O isosorbídeo, juntamente com o ácido láctico, é considerado importante monômero para a preparação de materiais poliméricos derivados de fontes renováveis. O presente trabalho descreve a aplicação de catalisadores de alta eficiência na síntese de poliésteres derivados de fontes renováveis. Diésteres alifáticos, isosorbídeo, lactídeo, 2-etilhexanoato de estanho II (SnOct2), triflato de itérbio [Yb(OTf)3] e triflato de ítrio [Y(OTf)3], foram utilizados como reagentes para a produção dos polímeros em estudo. O catalisador de estanho, por ser o mais comum na literatura para esse tipo de sistema, foi utilizado como referência para a aplicação dos catalisadores de alta eficiência derivados de ítrio e itérbio. A estratégia inicial adotada para a obtenção da maior massa molar possível dos polímeros foi a execução de um planejamento fatorial para avaliação de como três variáveis principais, temperatura, tempo reacional e quantidade de catalisador influenciam o processo de polimerização. Uma vez determinada a direção a ser seguida no processo de polimerização, ajustes empíricos baseados em dados e observações experimentais foram feitos com a finalidade de se otimizar as condições reacionais. Os produtos obtidos foram caracterizados por cromatografia por exclusão de tamanho, ressonância magnética nuclear de 1H e 13C, espectroscopia no infravermelho, calorimetria diferencial de varredura, análise termogravimétrica e espectrometria de massas. Catalisadores de alta eficiência foram utilizados na preparação de poliésteres de alta massa molar, sintetizados a partir de lactídeo, diésteres alifáticos e diol secundário estericamente impedido, o isosorbídeo. Polímeros ramificados inéditos foram obtidos e um novo mecanismo reacional proposto, permitindo uma melhor compreensão sobre o sistema de policondensação para derivados de isosorbídeo. / The isosorbide and lactic acid are considered important monomers from renewable sources for the preparation of biodegradable materials. The present study describes the use of high performance catalysts applied in the synthesis of polyesters from renewable sources. Aliphatic diesters, isosorbide, lactide, tin(II) 2-ethylhexanoate, ytterbium triflate and yttrium triflate were used as starting materials for producing the polymers under study. The tin catalyst, being most common in the literature for this type of system, was used as reference for application of high performance catalysts derived from ytterbium and yttrium. The initial strategy adopted to obtain the reaction conditions to reach the highest molar mass of the polymers was the implementation of an experimental design in order to evaluate how the three main variables - temperature, reaction time and amount of catalyst- influence the polymerization process. Once the direction of the polymerization process was determined based on experimental observations, further empirical adjustments were made in order to optimize the reaction conditions. The products obtained were characterized by size exclusion chromatography, 1H and 13C nuclear magnetic resonance, infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis and mass spectrometry. High efficiency catalysts were used in the preparation of high molecular weight polyesters derived from lactide, aliphatic diesters and sterically hindered diol, the isosorbide. Novel branched polymers were obtained and new mechanism was suggested, allowing a better understanding of the polycondensation reaction for isosorbide derived polymers.

