Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Aedes aegypti is the main transmitter of vector-borne diseases such, dengue, chikungunya and zika. Hence no vaccine exists as well as drugs to reduce viremia, major strategy to prevent these diseases is controlling vector spreading. The main larvicides used are organophosphates and pyrethroids, however the indiscriminate use of these compounds gave rise Ae. aegypti resistant strains. A viable alternative to classic insecticides / larvicides is the phytochemical research of molecules, like terpenoids, component of essential oils of several plants that exhibits larvicidal activity. In this context, the aim of this study was synthetize and evaluate the activity of monoterpene (-)-borneol and twelve derivatives against Ae. aegypti larvae, using QSAR as strategy for discovery of new larvicidal agents. Reactions were carried out by esterification with acid chloride in basic medium, (-)-borneol was modificated in hydroxyl group, changing size and type of the side chain. Compounds synthetized were purified in column chromatography and characterized by NMR ¹³C, ¹H, MS and IR. LC50 was evaluated thought larvicidal assay, in each test, twenty third instar larvae were exposed to various concentrations of derivatives to 24h. From mortality data obtained, LC50 was determined though Probit analysis. The bornylchloroacetate derivative exhibited the best activity (21 ppm), but bornyl heptanoate showed no activity. The physicochemical properties of the derivatives were obtained by GAMESS® module Chem3D Ultra 7.0® software from most stable conformation of the molecule. Descriptor chosen for QSAR study was Log P, since best correlation obtained and especially to be a highly informative parameter to measure influence on the larvicidal activity. Equation was obtained by MiniTab16 ™ software by linear regression between derivatives Log P, and the activity expressed in log (1/LC50). QSAR equation without outliers exhibited quality indexes of r² = 0.944; F = 58.71; q² = 0.8442; Spress = 0.0827, indicating high predictability of the model. It was observed influence of lipophilicity on (-)-borneol derivatives larvicidal activity, suggesting that molecules with Log P value around 4.5 have optimized activity. This study may be used as a basis to guide research of new larvicides candidates. / O mosquito Aedes aegypti é o principal transmissor de doenças de origem viral, como a dengue, chikungunya e zika. Na ausência de recursos específicos como a falta de vacinas e medicamentos eficazes, a principal estratégia para o manejo destas infecções se dá pelo controle do vetor. Os principais agentes utilizados no controle químico são os organofosforados e piretroides, contudo o seu uso indiscriminado fez surgir populações do Ae. aegypti resistentes. Uma alternativa viável a estes inseticidas/larvicidas clássicos é a pesquisa de moléculas fitoquímicas, como as da classe dos terpenoides, presentes nos óleos essenciais de diversas espécies vegetais que já possuem atividade larvicida documentada na literatura. Neste contexto, o objetivo deste trabalho foi sintetizar e avaliar a atividade do monoterpeno (-)-borneol e seus doze derivados frente as larvas do Ae. aegypti, utilizando o QSAR como estratégia de descoberta de novos candidatos a agentes larvicidas. Através da reação de esterificação em meio básico, utilizando cloreto de ácido, o (-)-borneol foi modificado a partir de sua hidroxila alcoólica, variando no tamanho e tipo de cadeia lateral. Os compostos sintetizados foram purificados em coluna cromatográfica e caracterizados por RMN ¹³C e ¹H, EM, e IR. A CL50 foi avaliada através do ensaio larvicida, onde a cada teste 20 larvas em terceiro estádio são expostas por 24h a diferentes concentrações (em triplicata) de composto. A partir dos dados de mortalidade das larvas, a CL50 é obtida com IC 95% pela análise Probit. O derivado cloroacetato de bornila exibiu a maior atividade (21 ppm), já o heptanoato de bornila demonstrou-se inativo. As propriedades físico-químicas dos derivados foram obtidas pelo módulo GAMESS® do programa Chem3D Ultra 7.0® a partir da conformação mais estável da molécula. O descritor escolhido para estudo de QSAR foi o Log P, por apresentar a melhor correlação, e principalmente por ser um parâmetro altamente informativo quanto a sua influência na atividade larvicida. A equação foi calculada pelo software MiniTab16™ através da regressão linear entre o Log P dos derivados e a atividade larvicida expressa em Log (1/CL50). O QSAR obtido sem os compostos outliers apresentou índices de qualidade de r² = 0,944; F = 58,71; q²= 0,8442; SPRESS = 0,0827 indicando alta preditibilidade do modelo. Foi observada a influência da lipofilicidade na atividade larvicida dos derivados do (-)-borneol, sugerindo que moléculas com Log P de aproximadamente 4,5 tem sua atividade otimizada. Este trabalho poderá ser utilizado como base para direcionar o planejamento de novos candidatos a agentes larvicidas.

