O presente trabalho trata da semissíntese de análogos de importantes compostos líderes (afidicolina, lausona, lapachol e CAPE) utilizando técnicas de química medicinal como bioisosterismo, adição de grupamento funcional e simplificação molecular. Dessa forma foi possível obter uma biblioteca de análogos racionais, visando a manipulação de parâmetros físico-químicos e estruturais, para fins de bioprospecção. Foram desenvolvidos derivados de afidicolina mais lipofílicos, por meio da acilação das hidroxilas presentes na estrutura química deste terpeno. Tentativas de formação de bioisósteros, sais e de ésteres fosfato das hidroxinaftoquinonas naturais - lapachol e lausona, foram realizadas visando avaliar a influência do pKa sobre a atividade deste tipo de moléculas, bem como aumentar hidrossolubilidade. Neste caso, foram observadas reações paralelas, como um rearranjo molecular para a formação de aminonaftoquinonas, no estudo da cicloadição de azida de sódio com grupos cianos. Ademais, foi estudado o efeito da simplificação molecular de CAPE (fenetil éster do ácido cafeico), visando entender os requisitos estruturais de atividade antitumoral desta classe de compostos. Neste trabalho, foram obtidas 14 moléculas e testadas para diferentes atividades biológicas. Derivados naftoquinoidais se mostraram ativos frente à inibição de DHODH em ensaio sobre a enzima e também em ensaio celular. Adicionalmente, análogos simplificados do CAPE apresentaram alta atividade antitumoral, com segurança, em comparação ao controle 5-fluorouracila. / The present study aimed the semi-synthesis of analogues from important lead compounds (aphidicolin, lausone, lapachol and CAPE) by using medicinal chemistry strategies, such as bioisosterism, addition of functional groups and molecular simplification. Thus, we obtained a library of rational analogues, aiming the manipulation of physicochemical and structural parameters with bioprospecting purposes. We developed more lipophilic aphidicolin derivatives by acylation of the hydroxyl groups present in the structure of this terpene. Attempts towards the development of phosphate salts bioisosters from the hydroxinaftoquinones lapachol and lausone in order to evaluate the influence the pKa in the biological activity of these class compounds as well as to increase the water solubility. In this last case, we observed parallel reactions, as a molecular rearrangement for the formation of the aminonaftoquinones during the study of cycloaddition with cyanides and azides. In addition, we studied the effects of molecular simplification of CAPE (caffeic acid phenethyl ester), to better understand the structural requirements for antitumoral activity of this class of compounds. In the present work we obtained 14 molecules which were also tested for different biological activities. Naftoquinoidais derivatives showed inhibition activity on enzymatic essay on DHODH and on cellular essay. Moreover, simplified molecules from CAPE showed high antitumoral activity and safety in comparison to the control 5- fluorouracil.

Submitted by Celso Magalhaes (celsomagalhaes@ufrrj.br) on 2017-09-06T12:10:14Z No. of bitstreams: 1 2017 - Paulo Pitasse Santos.pdf: 13320307 bytes, checksum: b714828ac2a5d9a1d2ab188470e04e9a (MD5) / Made available in DSpace on 2017-09-06T12:10:14Z (GMT). No. of bitstreams: 1 2017 - Paulo Pitasse Santos.pdf: 13320307 bytes, checksum: b714828ac2a5d9a1d2ab188470e04e9a (MD5) Previous issue date: 2017-02-20 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico - CNPq / Chagas disease was studied and described by the Brazilian sanitarist and physician Carlos Chagas in 1909. It is caused by the protozoan Trypanosoma cruzi and presents complex clinical manifestations. However, since its discovery, little progress has been made in the chemotherapeutic treatment of Chagas' disease. The only available drug for its treatment (benzonidazole) is not completely efficient and is associated with the development of several side effects. From the knowledge of the antiparasitic activity of the natural amidic alkaloid piperine, this work focused on the proposition of new structurally-similar molecules with trypanocidal potential. From the principles of bioisosterism, a series of new 1,2,4-oxadiazoles were proposed. Its synthesis was designed from the corresponding 3-arylacrylic acids to give the respective acyl chlorides by reaction with oxalyl chloride. The subsequent