Cette thèse propose de valoriser l’isosorbide (IS) dans le domaine des matériaux polymères biosourcés en proposant des voies originales. Après la présentation de cette molécule, nous avons détaillé les différentes voies de synthèse et d'application des composés organiques et des polymères déjà développés par la communauté scientifique. Ces derniers sont obtenus au travers de multiples étapes de fonctionnalisation ou de synthèse longues au travers de procédés peu économes en énergie ou en atomes ou même toxiques. Nous avons alors expliqué notre première stratégie visant à développer des polyacétals à base d'isosorbide (PAIS) jusqu'alors inédit. Un schéma de polymérisation reposant sur la réaction de l’isosorbide avec un halogénure de méthylène dans un solvant non toxique (DMSO) a été retenu. L’influence de différents paramètres expérimentaux (mode d'agitation, durée de réaction et stœchiométrie) a été analysée avec soin. Les meilleurs résultats ont été observés avec l’agitation mécanique à très haute vitesse (milieu réactionnel plus homogène et rendement quantitatif). Les concentrations les plus élevées d'isosorbide ont permis de produire exclusivement des polyacétals linéaires (L-PAIS) alors qu'une faible concentration et l’agitation magnétique ont également induit la formation d'oligomères cycliques. D'autres macrocycles (C-PAIS) de haute masse molaire ont pu être produits. Ces différentes classes de PAIS ont été caractérisés par de nombreuses techniques (RMN, MALDI-TOF IRTF, CES). Leurs performances physicochimiques ont également été étudiées (ATG, DSC, rhéologie..). L'allongement des chaines de L-PAIS étant concurrencé par la cyclisation, nous avons exploré l'intérêt du lactide (lévogyre et racémique) comme extenseur de chaine tout d'abord en réaction avec l'IS puis avec le L-PAIS. La catalyse organométallique a été plus efficace que la voie enzymatique (lipase PS). Les analyses chimiques et physiques menées sur les quatre grades de polymères à base d'IS et de lactide ont souligné la plus value offerte par la présence de la molécule d’isosorbide Des relations "structure-propriétés" précises et fiables incluant l'étude de la durabilité ont été menées avec soin. Enfin la même approche a pu être étendue à la production de copolymères linéaires de type PLLA-b-PAIS-b-PLLA et de PRLA-b-PAIS-b-PRLA. / This research work aims to valorise isosorbide (IS) for biobased polymeric materials using original methods. After a short introduction of this molecule, we presented the different synthesis pathways and application fields of chemical and polymers already developed in scientific community. These compounds are classically obtained through many functionalization/synthesis steps with processes far away from green chemistry. Our first strategy based on the development of polyacetals derived from isosorbide (PAIS) was explained. A reaction scheme involving isosorbide with methylene halogenate in a non-toxic solvent (DMSO) was retained. The influence of different experimental parameters (stirring mode, reaction period and stoichiometry) was carefully analysed. Best results were achieved with high-speed mechanical stirring (more homogenous reactive solution, quantitative yield). The highest isosorbide concentrations led to the exclusive production of linear polyacetals (L-PAIS) whereas a low concentration under magnetic stirring conditions induced the formation of cyclic oligomers. Other macro-cycles (C-PAIS) with high molar weight were also produced. These different kinds of PAIS were characterised by various techniques (NMR, MALDI-TOF FTIR, SEC). Their physicochemical performances were also studied (TGA, DSC, rheology…) The length increase of polymer L-PAIS chains being challenged by cyclisation, we also explored lactide use (L- and racemic) as chain extender first by the reaction with IS then with L-PAIS. The La organometallic catalysis was more efficient than enzymatic pathway (PS lipase). Both chemical and physical analyses carried out with four polymeric grades derived from IS et lactide showed the added value of isosorbide molecule. Precise and reliable "structure-properties" relations including durability study were also led. Finally, similar approach could be applied for producing linear copolymers (PLLA-b-PAIS-b-PLLA and PRLA-b-PAIS-b-PRLA)