This thesis describes methods to obtain value–addedcompounds from TMP-turpentine obtained from the spruce, Piceaabies. The methodology focuses on biotransformations using twoapproaches: an oxygenation approach (i.e. oxygenation ofterpene hydrocarbons by cell cultures) and an esterificationapproach (i.e. lipase-catalysed transesterification of vinylacetate with terpene alcohols, and a further fractionation ofthe TMP-turpentine). The main constituents of the turpentine, a-pinene, b-pineneand limonene, were subjected to a P. abies suspension culture.Allylic oxidation formed the major products for α-pineneand β-pinene, which were further oxidised to theirrespective aldehyde or ketone. One of the minor products froma-pinene, cis-verbenol, was not only transformed into verbenonebut also isomerised to trans-verbenol. Limonene gavelimonene-(1,2)-epoxide as the major product. Fractionation of monoterpenes is accomplished throughphysical separation methods, chromatography and distillation,and lipase-catalysed transesterification of vinyl acetate withterpene alcohols. The esters of myrtenol and trans-pinocarveolwere separated from the more slowly reacting alcohols such asborneol and carveol by use of a combination of the Mucor mieheilipase and Candida antarctica lipase A as catalysts.Furthermore, the non-reacting tertiary terpene alcohols wereseparated from the reacting alcohols in a single step byCandida antarctica lipase A. Lipase-catalysed (Candida antarctica lipase B andPseudomonas cepacia lipase) transesterification of vinylacetate with sterically hindered secondary alcoholsunexpectedly yielded hemiacetals or hemiacetal esters. Thereaction conditions required to obtain these side products havebeen studied. <b>Keywords:</b>Picea abies, Pinaceae, Essential oilscomposition; Terpene alcohol; Hemiacetal; Hemiacetal ester,TMP-turpentine; Monoterpene; α-Pinene; β-Pinene;Limonene; Verbenol; Pinocarveol; Borneol; Myrtenol; Suspensioncell culture; Biotransformation; Lipase-catalysed; Oxidation;Allylic oxidation; Transesterification; Autoxidation;Separation.

<p>This thesis describes methods to obtain value–addedcompounds from TMP-turpentine obtained from the spruce, Piceaabies. The methodology focuses on biotransformations using twoapproaches: an oxygenation approach (i.e. oxygenation ofterpene hydrocarbons by cell cultures) and an esterificationapproach (i.e. lipase-catalysed transesterification of vinylacetate with terpene alcohols, and a further fractionation ofthe TMP-turpentine).</p><p>The main constituents of the turpentine, a-pinene, b-pineneand limonene, were subjected to a P. abies suspension culture.Allylic oxidation formed the major products for α-pineneand β-pinene, which were further oxidised to theirrespective aldehyde or ketone. One of the minor products froma-pinene, cis-verbenol, was not only transformed into verbenonebut also isomerised to trans-verbenol. Limonene gavelimonene-(1,2)-epoxide as the major product.</p><p>Fractionation of monoterpenes is accomplished throughphysical separation methods, chromatography and distillation,and lipase-catalysed transesterification of vinyl acetate withterpene alcohols. The esters of myrtenol and trans-pinocarveolwere separated from the more slowly reacting alcohols such asborneol and carveol by use of a combination of the Mucor mieheilipase and Candida antarctica lipase A as catalysts.Furthermore, the non-reacting tertiary terpene alcohols wereseparated from the reacting alcohols in a single step byCandida antarctica lipase A.</p><p>Lipase-catalysed (Candida antarctica lipase B andPseudomonas cepacia lipase) transesterification of vinylacetate with sterically hindered secondary alcoholsunexpectedly yielded hemiacetals or hemiacetal esters. Thereaction conditions required to obtain these side products havebeen studied.</p><p><b>Keywords:</b>Picea abies, Pinaceae, Essential oilscomposition; Terpene alcohol; Hemiacetal; Hemiacetal ester,TMP-turpentine; Monoterpene; α-Pinene; β-Pinene;Limonene; Verbenol; Pinocarveol; Borneol; Myrtenol; Suspensioncell culture; Biotransformation; Lipase-catalysed; Oxidation;Allylic oxidation; Transesterification; Autoxidation;Separation.</p>