para as constantes de formação. As análises dos espectros de ressonância magnética nuclear das amostras sugerem que a inclusão ocorre através do grupo 1,1,2-trifluoro-2-trifluoro-metóxietóxi, do grupo fenila ou do anel benzofurânico para compostos de inclusão com NOV, DIF e ABA, respectivamente. Dados de espalhamento de luz dinâmico e potencial zeta demonstram que em todos os compostos de inclusão ocorrem alterações no tamanho das partículas em suspensão em relação aos precursores. Além disso, foi possível verificar através do perfil dos gráficos de solubilização que os compostos de inclusão, com exceção do NOV, apresentam maior solubilização quando comparados com as substâncias puras. Com base nas informações da caracterização em suspensão, o sólido caracteriza-se como um nanoprecipitado hidrofóbico instável com possibilidade de agregação. Com relação aos ensaios biológicos foi observado que em todas as análises os valores de dose letal a 50% das larvas de Aedes aegypti (DL50) ou porcentagem de inibição de emergência em 50% de sua população (% IE50) foram menores que 1 ppm, demonstrando a elevada ação inseticida desses compostos. A avaliação da atividade larvicida nos estádios L4 para a benzoilfenilureias e seus compostos de inclusão demonstrou-se pouco efetiva, porém sugeriu a possibilidade de maior atividade larvicida do composto de inclusão com NOV em relação ao seu precursor. Além disso, o teste de inibição de emergência para as benzoilfenilureias possibilitou confirmar o mecanismo de ação desses compostos durante o ciclo de vida do mosquito, verificar a relação direta entre dose e mortalidade, observar atraso no desenvolvimento das fases do mosquito nas amostras tratadas em relação ao controle e constatar a redução do valor de %EI50 para os compostos de inclusão. Nos experimentos nos estádios L1 e L4 para ABA e seu composto de inclusão foi verificada maior fragilidade do estádio L1 em relação ao L4 e a redução da DL50 para o composto de inclusão em todos os experimentos. Esses dados demonstram a maior atividade larvicida dos compostos de inclusão em relação às substâncias livres. Na avaliação de toxicidade através do ensaio do MTT em células de fibroblastos WI26UA4, foi confirmada que NOV e DIF e seus compostos de inclusão apresentaram baixa toxicidade, enquanto que a ABA e seu composto de inclusão apresentaram moderada toxicidade. Também foi verificado que os valores nos quais se observam elevada citotoxicidade em humanos são bem superiores aos necessários para causar a mortalidade das larvas, demonstrando a seletividade e segurança dessas nanocomposições. Desta forma, a estratégia de preparar os compostos de inclusão resultou em um aumento da atividade larvicida em todas as situações testadas, demonstrando que esta pode ser uma alternativa promissora no controle do mosquito Aedes aegypti. / In this work the inclusion compounds formed between benzoylphenylureas (novaluron - NOV and diflubenzuron - DIF) and avermectin (abamectin - ABA) with β-cyclodextrin (βCD) were prepared, characterized and evaluated their larvicide and cytotoxic activities. Changes in the infrared spectra and thermal profiles of the inclusion compounds in relation to mechanical mixtures and precursors suggested the occurrence of interaction between those compounds and the βCD. Thermodynamic data obtained by isothermal titration calorimetry allowed verifying the formation of inclusion compounds with stoichiometry 1: 1, and the spontaneous processes and distinct values for the formation constant. The analysis of the nuclear magnetic resonance spectra of the samples suggests that inclusion via 1,1,2-trifluoro-2-trifluoromethoxy- ethoxy group, the phenyl group, or benzofuran ring for inclusion compounds with NOV, DIF and ABA, respectively. The dynamic light scattering and zeta potential data from inclusion compounds demonstrated changes in the size of the particles in suspension in relation to precursors. Moreover, it was possible to verify by solubilization curves that inclusion compounds have greater solubility compared with the pure substances, except of NOV. Based on suspension data, the solid is characterized as an unstable hydrophobic nanoprecipitated with possibility of aggregation. In relation to biological assays, the lethal dose values to 50% of the larvae of Aedes aegypti (LD50) or emergency inhibition percentage at 50% of its population (% IE50) were less than 1 ppm for all compounds, demonstrating the high insecticidal activity of them. The evaluation of larvicidal activity in the L4 stage to benzoylphenylureas and their inclusion compounds proved to be ineffective, suggesting a probable increase in the larvicidal activity of the inclusion compound with NOV compared to its precursor. Furthermore, the emergence inhibition assay for benzoylphenylureas allowed to confirm the mechanism of action of these compounds during the mosquito’s life cycle, to verify direct relationship between dose and mortality; to observe the delay in the development stage of mosquitoes in the samples treated compared to control, and, to verify the reduction in % EI50 values for inclusion compounds. In the experiments realized in L1 and L4 stadia for ABA and its inclusion compound, it was verified a more fragility L1 stadium with respect to L4 and a reduction of LD50 values for the inclusion compounds in all experiments. These data demonstrate the highest larvicidal activity of inclusion compounds in relation to the free substances. In the evaluation of toxicity using the MTT assay WI26UA4 fibroblast cells it was confirmed that NOV and DIF and their inclusion compounds showed low toxicity, while the ABA and its inclusion compound showed moderate toxicity. It was also observed that the values to generate cytotoxicity in humans are much higher than those required to cause larval mortality, demonstrating the selectivity and safety of nano composition. Thus, the strategy for preparing the inclusion compound resulted in an increase in larvicidal activity in all situations tested, demonstrating that this may be a promising alternative for the control of Aedes aegypti.