L'isosorbide et ses dérivés sont des diols chiraux issus de l'amidon de maïs. L'utilisation de ce dernier en tant que monomère pour l'élaboration de polymères s'est révélée efficace, ces derniers égalant les propriétés des polymères conventionnels. Dans le cadre de cette thèse, ces diols sont employés pour synthétiser de nouvelles plateformes des monomères biosourcés AA et AB à partir des 1,4 :3,6- dianhydrohexitols. La synthèse d'intermédiaires à base de dinitriles ou de mononitriles et leurs dérivés à partir des trois isomères ainsi que les résultats d'essais de polymérisation de l'un de ces monomères prometteurs ont été décrits. Le polymère obtenu a révélé semi-cristallin grâce à l'agencement stéréorégulier des monomères AB. Ce travail est aussi le premier à décrire l'utilisation des réticulants chiraux à base de 1,4 :3,6-dianhydrohexitols participant à la formation du réseau tridimensionnel pour l'élaboration de polymères à empreintes (MIP) biosourcés pour la détéction de la Méthyltestostérone (MT). Les polymères synthétisés par polymérisation par précipitation ont été caractérisés. Les propriétés de rétention ont été évaluées en mode batch par HPLC-MS/MS. Ces MIPs présentent de bonnes propriétés d'adsorption vis-à-vis la MT avec des facteurs d'empreinte supérieurs à 1 montrant l'efficacité de l'impression. Ces matériaux présentent une bonne capacité d'adsorption comparée à la littérature. Les polymères non imprimés (NIP) ont même montré des capacités d'adsorption supérieure aux MIP classiques. La capacité d'adsorption la plus élevée a été observée pour cMIP-Is à base d'isosorbide, pour les concentrations importantes (500 mg L-1). Les données expérimentales ont été étudiées selon les modèles d'adsorption de Langmuir et Freundlich pour interpréter les phénomènes d'adsorption. Ces cMIP développés ont été adaptés pour l'extraction de la méthyltestotérone sur phase solide (SPE). Une procédure d'extraction a été développée en menant au travers d'une optimisation complète finalisée par une application aux eaux usées / The isosorbide and its derivatives are chiral diols obtained from cornstarch. The use of the latter as a monomer for the development of polymers has proved to be effective. The diols match the properties of conventional polymers. As part of this thesis, the diols are used to synthesize new platforms of bio based AA and AB from the 1,4: 3,6 - dianhydrohexitols monomers. The synthesis of intermediaries based on dinitriles or mononitrilies and their derivaties starting from the three isomers as well as the test results from one of these promising monomers polymerization which have been described. The resulting polymer revealed semi-cristallin through stereoregulier AB monomers layout. This work is also the first to describe the use of the reticulants chiral at base of 1.4: 3, 6-dianhydrohexitols participating in the formation of three-dimensional network for the development of polymers to footprints (MIP) Excelsior for detection of Methyltestosterone (MT). The polymers synthesized by polymerization have been characterized by precipitation. The properties of retention were evaluated in batch mode by HPLC-MS/MS. These MIPs present good properties of adsorption towards the MT with factors of footprint greater than 1 showing the effectiveness of printing. These materials have a good ability of adsorption compared to literature. Unprinted polymers (PIN) have shown even greater adsorption capacity than the conventional MIP. The high adsorption capacity was observed in cMIP-Is based on isosorbide for the concentrations (500 mg L-1). The experimental data have been studied according to Langmuir and Freundlich adsorption models to interpret the phenomena of adsorption these developed cMIP have been adapted for the methyltestoterone on the phase of extraction (SPE) solid. An extraction procedure has been developed leading through a full optimization finalized by an application in wastewater

Des complexes à base de palladium (II) ont été appliqués comme catalyseurs pour la réaction d’hydroestérification de l’isosorbide, matériau biosourcé, avec le 1-octène. Dans un premier temps, l’utilisation de liquides ioniques standards a permis l’immobilisation du catalyseur (palladium + phosphine) et la conversion du 1-octène. L’activité catalytique est dépendante de la nature du liquide ionique. Le liquide ionique sulfoné bSmimAPTS a permis l’obtention de conversions élevées, avec des rendements en diesters importants sur trois cycles catalytiques tout en s’affranchissant de l’emploi d’acide paratoluènesulfonique. Le catalyseur (palladium + phosphine sulfonée) est immobilisé dans la phase liquide ionique. La régiosélectivité de la réaction peut être modifiée (85/15 contre 75/25 dans les conditions classiques) avec le remplacement de la TPPTS par une phosphine bidentate sulfonée (XANTPHOS sulfonée). Un système constitué de Pd(OAc)2/APTS/NBu4Br s’est également montré très efficace dans la conversion du 1-octène en diester d’isosorbide mais n’est pas très stable dans le temps (recyclé à deux reprises). Dans un second temps, l’utilisation de charbons actifs commerciaux a permis d’immobiliser le métal (après filtration à froid) tout en conservant une activité catalytique élevée. Il est possible de convertir le 1-octène en substituant l’APTS par un matériau carboné sulfoné (obtenu par voie hydrothermale en une étape entre le saccharose et l’acide sulfurique). Les synthèses, caractérisations et applications d’un matériau carboné nanorépliqué sulfoné de type CMK-3 ont été considérées. Le matériau carboné sulfoné (MC-NR-saccharose-500-SO3H) a permis l’obtention de conversions et de rendements en diesters élevés, avec une sélectivité en large faveur de