Submitted by Isaac Francisco de Souza Dias (isaac.souzadias@ufpe.br) on 2016-02-17T17:30:12Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) 3 Dissertação -P gravar CD Duda 2015 (versão final).pdf: 5192599 bytes, checksum: dfb099d781a8981a1e63076b92e4a1ae (MD5) / Made available in DSpace on 2016-02-17T17:30:12Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) 3 Dissertação -P gravar CD Duda 2015 (versão final).pdf: 5192599 bytes, checksum: dfb099d781a8981a1e63076b92e4a1ae (MD5) Previous issue date: 2015-02-26 / CAPES / Estudos farmacológicos mostram que a Dietilcarbamazina (DEC) interfere no metabolismo do ácido araquidônico atuando como um fármaco anti-inflamatório. O objetivo deste estudo foi examinar o efeito da DEC sobre a fibrose hepática induzida pelo tetracloreto de carbono (CCl4). Quarenta camundongos machos da linhagem C57BL/6J foram divididos em 4 grupos experimentais (n=10/grupo): (1) grupo controle, (2) grupo DEC 50 mg/kg (3) grupo CCl4 e (4) grupo CCl4+DEC 50mg/kg. A solução de DEC (50mg/kg) foi diluída nos bebedouros dos animais em volume total de 150 ml, por 12 dias. A fibrose foi induzida pelo CCl4 (0,5μl/g) por 8 semanas (2 injeções por semana). Após o esquema terapêutico, os animais foram eutanasiados e fragmentos hepáticos foram processados para histopatologia (HE), histoquímica para colágeno (Sirius red), ultraestrutura, imunohistoquímica, western blot e RT-qPCR. Nos resultados histopatológicos do grupo controle e grupo DEC 50mg/kg não apresentaram alterações em sua morfologia padrão. No grupo dos animais expostos ao CCl4 foi observada marcante degeneração citoplasmática e nuclear, com a presença de fibrose e infiltrados inflamatórios. Através da microscopia eletrônica foi possível observar mitocôndrias em degeneração, rompimento do retículo endoplasmático e grande presença de lipídeos. Os animais tratados com CCl4+DEC, mostraram uma diminuição de todas as lesões observadas no grupo CCl4. Na marcação para colágeno do grupo CCl4, observou-se intensa marcação nas áreas fibróticas. No entanto, o grupo CCl4+DEC apresentou redução da marcação de colágeno, semelhantemente ao grupo controle. Resultados da imunohistoquímica revelaram aumento da expressão de COX-2, α-SMA, TGF-β, p-JNK e p-p38 nas áreas fibróticas e nos infiltrados mononucleares, principalmente em áreas perivenulares no grupo CCl4. O tratamento com 50mg/kg de DEC promoveu a redução da imunoreatividade desses marcadores. Análises realizadas por western blot e RT-qPCR mostraram aumento da expressão dos marcadores fibróticos como α-SMA, TGF-β, colágeno-1, MMP2 e TIMP1, bem como das proteínas da via das MAPKs como p-JNK e p-p38 no grupo CCl4 e uma significativa redução da expressão destas proteínas após tratamento com DEC 50mg/kg. De acordo com o presente estudo, a DEC é uma possível alternativa terapêutica para a fibrose hepática. / Pharmacological studies show that DEC interferes in the arachidonic acid metabolism, acting as an anti-inflammatory drug. The aim of the study was to examine the effect of DEC on liver fibrosis induced by carbon tetrachloride (CCl4). Forty male mice C57BL/6J strain were divided into 4 groups (n = 10/group): (1) control group, (2) DEC 50mg kg group (3) CCl4 group and (4) CCl4 + DEC 50mg/kg group. The solution of DEC (50mg/kg) was administered to the animals in the drinking water in total volume of 150 ml for 12 days. The induction of fibrosis was made by CCl4 (0.5mL/g) for 8 weeks (2 injections per week). After the treatment, the animals were euthanized and liver fragments were processed for histological (HE), staining for collagen (Sirius red), ultrastructure, immunohistochemistry, western blot and RT-qPCR. The control and DEC 50mg/kg groups showed no change in their morphology pattern. The group of animals exposed to CCl4 a striking cytoplasmic and nuclear degeneration were observed, besides the presence of fibrosis and inflammatory infiltration. By electron microscopy several damage were observed, such as, mitochondria degeneration, rupture of the endoplasmic reticulum and large presence of lipids. The animals treated with CCl4 + DEC showed a decrease of all lesions observed in CCl4 group. In staining specific for collagen the CCl4 group showed intense staining in fibrotic areas. In contrary, CCl4 + DEC group showed reduced collagen labeling, similar to the control group. Results of immunohistochemistry revealed increased expression of as COX-2, α-SMA, TGF-β, p-JNK and p-p38 in fibrotic areas and mononuclear infiltrates, especially in areas perivenulares in CCl4 group. Treatment with DEC 50 mg / kg promoted a reduction of immunoreactivity of these markers. Western blot and RT-qPCR analyzes showed increased expression of fibrotic markers such as α-SMA, TGF-β, collagen-1, MMP2 e TIMP1, as well as the proteins pathway of MAPKs such as p-JNK and p-p38 in the CCl4 group and there was a significant decrease in expression of these proteins after treatment with DEC 50mg/kg. According to the present results, DEC is a possible alternative treatment for liver fibrosis induced by CCl4.