step involves O-acylation of the properly substituted benzamidoxime following the cyclization reaction of the oxadiazolic ring, which occurs in solid support (silica gel) using microwave irradiation. The characterization of the products was done by determination of melting points, 1H and 13C NMR, infrared espectrometry and high and low resolution mass spectrometry. The present work also presents information about the biological activity profile of the molecules synthesized against epimastigote forms of the T. cruzi protozoan and against primary mammalian cells, allowing the calculation of their selectivity indexes. Investigations about the possible mechanisms of action of the derivatives on T. cruzi indicate that there are no influences on the enzymatic action of the protease cruazain, on the cell cycle of the parasite or on the biosynthesis of membrane sterols catalyzed by the enzyme CYP51. The developed sinthetic methodology can be applied in the expansion of the series of analogues derivatives. The perspectives of this work also include the biological evaluation against amastigote and trypomastigote forms of the parasite. / A doen?a de Chagas foi estudada e descrita pelo m?dico sanitarista e cientista brasileiro Carlos Chagas, em 1909. ? causada pelo protozo?rio Trypanossoma cruzi, apresentando manifesta??es cl?nicas complexas. No entanto, desde sua descoberta, pouco se avan?ou no tratamento quimioter?pico da doen?a de Chagas, sendo o f?rmaco dispon?vel (benzonidazol) pouco eficiente e associado ? manifesta??o de diversos efeitos colaterais. A partir do conhecimento da atividade antiparasit?ria da amida natural piperina, este trabalho focou-se na proposi??o de novas mol?culas estruturalmente semelhantes com potencial tripanocida. A partir dos princ?pios do bioisosterismo, foi proposta uma s?rie de novos 1,2,4-oxadiaz?is diferentemente substitu?dos. Sua s?ntese foi concebida partir dos ?cidos 3-arilacr?licos correspondentes, obtendo-se os respectivos cloretos de acila, atrav?s da rea??o com cloreto de oxalila. A etapa posterior envolve a O-acila??o da benzamidoxima adequadamente substitu?da, seguida do fechamento do anel oxadiaz?lico, que se d? em em suporte s?lido (s?lica-gel) empregando-se irradia??o de micro-ondas. A caracteriza??o dos produtos foi feita atrav?s de ponto de fus?o, RMN 1H e 13C, espectrometria no infravermelho e espectrometria de massas de alta e baixa resolu??o. O presente trabalho ainda traz informa??es quanto ao perfil de atividade biol?gica das mol?culas sintetizadas frente a formas epimastigotas do protozo?rio Trypanosoma cruzi e frente a c?lulas prim?rias de mam?feros, permitindo que se calculasse o seu ?ndice de seletividade. Investiga??es quanto a poss?veis mecanismos de a??o dos derivados sobre o T. cruzi indicam n?o haver influ?ncias sobre a a??o enzim?tica da protease cruza?na, sobre o ciclo celular do parasito, nem sobre a bioss?ntese de ester?is de membrana, catalisada pela enzima CYP51. A metodologia qu?mica desenvolvida poder? ser aplicada na s?ntese de outros an?logos. As perspectivas deste trabalho incluem ainda a avalia??o biol?gica frente a formas amastigota e tripomastigota do parasito

O presente trabalho trata da semissíntese de análogos de importantes compostos líderes (afidicolina, lausona, lapachol e CAPE) utilizando técnicas de química medicinal como bioisosterismo, adição de grupamento funcional e simplificação molecular. Dessa forma foi possível obter uma biblioteca de análogos racionais, visando a manipulação de parâmetros físico-químicos e estruturais, para fins de bioprospecção. Foram desenvolvidos derivados de afidicolina mais lipofílicos, por meio da acilação das hidroxilas presentes na estrutura química deste terpeno. Tentativas de formação de bioisósteros, sais e de ésteres fosfato das hidroxinaftoquinonas naturais - lapachol e lausona, foram realizadas visando avaliar a influência do pKa sobre a atividade deste tipo de moléculas, bem como aumentar hidrossolubilidade. Neste caso, foram observadas reações paralelas, como um rearranjo molecular para a formação de aminonaftoquinonas, no estudo da cicloadição de azida de sódio com grupos cianos. Ademais, foi estudado o efeito da simplificação molecular de CAPE (fenetil éster do ácido cafeico), visando entender os requisitos estruturais de atividade antitumoral desta classe de compostos. Neste trabalho, foram obtidas 14 moléculas e testadas para diferentes atividades