l’isomère linéaire (rapport l/b=92/8). Une extension à été étudiée avec la synthèse d’un matériau hybride sulfoné (MCSi 10.4-SO3H) et a également conduit à une activité catalytique élevée avec une sélectivité importante en isomère linéaire (rapport l/b=92/8). Des tests avec des matériaux acides contrôles (résine commerciale sulfonée et silice sulfonée) ont été réalisés. / Complex based on palladium salt (II) were applied as catalysts for the hydroesterification of isosorbide, a biobased molecule, with 1-octen. First, the use of standard ionic liquids permits the immobilization of the catalyst (palladium + phosphine) and the conversion of 1-octen. The catalytic activity is dependent on the nature of the ionic liquid. The sulfonated ionic liquid bSmimAPTS permit the obtention of high conversions, with important yield in diester during three catalytic cycles, and avoid the use of paratoluenesulfonic acid. The catalyst (palladium + sulfonated phopshine) is immobilized in the ionic liquid phase. The regioselctivity of the reaction can be changed with the replacement of the TPPTS by a sulfonated bidentate phosphine (XANTPHOS, l/b ratio= 85/15 against 75/25 in classical condition). A system containing Pd(OAc)2/APTS/NBu4Br proved also highly effective in the conversion of 1-octen but it was not very stable over time (recycled just two times). Secondly, the use of commercial activated carbons has immobilized the palladium after cold filtration while maintaining high catalytic activity. It’s possible to convert the 1-octen using a sulfonted carbonaceous material (obtained by hydrothermally condition in one step between sucrose en sulfuric acid). Synthesis, characterization and applications of a sulfonated nanoreplicated carbonaceous material, as CMK-3, were considered. This one (MC-NR-saccharose-500(SO3H) permit the obtention of high conversions and high yields of diesters, with a selectivity in favor of the linear isomer (l/b ratio= 92/8). An extension was studied with the synthesis of a sulfonated hybrid material (MCSi 10.4-SO3H) and also results in high conversion and high selectivity in linear isomer (l/b ratio= 92/8). Tests with acidics materials controls (sulfonated commercial resin and sulfonated silica) were performed.

Cette thèse porte sur la préparation de nouveaux catalyseurs chiraux à partir de composés naturels issus de la biomasse, et leurs applications en organocatalyse asymétrique. La première partie décrit la synthèse de thiourées énantiomériquement pures dérivées de l'isosorbide et l’isommanide. Ces thiourées ont été évaluées comme catalyseurs organiques dans des réactions asymétriques de Friedel-Crafts, d’alkylation, d’addition de type aza-Michael, d’hydroamination et de type Morita-Baylis-Hillman (MBH). Les meilleurs résultats en termes de réactivité et d’induction asymétrique, ont été obtenus dans le cas de la réaction de Friedel-Crafts. La deuxième partie est consacrée à la conception et la synthèse de thiourée-phosphines chirales à partir de la L-proline. Ces thiourée-phosphines sont capables de promouvoir la formation de liaisons C-N et C-S, selon un processus de substitution allylique énantiosélectif d’adduits modifiés de MBH. De très bons rendements (jusqu’à 98%) et énantiosélectivités (jusqu'à 93%) ont été obtenus. Dans la troisième partie, nous avons développé le premier exemple de cyclisation [4 + 2] entre un allénoate et un alcène tétrasubstitué, catalysée par une amine tertiaire. Nous avons montré que des composés de type 4H-pyranniques peuvent être sélectivement obtenus, avec d’excellents rendements, en utilisant le DABCO comme catalyseur. Dans le cas de catalyseur organique de type alcaloïde, le β-ICD conduit sélectivement aux composés 2H-pyranniques avec des excès énantiomériques jusqu’à 71 % ee. / The thesis focused on the preparation of new chiral catalysts derived from biomass and their applications in asymmetric organocatalysis. The first part described the synthesis of chiral thioureas derived from isosorbide and isomanide, naturally renewable resource, in moderate to good overall yields. These thioureas were evaluated in asymmetric reactions such as Friedel-Crafts alkylation, aza-Michael addition, hydroamination, Morita-Baylis-Hillman reaction. Good yields and enantioselectivities were obtained. The second part of our work went on the design and synthesis of chiral thiourea-phosphines from L-Proline. These thiourea-phosphines promoted C-N and C-S bond formation via the asymmetric allylic substitution of tert-butoxycarbonyloxy adducts. Good yields (up to 98 %) and enantioselectivities (up to 93 %) were observed. In the third part, we have developed the first example [4+2] annulation of allenoate and all-carbon tetrasubstituted alkenes catalyzed by an amine. In the case of DABCO catalyst, 4H-pyrans were isolated exclusively in good to excellent yield under mild reaction conditions. While employing β-ICD as catalyst, the enantioenriched 2H-pyran derivatives were obtained with enantiomeric excess up to 71 % ee.