Memoria para optar al título de Químico Farmacéutico / Estudios de funcionalización del 1H-indol, condujeron a la familia de N-{4-[4-(1H-Indol-3-carbonil)-1-piperazinil]-fenil}-arilamidas 6(a-h) (Familia I) como potenciales ligandos provistos de acción serotoninérgica en el sistema nervioso central. La obtención de esta familia tomó lugar en una secuencia de 5 pasos, obteniéndose con rendimiento de un 66- 77% en la última etapa. La secuencia sintética utilizada se basó en la reacción inicial de Vilsmeier-Haack para obtener el 3-formil-1H-indol (2), en un 97%, posterior oxidación a su derivado carboxílico (3) (70%) y tratamiento con N,N´-Diciclohexilcarbodimida y 4-nitro-fenilpiperazina, generó la 4-nitrofenilpiperazinilamida (4) con un 63%. La reducción de (4) generó la amina correspondiente (5) en un 50%, que fue reaccionada con una serie de haluros de aroílo para dar la familia 6(a-h). Como un aporte exploratorio se sintetizaron 3 nuevos hetero-bis-índoles reducidos 11(a-c) vía aminación reductiva del derivado amina (5) y formil indol (2). Se realizaron estudios de modelación molecular del receptor (5HT1A), acompañados de estudios de docking en los compuestos 6(a-d) obteniéndose los puntajes de docking favorables de interacción ligando-receptor. Asimismo, se complementó este estudio con el análisis de docking de 8 nuevas agrupaciones indólicas estructuralmente relacionadas a las anteriores, (derivados reducidos) exhibiendo una afinidad teórica mejorada / Functionalyzation studies on 1H-indol, led us to obtain a family of N-{4-[4-(1H-Indole-3-carbonyl)-1-piperazinyl]-phenyl}-arylamides 6(a-h) with potential serotonergic ligands in the central nervous system. The synthetic route was achieved in a five step sequence with a last-step yield between (66-77%). The synthetic sequence was initially based on Vilsmeier-Haack reaction to afford the 3-formyl-1H-indole (2), in a 97% (yield), subsequent oxidation provided the carboxylic acid derivative (3) in 70% yield, which was reacted with N,N´-Diciclohexylcarbodiimide and 4-nitrophenylpiperazine giving the amide (4) (63% yield). Further reduction of (4) provided the corresponding amine (5) (50% yield) which was reacted with a series of aroylhalydes to give compounds 6(a-h). As an exploratory study 3 new reduced hetero-bis-indoles 11(a-c) were synthesized, through reductive amination between amine (5) and aldehyde(2). A molecular modeling study was also carried out on the 5-HT1A receptor along with docking studies for compounds 6(a-d), displaying a more favorable docking score. Likewise new docking analysis were carried out by using 8 new theoretical compounds bearing an indolic frameworks structurally related to family (I); these compounds showed improved affinities compared to family (I). / Fondecyt

Memoria para optar al título de Químico / Las arilpiperazinas constituyen una familia de compuestos de interés en el ámbito neurofarmacológico principalmente por sus acciones ansiolíticas y antidepresivas, a través de interacciones con el receptor serotoninérgico 5-HT1A. El presente trabajo de tesis informa de la síntesis de una serie de compuestos benzotiofenarilpiperazínicos 10 (a-f) adecuadamente funcionalizados. El acceso sintético a esta serie tiene lugar a través de una secuencia de 6 pasos a partir de 3,6-dimetoxi-2-nitrobenzaldehído con tioglicolato de metilo en medio básico. Como primer producto se obtuvo el 4,7-dimetoxi-benzotiofen ester 4 en buen rendimiento, el cual fue hidrolizado a su correspondiente ácido 4,7-dimetoxi-benzotiofen-2-carboxílico 5 con un 90% de rendimiento. La posterior derivatización de 5 en su haluro de acilo 6 ocurrió con un 90%, este fue