Les alcaloïdes indolo-monoterpéniques (AIMs) constituent une classe de molécules naturelles très étudiée en raison d’un fort potentiel pharmacologique et thérapeutique et d’une grande diversité structurale. D’autre part, les techniques de déréplication par chromatographie liquide couplée à la spectrométrie de masse tandem ont évolué récemment, avec l’émergence de l’approche par réseaux moléculaires (molecular networking). Dans ce contexte, nous avons créé une base de données de spectres de masse tandem moyennés de 172 AIMs témoins, en collaboration avec plusieurs équipes de pharmacognosie dans le monde. Cette base de données, nommée MIADB (Monoterpene Indole Alkaloids DataBase), rendue publique, peut être utilisée comme référence dans des stratégies de déréplication fondées sur l’utilisation des réseaux moléculaires. Nous avons ensuite exploité la MIADB pour l’étude phytochimique de deux Apocynaceae : Geissospermum laeve (Vell.) Miers et Alstonia balansae Guillaumin. Dans un premier temps, l’annotation par la MIADB d’un extrait alcaloïdique des écorces de G. laeve a permis l’isolement et l’élucidation structurale de 3 nouveaux AIMs, dont deux à motif butyrolactone. Par la suite, notre approche a été améliorée par l’emploi du nouvel outil d’annotation in silico MetWork, fondé sur une prédiction métabolique et la modélisation de spectres de masse tandem. C’est ainsi que l’exploration de l’espace chimique d’un extrait alcaloïdique des feuilles d’A. balansae a permis l’identification, puis l’isolement, de 5 nouveaux AIMs du type N-oxyde-sarpagane. La stéréochimie des nouveaux composés a pu être déterminée par l’exploitation de spectres prédits et expérimentaux de dichroïsme circulaire éléctronique.Ce manuscrit décrit, après une introduction consacrée notamment aux emplois du molecular networking pour le ciblage et la découverte de petites molécules naturelles puis aux interconnections biosynthétiques en série AIM, la création puis l’évolution de la MIADB, puis son utilisation dans un workflow de déréplication efficace et de ciblage de nouveaux composés dans des mélanges complexes issus d’Apocynaceae. / Monoterpene indole alkaloids (MIAs) constitute a class of natural products that has been extensively studied due to its important pharmacological and therapeutic potentials, and to its large structural diversity. Dereplication techniques based on liquid chromatography coupled to tandem mass spectrometry have recently evolved, with the implementation of molecular networking-based approaches.In this context, we have created a spectral database that encompasses the averaged tandem mass spectra of 172 reference MIAs, in collaboration with several pharmacognosy research teams around the world. This database, named MIADB (standing for Monoterpene Indole Alkaloids DataBase), was made publicly available and can be used as a reference in the application of molecular networking as a dereplication strategy. Thereafter, we used the MIADB to carry out the phytochemical investigation of two Apocynaceae species: Geissospermum laeve (Vell.) Miers and Alstonia balansae Guillaumin. As a first application, the MIADB-based annotation of an alkaloid extract of the barks of G. laeve led to the isolation and the structural elucidation of three new MIAs, two having a butyrolactone moiety. Afterwards, this approach was improved by the application of a new tool for in silico annotation called MetWork, which is based on metabolic prediction and on the generation of predicted tandem mass spectra. Following this approach, the exploration of the chemical space of an alkaloid extract of the leaves of A. balansae allowed the anticipation and further isolation of five novel MIAs of the N-oxide-sarpagine type. The stereochemistry of all the new molecules could be determined on the basis of experimental and predicted electronic circular dichroism spectra.In the introduction of this manuscript the multiple uses of molecular networking for the identification of small natural molecules are described, as well as the biosynthetic interconnections in the MIAs group. The creation and evolution of the MIADB are then presented, followed by its utilization in efficient dereplication workflows for the targeting of new natural products within complex mixtures from Apocynaceae species.

No description available.