L’objectif du projet est de préparer de nouveaux copolyéthers hydrophiles biosourcés, non ioniques, pour des applications cosmétiques proches de celles du polyéthylène glycol (PEG). Le polytriméthylène éther glycol (PTEG), dont la structure ressemble à celle du PEG, a été synthétisé par polymérisation du 1,3-propanediol biosourcé (PDO) en catalyse acide. Parmi les catalyseurs testés, l’acide sulfurique est le plus approprié pour polymériser le PDO sans dégradation excessive. Pour augmenter la solubilité du PTEG dans l’eau, des copolymères associant des unités PDO et des unités hydrosolubles type isosorbide et glycérol ont été envisagés. Ainsi, nous avons montré que l’éthérification en catalyse acide entre l’isosorbide et le PDO (ou le PTEG) conduit à de nouvelles structures de copolyéthers que nous avons finement caractérisés par RMN et spectrométrie de masse. Ces copolyéthers ont des extrémités préférentiellement constituées d’unités isosorbide, du fait d’un différentiel de réactivité entre le PDO et l’isosorbide. En revanche, l’éthérification du PDO et du glycérol par catalyse à l’acide sulfurique ou par catalyse basique n’a pas abouti. En effet, dans le premier cas, on observe une très forte dégradation voire une réticulation et dans le deuxième cas, seule l’homopolymérisation du glycérol est observée. Pour compléter, la réaction entre du carbonate de glycérol et un oligomère de PTEG donne les dérivés souhaités, même si le milieu réactionnel reste riche en polyglycérol libre. Les produits les plus prometteurs de l’étude sont des copolyéthers de PDO et d’isosorbide, d’environ 600 g/mol, obtenus par éthérification en catalyse acide. Ces nouveaux copolyéthers ont des bouts de chaînes constitués d’unités isosorbide, sont hydrosolubles et ont une stabilité thermique améliorée par rapport aux PTEG. / The aim of this project is to prepare some new hydrophilic biobased copolyethers for cosmetic applications, similar to those of polyethylene glycol (PEG). Synthesis of polytrimethylene ether glycol (PTEG) which has a chemical structure close to the PEG was studied by polymerizing 1,3-propanediol (PDO) with sulfuric acid as catalyst. This acid catalyst is appropriate to promote the polymerization of PDO without excessive degradation. We tried to increase the solubility of PTEG in water by combining to PDO units hydrophilic monomers, such as isosorbide and glycerol, to the PDO units. We showed that etherification of isosorbide and PDO (or PTEG), in the presence of acid catalyst, gives new copolyethers structures, deeply characterized by NMR and mass spectroscopy. These copolyethers are preferably ended by isosorbide units due to different reactivity between isosorbide and PDO. The etherification of the PDO and glycerol with sulfuric acid results in a cross-linked and degraded product. Basic catalytic route favored the polymerization of glycerol on itself rather than the etherification on PDO units. We also grafted glycerol carbonate on PTEG oligomer but obtained a complex composition mixture rich in polyglycerol. The most promising products of the study are PDO and isosorbide copolyethers with a molar mass of 600 g/mol, obtained by etherification with sulfuric acid as catalyst. These copolyethers have chain ends constituted by isosorbide units, are water soluble and have a higher thermal stability compared to PTEG.