reaccionado con 4-nitro-fenilpiperazina 7 generando la benzotiofen amida 8 con un 85% de rendimiento. La nitroamida fue reducida a su correspondiente aminofenipiperazino derivado 9 con un 90% de rendimiento intermediario clave en la obtención de nuestra familia 10(a-f). Este intermediario fue finalmente reaccionado con una serie de haluros de acilo comerciales (3) y preparados en laboratorio (3) en medio anhidro, generándose las 6 benzotiofen diamidas 10(a-f) en un rendimiento de 87-30% / The arylpiperazines constitute a family of compounds of interest in the neuropharmacologist area principally for the anxiolytic and antidepressing action, across interactions with the serotoninergic receptors 5-HT1A. The present thesis decribes the synthesis of a series of benzothiophene arylpiperazines 10(a-f) properly functionalized. The synthetic strategy took place through a six steps sequence starting by the condensation between 3,6-dimethoxy-2-nitro-benzaldehyde and methylthioglycolate in basic medium to provide benzothiophene ester 4 in good yield,. The 4,7-dimethoxy-benzothiophen ester 4 was hydrolyzed to the corresponding 4,7-dimethoxy-benzothiophen carboxylic acid 5 in 90% yield. The acid 5 was subsequently treated with thionyl chloride to afford the acyl halide 6 (90% yield), which reacted with the 4-nitroarylpiperazine 7 providing the benzothiophenamide 8 in a 85% yield. This nitroamide was reduced to the corresponding aminophenylpiperazine derivative 9 in a 90% yield, representing a key intermediate in the synthetic route to the 10 (a-f) preparation. The amine 9 was finally reacted with a series of acyl halides either commercially availables or prepared in our laboratory to afford the 6 benzothiophene amides 10(a-f) in a 87-30% yield

Memoria para optar al título de Químico Farmacéutico / Estudios de funcionalización del 1H-indol-2-acido carboxílico, condujeron a la síntesis de una familia de compuestos N-{4-[4-(1H-Indol-2-carbonil)-1-piperazinil]-fenil}- arilamidas 4(a-h) con potencial actividad serotoninérgica en el sistema nervioso central. La obtención de este grupo de compuestos cursó en una secuencia de 3 pasos, obteniéndose con rendimiento global moderado. La secuencia sintética utilizada se inició mediante la reacción del 1H-indol-2-acido carboxílico con N,N´-Diciclohexilcarbodiimida y 4-nitro-fenilpiperazina, generando la 4- nitrofenilpiperazinilamida (2) en un 78% de rendimiento. La reducción de (2) generó la amina correspondiente (3) en un 50%, que fue sometida a reacción con una serie de haluros de acilo para dar finalmente la familia 4(a-h) con rendimientos entre un 65 a 75%. Se realizaron estudios de docking de los compuestos 4(a-h) en el receptor 5-HT1A obteniéndose puntajes de docking favorables de interacción entre los ligandos sintetizados y el receptor. / Functionalyzation studies on 1H-indol-2-carboxylic acid, led us to the synthesis of a series of N-{4-[4-(1H-indole-2-carbonyl)-1-piperazinyl]-phenyl}-arylamides 4(a-h), with potential serotonergic activity at the 5-HT1A R. The synthetic sequence took place in a three steps sequence and started by reaction between 1H-indol-2-carboxylic acid and N,N´-Diciclohexylcarbodiimide with 4- nitrophenylpiperazine, to give the amide (2) (78% yield). Further reduction of (4) provided the corresponding amine (5) in a 50% yield, which was finally reacted with a series of acil halide to give compounds 4(a-h) with yields between 65 to 75%. Docking studies were carried out for compounds 4(a-h) on the 5-HT1A R displaying favorable docking scores of interaction between receptor and ligand synthesized / FONDECYT