L’apparition de P. falciparum résistants aux CTAs est un problème majeur en Asie du Sud-Est. Il est nécessaire de rechercher des molécules présentant des mécanismes d’actions nouveaux. Une cible d’intérêt est l’apicoplaste, un organite de Plasmodium issu d’une endosymbiose avec une algue rouge. Les algues rouges pourraient présenter une source privilégiée de nouvelles molécules antipaludiques ciblant notamment les voies de biosynthèse apicoplastique. Cette thèse porte sur l’identification de ces métabolites secondaires bioactifs via le développement d’une nouvelle stratégie analytique. Un programme informatique nommé Plasmodesma a été créé et permet l’analyse différentielle de manière automatique de spectres RMN 2D 1H-1H et 1H-13C. Les molécules actives peuvent ensuite être isolées et identifiées par HPLC-SPE-RMN. L’activité antipaludique mise en évidence dans les algues rouges étudiées serait due à la présence de molécules de classes chimiques différentes dont des stérols. / Malaria is responsible for 445 000 deaths in 2016. The emergence and the spread of resistant P. falciparum to artemisinin-based combinations is a major health problem in South-East Asia. Research must continue to find compounds with a novel mechanism of action. The apicoplast is an interesting target. It is a Plasmodium organelle derived from a secondary endosymbiosis with a red alga. Red algae could be a special source of new antiplasmodial compounds targeting the isoprenoid biosynthesis pathway in the apicoplast. This thesis focuses on bioactive secondary metabolites identification via a new analytical strategy. A computer program called Plasmodesma was created and achieves an automatic differential analysis of 1H-1H and 1H-13C 2D NMR spectra. Bioactive compounds are isolated and identified by hyphenated HPLC-SPE-NMR. The presence of different classes of compounds including sterols could explain the antiplasmodial activity in studied the red algae species.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Este trabalho descreve o estudo fitoquÃmico de Solanum campaniforme (Solanaceae), visando o isolamento e elucidaÃÃo estrutural de novos constituintes quÃmicos bioativos, bem como o estudo do padrÃo de fragmentaÃÃo por espectrometria de massas seqÃencial com ionizaÃÃo por electrospray (IES-EM/EM) dos alcalÃides obtidos. A investigaÃÃo quÃmica realizada com o extrato etanÃlico das folhas da referida espÃcie, atravÃs de mÃtodos cromatogrÃficos, incluindo CLAE (fase reversa), resultou no isolamento e identificaÃÃo de dezenove substÃncias, sendo quatro derivados fenÃlicos: Ãcido cafÃico (SC-1), Ãster etÃlico do Ãcido cafÃico (SC-2), canferol-3-O-rutinosÃdeo (SC-3) e tiramina (SC-4), e quinze alcalÃides esteroidais: 22,23-epoxi-solanida-1,4,9-trien-3-ona (SC-5), 22,23-epoxi-solanida-1,4-dien-3-ona (SC-6), 3,9-dihidroxi-22,23-epoxi-9,10-seco-solanida-1,3,5(10)-trieno (SC-7), 12-acetiloxi-(25S)-22N-espirosol-4-en-3-ona (SC-8), (25S)-2N-espirosol-1,4-dien-3-ona (SC-9), (25S)-22N-espirosol-4-en-3-ona (SC-10), 22,23-epoxi-solanida-1,4-dien-3-ona (SC-11), 22,23-epoxi-10-epi-solanida-1,4,9-trien-3-ona (SC-12), 12-hidroxi-(25S)-22N-espirosol-4-en-3-ona (SC-13), 22,23-epoxi-solanida-4-en-3-ona (SC-14) e 22,23-epoxi-solanida-4-en-3-ona (SC-15), (E)-N-[8â(4-hidroxifenil)etil]-22,23-epoxi-solanida-1,4,9-trien-3-imina (SC-16), (E)-N-[8â(4-hidroxifenil)etil]-22,23-epoxi-solanida-1,4-dien-3-imina (SC-17), (Z)-N-[8â(4-hidroxifenil)etil]-22,23-epoxi-solanida-1,4,9-trien-3-imina (SC-18) e (Z)-N-[8â(4-hidroxifenil)etil]-22,23-epoxi-solanida-1,4-dien-3-imina (SC-19). Com exceÃÃo dos alcalÃides SC-9 e SC-10, os quais estÃo sendo relatados