Chronic anal fissures are benign, painful, found deep ulcers in the anal canal. Affecting young adults and occur especially by the trauma of hard stools, the sphincter hypertonia and poor vascularization in the anterior and posterior regions of the anus. Its main symptom is pain evacuation. Surgical treatment is most effective with high cure rates, but with significant adverse effects such as later anal incontinence. The option of conservative treatment is growing, has managed to decrease temporary the pressure at rest (PREP) and increased blood flow to the anal canal, healing large number of lesions without muscle damage. In order to evaluate the treatment of chronic anal fissure with isosorbide (ISO) 1% topical has conducted a clinical trial, double-blind study in patients enrolled in the service of coloproctology Federal University of Sergipe, in the period of one year. We studied 24 patients, distributed as follows: 14 in group 1 cream isosorbide, and 10 in group 2 placebo. We evaluated the behavior of the PREP, pain relief and degree of wound healing with and without ISO. The results showed that the patients ages ranged from 21 to 69 years, the cleft affects more women and the predominant symptom was pain. Constipation was observed in 58.3%. As for pain, lower intensity was obtained in group 2, but without significance. The healing after 60 days was similar in both groups (50%). The profile of the average PREP 30 and 60 days, there was a decrease in the standard in both groups, but without statistical significance. It was observed that patients cured were those with the greatest reduction in PREP. It was concluded that the ISO did not alter the response pattern gauge, however there was significant clinical improvement in both groups. The healing rate was similar in both groups. / As fissuras anais crônicas são úlceras benignas, dolorosas, profundas encontradas no canal anal. Acometem adultos jovens e ocorrem especialmente pelo trauma das fezes endurecidas, pela hipertonia esfincteriana e pela pobre vascularização nas regiões anterior e posterior do ânus. Seu principal sintoma é a dor evacuatória. O tratamento cirúrgico é o mais efetivo, com altos índices de cura, porém com efeitos adversos importantes como incontinência anal tardia. A adoção da terapêutica conservadora vem crescendo, tem conseguido o decréscimo transitório da pressão de repouso (PREP) e o aumento do fluxo sanguíneo do canal anal, cicatrizando grande número de lesões, sem dano muscular. Com o objetivo de avaliar o tratamento de fissuras anais crônicas com isossorbida (ISO) a 1% tópica, foi realizado um ensaio clínico, duplo-cego em pacientes atendidos no serviço de coloproctologia da Universidade Federal de Sergipe, no período de um ano. Foram estudados 24 pacientes, assim distribuídos: 14 no grupo 1 - creme com isossorbida, e 10 no grupo 2 - placebo. Avaliaram-se comportamento da PREP, melhora da dor e grau de cicatrização das feridas com e sem ISO. Os resultados mostraram que a idade dos pacientes variou de 21 a 69 anos, a fissura acometeu mais as mulheres e o sintoma predominante foi a dor. Constipação foi observada em 58,3%. Quanto à dor, obteve-se menor intensidade no grupo 2, mas sem significância. A cicatrização ao fim de 60 dias foi igual nos dois grupos (50%). Quanto ao perfil das médias de PREP com 30 e 60 dias, houve uma queda no padrão em ambos os grupos, porém sem significância estatística. Observou-se que os pacientes curados foram aqueles com maior redução de PREP. Concluiu-se que a ISO 7 não modificou o padrão de resposta manométrica, no entanto houve melhora clínica importante nos dois grupos. A taxa de cicatrização foi igual em ambos os grupos.