Submitted by Reginaldo Soares de Freitas (reginaldo.freitas@ufv.br) on 2016-09-05T16:30:56Z No. of bitstreams: 1 texto completo.pdf: 1163013 bytes, checksum: 9b6e165d1c8c35cdfc5b2abea3b1307d (MD5) / Made available in DSpace on 2016-09-05T16:30:56Z (GMT). No. of bitstreams: 1 texto completo.pdf: 1163013 bytes, checksum: 9b6e165d1c8c35cdfc5b2abea3b1307d (MD5) Previous issue date: 1998-08-19 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A busca de soluções para o controle de fitonematóides é um trabalho constante conduzido pela pesquisa química. No presente estudo foram sintetizadas as amidas 1,4-dietanoilpiperazina [19, 89,2%], cloridrato de 1,4-bis- (3,5-dinitrobenzoil)piperazina [20, 67,1%], 1,4-dibenzoilpiperazina [21, 52%], 1- (metoxicarbonil)piperazina [30, 46%], 1,4-bis(metoxicarbonil)piperazina [31, 24%], 1-benzoil-4-(metoxicarbonil)piperazina [34 a, 59,1%], 1-(3,5- dinitrobenzoil)-4-metilpiperazina [37, 58%], além do trifluoroacetato de piperazina [19]. As amidas dissubstituídas foram preparadas a partir de reações diretas entre a piperazina e os cloretos de acila, utilizando-se THF anidro como solvente. Para a síntese dos compostos monossubstituídos, a piperazina teve, primeiramente, um dos seus grupos NH protegidos através de reação com o cloroformato de metila. Após a produção da amida em reação com o cloreto de ácido, o produto foi desprotegido através de hidrólise ácida. Uma vez que alguns cloretos de acila não se encontravam disponíveis, a sua síntese foi realizada reagindo-se o correspondente ácido carboxílico com cloreto de tionila. Todavia, uma vez formados os cloretos de acila, estes sofreram reação com o THF, produzindo-se os ésteres octadecanoato de 4-clorobutila [22, 38%], oleato de 4- clorobutila [23, 39,6%], octanoato de 4-clorobutila [25, 77,9%], cinamoato de 4- clorobutila [27, 67,1%] e hexadecanoato de 4-clorobutila [38, 41,7%]. A avaliação da atividade nematicida desses produtos, da metilpiperazina, fenilpiperazina e dos ácidos octanóico, esteárico, cinâmico, gálico, oleico e propanóico foi feita em ensaios, sob condições de laboratório, com os fitonematóides Heterodera glycines e Meloidogyne incognita raça 3, utilizando- se uma dose fixa de 20 μg mL-1 do composto sintetizado. Nesses bioensaios, os índices de mortalidade variaram de 0 a 71% para o fitonematóide Meloidogyne incognita e de 7 a 58% para o Heterodera glycines. Em vista desses resultados, torna-se necessária a realização de novos ensaios, com outras concentrações e outros fitonematóides, testando-se outras formulações e doses, a fim de se obter conclusão definitiva sobre o potencial nematicida dos novos compostos analisados. / Finding solution to control phyto-nematodes is an endless job. The following amides were synthesised: 1,4-diethanoilpiperazine [19, 89,2%], chloride 1,4-bis(3,5-dinitrobenzoyl)piperazine [20, 67,1%], 1,4- dibenzoylpiperazine [21, 52%], 1-(methoxycarbonyl)piperazine [30, 46%], 1,4- bis(methoxicarbonyl)piperazine [31, 24%], 1-(3,5-dinitrobenzoyl)-4- methylpiperazine [37, 58%], and trifluoracetate piperazine [19]. The disubstituted amides were prepared from direct reactions between piperazines and acyl chloride in anhydrous THF. In order to synthesise the monosubstituted compounds, piperazine had one of its NH groups protected through a reaction with methyl chloroformate. The amides were obtained after reaction with acid chloride and hydrolysis. As some of the acyl chlorides were not available they were synthesed by reaction of correspondent carboxylic acid with thionyl chloride. In reaction with THF, the acyl chlorides produced the esters octadecanoate 4-chlorobutyl [22, 38%], oleate 4-chlorobutyl [23, 39,6%], octanoate 4-chlorobutyl [25, 77,9%], cinnamoate 4-chlorobutyl [27, 67,1%] and hexadecanoate 4-chlorobutyl [38, 41,75%]. The evaluation of the effectiveness of those following products: 1-methylpiperazine, 1-phenylpiperazine and acids such as octanoic, estearic, cinnamic, gallic, oleic and propanoic on controlling nematodes were carried out trials under laboratory conditions, using Heterodera glycines and Meloidogyne incognita race-3 which received 20 μg mL-1 of the synthesised compound. The rate of mortality varied from 0 to 71% for Meloidogyne incognita and 7 to 58% for Heterodera glycines. According to the present results new trials should be carried out with different phyto-nematodes, formulations and doses in order to obtain a definite conclusion about the potential of the new compounds on the control of phytonematodes. / Não foi encontrado o cpf do autor.

Memoria para optar al título de Químico Farmacéutico / En la presente tesis se expone un estudio sintético orientado a la obtención de dos familias estructuralmente relacionadas al esqueleto de aril(alquil)piperazinil indoles. La familia (I): 1-bencil-3-[(4-aril-1-piperazinil)metil]-1H-indoles, y la familia (II): Derivados substituidos de 3-((4-(3-(1H-3-indolil)propil)-1-piperazinil)metil)-1-bencil-1H-indoles. Su síntesis se basó en las destacadas y potentes acciones farmacológicas descritas en los receptores serotoninérgicos (5-HT1A) y dopaminérgicos (D3-D4) de análogos estructuralmente relacionados a nuestras agrupaciones heterocíclicas. Las estrategias sintéticas para acceder a la familia (I) se basaron en reacciones llevadas a cabo en el 3-formilindol (1) obtenido por el método de Vilsmeier-Haack. Posterior protección del nitrógeno indólico seguido de reducción del grupo aldehído, condujo al 3-indolilmetanol (3) que fue finalmente transformado en su mesilderivado (4), reaccionando finalmente con arilpiperazinas comerciales para generar los productos de substitución nucleofílica (5-12). Asimismo se exploró la obtención de bis ligandos alquilindólicos (familia II) donde se conectaron dos unidades indólicas por una cadena metilénica de longitud variable. La generación de esta serie se llevo a cabo por reacción de 3-indolil-metilmesilato (4) con 3-indolil-propilpiperazina / In this thesis, a synthetic study of new aryl(alkyl)pipirazinyl indoles is described. The 1-Benzyl-3-[(4-aryl-1-piperazinyl)methyl]-1H-Indoles (I), and the 3-((4-(3-(1H-3-indolyl)propyl)-1-piperazinyl)methyl)-1-Benzyl-1H-Indole family (II). Structurally. The synthetic approach was based on the outstanding and potent pharmacological activities described at 5-HT1A serotonergic and D3-D4 dopaminergic receptors in structurally parents compounds. The synthetic strategy to obtain the target molecules, involved preparation of 3-formyl-indole (1) by a Willsmeier-Haack reaction. Subsequent N-protection of the indole ring, followed by aldehyde reduction, provided the 3-indolylmethanol (3) which was finally converted in their mesyl derivate (4). Finally a nucleophilic displacement between the mesyl compound and commercial arylpiperazines, afforded the expected products (5-12). As a complementary work, new synthetic approaches for the synthesis of alkylindoles as bis ligands (family II) was also performed. The strategy employed, linked the indole moieties by a polimethylenic chain of variable length. This products, were obtained by reaction of the 3-indolyl-methylmesylate (4) and 3-indolyl-propylpiperazines