biológicas. Derivados naftoquinoidais se mostraram ativos frente à inibição de DHODH em ensaio sobre a enzima e também em ensaio celular. Adicionalmente, análogos simplificados do CAPE apresentaram alta atividade antitumoral, com segurança, em comparação ao controle 5-fluorouracila. / The present study aimed the semi-synthesis of analogues from important lead compounds (aphidicolin, lausone, lapachol and CAPE) by using medicinal chemistry strategies, such as bioisosterism, addition of functional groups and molecular simplification. Thus, we obtained a library of rational analogues, aiming the manipulation of physicochemical and structural parameters with bioprospecting purposes. We developed more lipophilic aphidicolin derivatives by acylation of the hydroxyl groups present in the structure of this terpene. Attempts towards the development of phosphate salts bioisosters from the hydroxinaftoquinones lapachol and lausone in order to evaluate the influence the pKa in the biological activity of these class compounds as well as to increase the water solubility. In this last case, we observed parallel reactions, as a molecular rearrangement for the formation of the aminonaftoquinones during the study of cycloaddition with cyanides and azides. In addition, we studied the effects of molecular simplification of CAPE (caffeic acid phenethyl ester), to better understand the structural requirements for antitumoral activity of this class of compounds. In the present work we obtained 14 molecules which were also tested for different biological activities. Naftoquinoidais derivatives showed inhibition activity on enzymatic essay on DHODH and on cellular essay. Moreover, simplified molecules from CAPE showed high antitumoral activity and safety in comparison to the control 5- fluorouracil.

Les hétérocycles azotés en chimie médicinale sont une classe très importante de composés présents dans une panoplie de médicaments sur le marché. De ces structures, la pipérazine et ses analogues occupent une place importante en chimie médicinale. Plus particulièrement son similaire, l’acide pipérazine-2-carboxylique permet une plus vaste fonctionnalisation en raison de son groupement acide carboxylique qui peut être fonctionnalisé en ester, en amide, en alcool et en éther pour ne nommer qu’eux. La bioisostérie est un concept important en chimie médicinale permettant de moduler les effets pharmacologiques d’une molécule. Notamment, la tridimensionnalité et la rigidité d’une structure moléculaire par rapport à une autre permet, entre autres, une meilleure affinité dans des sites actifs de récepteurs ou d’enzymes. Alors, nous avons proposé la structure de 4 composés azabicycliques pouvant agir comme bioisostères de l’acide pipérazine-2-carboxylique. Ces structures seraient des bons candidats comme remplacement pour des tests biologique futurs in vitro en les comparant à la molécule mère. Nous avons synthétisé et caractérisé les 4 structures proposées avec de bons rendements et des réactions fiables et robustes. Nous avons utlisé les chiron 4-trans-hydroxy L-proline et L-pyroglutaminol comme produits de départ, qui sont peu dispendieux et très disponibles. / Nitrogen heterocycles in medicinal chemistry are a very important class of compounds present in a wide range of drugs on the market. Of these structures, piperazine and its analogues occupy an important place in medicinal chemistry. More particularly its similar, piperazine-2-carboxylic acid allows a broader functionalization due to its carboxylic acid group which can be functionalized into esters, amide, alcohols and ethers to name a few. Bioisostery is an important concept in medicinal chemistry making it possible to modulate the pharmacological effects of a molecule. In particular, three-dimensionality and rigidity of one molecular structure compared to another allows, among other things, a better affinity in active sites of biological receptors or enzymes. So, we proposed the structure of 4 azabicyclic compounds that could act as bioisosteres of piperazine-2-carboxylic acid. These structures would be good candidates as a replacement for future in vitro biological tests by comparing them to the parent molecule. We have synthesized and characterized the 4 proposed structures with reliable yields and robust reactions. We used chiron 4-trans-hydroxy L-proline and L-pyroglutaminol as starting materials, which are inexpensive and very available.