Submitted by Biblioteca da Faculdade de Farmácia (bff@ndc.uff.br) on 2017-03-17T18:50:12Z No. of bitstreams: 1 Portela, Aline Cordeiro [Dissertação, 2014].pdf: 9279752 bytes, checksum: 9172b58477a24ce8a80f3405e0759adb (MD5) / Made available in DSpace on 2017-03-17T18:50:12Z (GMT). No. of bitstreams: 1 Portela, Aline Cordeiro [Dissertação, 2014].pdf: 9279752 bytes, checksum: 9172b58477a24ce8a80f3405e0759adb (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A dengue é um problema de saúde pública mundial, acometendo cerca de 50 milhões de pessoas por ano. O HCV é a principal causa de hepatite crônica e estima-se que 200 milhões de pessoas estejam infectadas no mundo. A terapia atual contra o HCV apresenta eficácia limitada e baixa tolerância, enquanto que para a dengue não existe um tratamento antiviral específico. Com o objetivo de explorar essa demanda, o presente trabalho descreve a síntese para a obtenção de quinze compostos peptideomiméticos inéditos, contendo o cerne rígido proveniente do isosorbídeo, como potenciais agentes inibidores da enzima NS3 protease de ambos os vírus. A estratégia de síntese dos peptideomiméticos consistiu inicialmente na obtenção de dez compostos inéditos, das séries 28a-c (derivada de oxazolonas) e 29a-g (derivada de aminoácidos N-protegidos). Os compostos foram inicialmente testados frente à inibição da protease do DENV-2, os quais não apresentaram resultados significativos. Entretanto, os resultados de inibição enzimática dos compostos frente à NS3/4A do HCV-1b foram mais satisfatórios, sendo o composto 28a (1,4:3,6-dianidro-5-[[(2Z)-2-(benzoilamino)-1-oxo-3-(2-tienil)-2-propen-1-il]amino] -2-deoxi-2-O-(fenilmetil)-D-iditiol, o mais ativo, com IC50 = 88μm. Estudos de docking molecular foram realizados para avaliar o modo de interação dos ligantes com a serina protease NS3/4A do HCV. Dentre os compostos sintetizados, 28a foi considerado protótipo para o desenvolvimento de novos compostos com potencial de inibição da enzima em questão. A partir de 28a, a nova série de compostos inéditos 42a-e foi proposta e obtida. Os resultados dos ensaios farmacológicos frente à NS3/4A do HCV-1b permitiram-nos inferir que a substituição do tiofeno de 28a pelo furano e 3-metiltiofeno em 42b e 42c, respectivamente, resultou em um aumento de cerca de 30% no perfil de inibição enzimática, com inibição de 70% dessa enzima viral. Dessa forma, podemos identificar esses dois novos compostos como protótipos para o planejamento de futuras moléculas potencialmente inibidoras da enzima serina protease do vírus da Hepatite C / Dengue fever is a worldwide public health concern, affecting approximately 50 million people per year. HCV is the main cause of chronic hepatitis and it is estimated that 200 million people are infected worldwide. Current therapy against HCV has limited efficacy and low tolerance, and there is no specific antiviral treatment for dengue fever. In order to exploit this demand, this work describes the synthesis for obtaining fifteen novel peptidemimetic compounds, isosorbide derivatives as potential inhibitory agents of the NS3 protease enzyme of both viruses. Initially the synthetic strategy of peptidemimetics consisted in obtaining ten novel compounds: 28a-c (derived from oxazolones) and 29a-g (derived from N-protected amino acids) series. The compounds were initially tested on the inhibition of protease DENV-2 , which results were not significant. However, the results of enzymatic inhibition of the compounds against the NS3/4A HCV-1b was more satisfactory, and the compound 28a (1,4 : 3,6- dianhydro -5 - [[( 2Z ) -2- ( benzoylamino) -1 -oxo- 3- (2- thienyl) -2 - propen -1- yl] amino] -2- deoxy -2- O- ( phenylmethyl ) -D- iditiol) , the most active , presenting IC50 = 88μm. Molecular docking studies were performed to assess the compounds mode of interaction with the serine protease NS3 / 4A HCV. Among the compounds synthesized, 28a was considered a prototype for the development of new compounds with a potential inhibition of the enzyme in question. Staring from 28a as a prototype the 42a-e serie was proposed and obtained. The results of pharmacological tests against the NS3/ 4A HCV -1b allowed us to conclude that substitution of the 28a furan thiophene and 3- methylthiophene in 42b and 42c respectively resulted in an increase of 30 % in the profile enzyme inhibition , with inhibition of 70 % of the viral enzyme . Thus , we can identify these new compounds as prototypes for planning future potentially molecule inhibitors of serine protease enzyme of the Hepatitis C virus

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