Considerando-se a necessidade brasileira de se obterem fármacos a preços competitivos e usando tecnologia nacional, visamos sintetizar um fragmento do Indinavir empregando como material de partida a L-serina, um aminoácido natural de baixo custo. Desta maneira, desenvolvemos a seguinte rota, em 6 etapas: p-tosilação da serina, pelo uso de cloreto de p-tosila / NaOH; amidação da p-tosilserina, empregando-se o sal de terc-butilamônio da N-hidroxissuccinimida / DCC; ciclização da (S)-2-terc-butil-N-p-tosilserina, em condição de transferência de fase, com cloreto de p-tosila / carbonato de potássio / TEBAC; abertura regiosseletiva do anel da aziridina pela 3-picolilamina; N,N-bis-alquilação da resultante diamina, com triflato de vinildifenilsulfônio e destosilação da piperazina obtida, promovida por HBr 30%, em ácido acético. Deste modo, o fragmento (S)- N-terc-butil-4-(piridin-3-ilmetil)piperazina-2-carboxamida foi obtido em 7 % de rendimento global e pode ser usado em uma rota alternativa para a síntese do Indinavir. / Considering the Brazilian need to obtain drugs at competitive prices and using national technology, we aimed to synthesize a fragment of Indinavir using L-serine, an inexpensive natural amino acid. Thus, we developed the following route in 6 steps: p-tosylation of serine by using p-tosyl chloride / NaOH; amidation of p-tosylserine employing the N-hydroxisuccinimide terc-butylammonium salt / DCC; cyclization of (S)-2-terc-butyl-N-p-tosylserine under phase transfer catalysis with p-tosyl chloride / potassium carbonate / TEBAC; aziridine ring opening with 3-picolylamine; N,N-bisalkylation of the resulting diamine with vinyldiphenylsulfonium triflate and detosylation of the obtained piperazine promoted by HBr 30% in acetic acid. In this way, the (S)-N-terc-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide fragment was obtained in 7 % overall yield and can be used in an alternative route for the synthesis of Indinavir.

Considerando-se a necessidade brasileira de se obterem fármacos a preços competitivos e usando tecnologia nacional, visamos sintetizar um fragmento do Indinavir empregando como material de partida a L-serina, um aminoácido natural de baixo custo. Desta maneira, desenvolvemos a seguinte rota, em 6 etapas: p-tosilação da serina, pelo uso de cloreto de p-tosila / NaOH; amidação da p-tosilserina, empregando-se o sal de terc-butilamônio da N-hidroxissuccinimida / DCC; ciclização da (S)-2-terc-butil-N-p-tosilserina, em condição de transferência de fase, com cloreto de p-tosila / carbonato de potássio / TEBAC; abertura regiosseletiva do anel da aziridina pela 3-picolilamina; N,N-bis-alquilação da resultante diamina, com triflato de vinildifenilsulfônio e destosilação da piperazina obtida, promovida por HBr 30%, em ácido acético. Deste modo, o fragmento (S)- N-terc-butil-4-(piridin-3-ilmetil)piperazina-2-carboxamida foi obtido em 7 % de rendimento global e pode ser usado em uma rota alternativa para a síntese do Indinavir. / Considering the Brazilian need to obtain drugs at competitive prices and using national technology, we aimed to synthesize a fragment of Indinavir using L-serine, an inexpensive natural amino acid. Thus, we developed the following route in 6 steps: p-tosylation of serine by using p-tosyl chloride / NaOH; amidation of p-tosylserine employing the N-hydroxisuccinimide terc-butylammonium salt / DCC; cyclization of (S)-2-terc-butyl-N-p-tosylserine under phase transfer catalysis with p-tosyl chloride / potassium carbonate / TEBAC; aziridine ring opening with 3-picolylamine; N,N-bisalkylation of the resulting diamine with vinyldiphenylsulfonium triflate and detosylation of the obtained piperazine promoted by HBr 30% in acetic acid. In this way, the (S)-N-terc-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide fragment was obtained in 7 % overall yield and can be used in an alternative route for the synthesis of Indinavir.