como produtos naturais pela primeira vez, todos os demais sÃo inÃditos. As substÃncias isoladas tiveram suas estruturas elucidadas por mÃtodos espectromÃtricos (IV, EM e RMN 1H e 13C 1D e 2D), alÃm de comparaÃÃo com dados da literatura. O padrÃo de fragmentaÃÃo dos alcalÃides foi estabelecido com base nos experimentos EM/EM e os dados obtidos foram usados na anÃlise de desreplicaÃÃo destes compostos no extrato etanÃlico bruto das folhas da espÃcie em estudo. O potencial citotÃxico dos alcalÃides majoritÃrios (SC-5 a SC-7) foi avaliado frente Ãs linhagens de cÃlulas tumorais humanas: cÃlon (HCT8), mama (MDA-MB-435), leucemia (HL60) e cÃrebro (SF295), porÃm mostraram-se inativos. Estes compostos tambÃm foram investigados quanto as suas propriedades antiofÃdicas frente ao veneno de Bothrops pauloensis, mostrando significativos efeitos anti-miotÃxico, anti-hemorrÃgico e anti-necrosante. AlÃm disso, foi avaliado o efeito da tiramina sobre o metabolismo de animais com dislipidemia e obesidade, a qual apresentou efeito terapÃutico relacionado à reduÃÃo dos nÃveis de colesterol. / Este trabalho descreve o estudo fitoquÃmico de Solanum campaniforme (Solanaceae), visando o isolamento e elucidaÃÃo estrutural de novos constituintes quÃmicos bioativos, bem como o estudo do padrÃo de fragmentaÃÃo por espectrometria de massas seqÃencial com ionizaÃÃo por electrospray (IES-EM/EM) dos alcalÃides obtidos. A investigaÃÃo quÃmica realizada com o extrato etanÃlico das folhas da referida espÃcie, atravÃs de mÃtodos cromatogrÃficos, incluindo CLAE (fase reversa), resultou no isolamento e identificaÃÃo de dezenove substÃncias, sendo quatro derivados fenÃlicos: Ãcido cafÃico (SC-1), Ãster etÃlico do Ãcido cafÃico (SC-2), canferol-3-O-rutinosÃdeo (SC-3) e tiramina (SC-4), e quinze alcalÃides esteroidais: 22,23-epoxi-solanida-1,4,9-trien-3-ona (SC-5), 22,23-epoxi-solanida-1,4-dien-3-ona (SC-6), 3,9-dihidroxi-22,23-epoxi-9,10-seco-solanida-1,3,5(10)-trieno (SC-7), 12-acetiloxi-(25S)-22N-espirosol-4-en-3-ona (SC-8), (25S)-2N-espirosol-1,4-dien-3-ona (SC-9), (25S)-22N-espirosol-4-en-3-ona (SC-10), 22,23-epoxi-solanida-1,4-dien-3-ona (SC-11), 22,23-epoxi-10-epi-solanida-1,4,9-trien-3-ona (SC-12), 12-hidroxi-(25S)-22N-espirosol-4-en-3-ona (SC-13), 22,23-epoxi-solanida-4-en-3-ona (SC-14) e 22,23-epoxi-solanida-4-en-3-ona (SC-15), (E)-N-[8â(4-hidroxifenil)etil]-22,23-epoxi-solanida-1,4,9-trien-3-imina (SC-16), (E)-N-[8â(4-hidroxifenil)etil]-22,23-epoxi-solanida-1,4-dien-3-imina (SC-17), (Z)-N-[8â(4-hidroxifenil)etil]-22,23-epoxi-solanida-1,4,9-trien-3-imina (SC-18) e (Z)-N-[8â(4-hidroxifenil)etil]-22,23-epoxi-solanida-1,4-dien-3-imina (SC-19). Com exceÃÃo dos alcalÃides SC-9 e SC-10, os quais estÃo sendo relatados como produtos naturais pela primeira vez, todos os demais sÃo inÃditos. As substÃncias isoladas tiveram suas estruturas elucidadas por mÃtodos espectromÃtricos (IV, EM e RMN 1H e 13C 1D e 2D), alÃm de comparaÃÃo com dados da literatura. O padrÃo de fragmentaÃÃo dos alcalÃides foi estabelecido com base nos experimentos EM/EM e os dados obtidos foram usados na anÃlise de desreplicaÃÃo destes compostos no extrato etanÃlico bruto das folhas da espÃcie em estudo. O potencial citotÃxico dos alcalÃides majoritÃrios (SC-5 a SC-7) foi avaliado frente Ãs linhagens de cÃlulas tumorais humanas: cÃlon (HCT8), mama (MDA-MB-435), leucemia (HL60) e cÃrebro (SF295), porÃm mostraram-se inativos. Estes compostos tambÃm foram investigados quanto as suas propriedades antiofÃdicas frente ao veneno de Bothrops pauloensis, mostrando significativos efeitos anti-miotÃxico, anti-hemorrÃgico e anti-necrosante. AlÃm disso, foi avaliado o efeito