Submitted by Reginaldo Soares de Freitas (reginaldo.freitas@ufv.br) on 2016-09-21T11:29:40Z No. of bitstreams: 1 texto completo.pdf: 414321 bytes, checksum: 1217b68cf39d80cb3ce2b85b1eae2eea (MD5) / Made available in DSpace on 2016-09-21T11:29:40Z (GMT). No. of bitstreams: 1 texto completo.pdf: 414321 bytes, checksum: 1217b68cf39d80cb3ce2b85b1eae2eea (MD5) Previous issue date: 1999-07-14 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Neste trabalho foram sintetizados a timoquinona [15] e os éteres derivados do timol, 2-benziloxi-1-isopropil-4-metilbenzeno [8; 35,8%], 2-etoxi- 1-isopropil-4-metilbenzeno [9; 18,8%], 1-isopropil-4-metil-2-octiloxibenzeno [10; 23,6%], 1-isopropil-4-metil-2-octadeciloxibenzeno [11; 33,0%], 2- (2’,3’,4’,5’,6’-pentafluorobenziloxi)-1-isopropil-4-metilbenzeno [12; 32,0%] e 1- isopropil-4-metil-2-metoxibenzeno [13; 75,8%]. Foram também sintetizados os sais derivados de piperazina: cloreto de piperazina [17], citrato de piperazina [18], fosfato de piperazina [19], oxalato de piperazina [20] e sulfato de piperazina [21]. Os éteres derivados do timol foram preparados através da síntese de Williamson, entre o timol e os compostos halogenados aromáticos e alifáticos. A timoquinona [15] foi obtida como produto da nitração do timol, utilizando ácido sulfúrico/nitrato de sódio. Os sais derivados da piperazina foram sintetizados mediante reação entre a piperazina e um ácido, apresentando rendimento quantitativo. Os ensaios biológicos dos produtos sintetizados e do timol foram realizados in vitro, com os nematóides Meloidogyne incognita raça 3 e Heterodera glycines, utilizando-se doses de 5 e 50 μg mL-1 dos compostos sintetizados. Nestes bioensaios, os índices de mortalidade para o Meloidogyne incognita variaram de 1,8 a 81,8% na concentração de 5 μg mL-1 e de 5,3 a 86,7% na concentração de 50 μg mL-1. Para Heterodera glycines estes índices variaram de 0 a 83% na concentração de 5 μg mL-1 e de 0 a 88% na concentração de 50 μg mL-1. Estes resultados permitiram observar a influência dos diferentes grupos substituintes, dos ânions e da concentração dos compostos sintetizados sobre sua atividade nematicida. Observou-se também diferença entre os mecanismos de ação destes compostos nas espécies Meloidogyne incognita e Heterodera glycines, sugerindo que uma abordagem diferente deve ser feita para a síntese de nematicidas que visam ao controle de Heterodera glycines. / In this work were synthesized the thymoquinone [15] and the derivatives ethers of the thymol, 2-benzyloxy-1-isopropyl-4-methylbenzene [8; 35.8%], 2- ethoxy-1-isopropyl-4-methylbenzene [9; 18.8%], 1-isopropyl-4-methyl-2- octyloxybenzene [10; 23.6%], 1-isopropyl-4-methyl-2-octadecyloxybenzene [11; 33.0%], 2-(2',3',4',5',6'-pentafluorobenzyloxy)-1-isopropyl-4-methylbenzene [12; 32.0%] and 1-isopropyl-4-methyl-2-methoxybenzene [13; 75.8%]. they were also synthesized the derived salts of piperazine: piperazine chloride [17], piperazine citrate [18], piperazine phosphate [19], piperazine oxalate [20] and piperazine sulphate [21]. The derived ethers of the thymol were prepared through the Williamson synthesis, between the thymol and the halogenates compounds aromatics and aliphatics. The thymoquinone [15] was obtained as product of the nitration of the thymol, using sulfuric acid/sodium nitrate. The derived salts of the piperazine were synthesized by means of reaction between the piperazine and an acid, presenting quantitative yeld. The biological assays of the synthesized products and of the thimol were carried in vitro, with the nematodes Meloidogyne incognita strain 3 and Heterodera glycines, using doses of 5 and 50 mg mL-1 of the synthesized compounds. In these bioassays, the mortality rate for Meloidogyne incognita varied from 1.8 to 81.8% at a 5 mg mL-1 concentration and of 5.3 to 86.7% at a 50 mg mL-1 concentration. For Heterodera glycines these rates varied from 0 to 83% at a 5 mg mL-1 concentration and from 0 to 88% at a 50 mg mL-1 concentration. These results allowed to observe the influence of the different substituents groups, of the anions and of the concentration of the synthesized compounds, on its nematicidal activity. It was also observed difference among the action mechanism of these compounds in Meloidogyne incognita and Heterodera glycines, suggesting that a different approach should be made for the synthesis of nematicides that seek the control of Heterodera glycines.

Memoria para optar al título de Químico Farmacéutico / Las arilpiperazinas representan uno de los grupos de ligandos más estudiados frente al receptor 5HT1A. Estas estructuras destacan principalmente por poseer una actividad antidepresiva y ansiolítica. Asimismo el receptor 5-HT1A ha sido ampliamente estudiado, estando ya comprobada su vinculación a trastornos mentales como la depresión. Esta tesis presenta la síntesis y modelación teórica de una nueva familia de diez arilpiperazinilpropilindoles 12 (a-j) con diversos sustituyentes en la porción arílica. La síntesis de la serie se lleva a cabo en una secuencia de 3 pasos. El primer producto, 3-indolil-propanol 10a fue obtenido en un 74% de rendimiento utilizando la síntesis de Fischer para indoles. Se empleó como producto de partida clorhidrato de fenilhidracina. Posterior reacción con Cloruro de 4-Toluen Sulfonilo a temperatura ambiente, se generó el 3-(3-Indolil)propil-4-metilbencensulfonato 11a con un 64% de rendimiento. Finalmente el tosil derivado 11a se hizo reaccionar con diferentes arilpiperazinas comerciales (probablemente a través de una sustitución nucleofílica SN2) para dar origen a la serie arilpiperazinilpropilindoles 12 (a-j) con rendimientos entre 55% y 96%. La familia de arilpiperazinilpropilindoles 12 (a-j) fue sujeto de un estudio teórico de acoplamiento molecular (docking) utilizando un modelo por homología de la estructura 3D del receptor 5-HT1A. La serie se ubicó en la porción extracelular del receptor, en la cavidad formada entre las transmembranas (TM) TM2, TM3, TM5, TM6 y TM7. Los compuestos presentaron interacciones de tipo puente de hidrógeno, hidrofóbicas y electroestáticas con los aminoácidos Ser199, Asp91, Tyr390, Cys187 y Phe362 / The arylpiperazines embody one of the most studied groups of 5-HT1A ligands receptor. These structures stand out mainly for having antidepressive and anxiolytic activities. The 5-HT1A receptors have been also widely studied, and are currently well documented on mental disorders such as depression. This thesis reports the synthesis and theoretical study of a new family of arylpiperazinilpropylindoles 12 (a-j) bearing different substitutions at the arylpiperazine moiety. The synthesis of the series was carried out in a three steps sequence. The first product the 3-indolyl-propanol 10a was obtained in a 74% yield by using the Fischer reaction for indoles, in which the starting product was phenylhydrazine hydrochloride. Subsequent reaction with 4-toluenesulfonyl chloride at room temperature provided the 3-(3-Indolyl)-propyl-4-methylbencensulfonate 11a in 64% yield. Finally, this tosyl derivative 11a was reacted with different commercial arylpiperazines (probably through a nucleophilic substitution SN2), to afford the arylpiperazinilpropylindoles series 12 (a-j) with results that ranged from 55% to 96% yields. The arylpiperazinilpropylindoles 12(a-j) family was subjected to a docking study with the 5-HT1A receptor. The ligands were located in the extracellular portion of the receptor, in the cavity between the transmembranes TM2, TM3, TM5, TM6 and TM7, displaying several hydrogen bonds, hydrophobic and electrostatic interactions between the ligand and the a group of aminoacid residues in the neighborhood of the described binding site, namely: Ser199, Asp116, Tyr390, Cys187 and Phe362