da tiramina sobre o metabolismo de animais com dislipidemia e obesidade, a qual apresentou efeito terapÃutico relacionado à reduÃÃo dos nÃveis de colesterol. / This work describes the phytochemical investigation of Solanum campaniforme (Solanaceae), aiming the isolation and structural elucidation of new bioactive chemical constituents, as well as the study of their fragmentation pattern under electrospray ionization tandem mass spectrometry (ESI-MS/MS) of the isolated alkaloids. The chemical investigation performed with the ethanol extract from leaves of this species by chromatographic methods, including HPLC (reverse phase), resulted in the isolation and identification of nineteen compounds, being four of them phenol derivatives: caffeic acid (SC-1), caffeic acid ethyl ester (SC-2), kaempferol-3-rutinoside (SC-3) and tyramine (SC-4), and fifteen steroidal alkaloids: 22,23-epoxy-solanida-1,4,9-trien-3-one (SC-5), 22,23-epoxy-solanida-1,4-dien-3-one, (SC-6), 3,9-dihydroxy-22,23-epoxy-9(10)-seco-solanida-1,3,5(10)-triene (SC-7), 12-acetoxyl-(25S)-22N-spirosol-4-en-3-one (SC-8), (25S)-22N-spirosol-1,4-dien-3-one (SC-9), (25S)-22-N-spirosol-4-en-3-one (SC-10), 22,23-epoxy-solanida-1,4-dien-3-one (SC-11), 22,23-epoxy-10-epi-solanida-1,4,9-trien-3-one (SC-12), 12-hydroxy-(25S)-22N-spirosol-4-en-3-one (SC-13), 22,23-epoxy-solanida-4-en-3-one (SC-14) and 22,23-epoxy-solanida-4-en-3-one (SC-15), (E)-N-[8â(4-hydroxyphenyl)ethyl]-22,23-epoxy-solanida-1,4,9-trien-3-imine (SC-16), (E)-N-[8â(4-hydroxyphenyl)ethyl]-22,23-epoxy-solanida-1,4-dien-3-imine (SC-17), (Z)-N-[8â(4-hydroxyphenyl)ethyl]-22,23-epoxy-solanida-1,4,9-trien-3-imine (SC-18) and (Z)-N-[8â(4-hydroxyphenyl)ethyl]-22,23-epoxy-solanida-1,4-dien-3-imine (SC-19). Except the alkaloids SC-9 and SC-10, which are being reported as natural products for the first time, all others are unknowns. The structure of all isolated compounds were elucidated by spectral) methods (IR, HR-ESI-MS, 1H and 13C NMR 1D and 2D and by comparison with literature data. The fragmentation pattern of the alkaloids was established based on MS/MS experiments and the data were used for the dereplication these compounds present in the crude ethanol extract from leaves of S. campaniforme. The cytotoxic potencial of the main alkaloids (SC-5 and SC-7) was evaluated against the human tumor cell lines (HCT8, MDA-MB-435, HL6 and SF295), however, no one showed any activity. The antiophidic properties of the same compounds were also investigated against Bothrops pauloensis venom, showing anti-myotoxic, anti-hemorrhagic and anti-necrosis effects. In addition, was evaluated the effect of tyramine on the metabolism of animals with dyslipidemia and obesity, which exhibited therapeutic effect associated to reduction of the cholesterol levels / This work describes the phytochemical investigation of Solanum campaniforme (Solanaceae), aiming the isolation and structural elucidation of new bioactive chemical constituents, as well as the study of their fragmentation pattern under electrospray ionization tandem mass spectrometry (ESI-MS/MS) of the isolated alkaloids. The chemical investigation performed with the ethanol extract from leaves of this species by chromatographic methods, including HPLC (reverse phase), resulted in the isolation and identification of nineteen compounds, being four of them phenol derivatives: caffeic acid (SC-1), caffeic acid ethyl ester (SC-2), kaempferol-3-rutinoside (SC-3) and tyramine (SC-4), and fifteen steroidal alkaloids: 22,23-epoxy-solanida-1,4,9-trien-3-one (SC-5), 22,23-epoxy-solanida-1,4-dien-3-one, (SC-6), 3,9-dihydroxy-22,23-epoxy-9(10)-seco-solanida-1,3,5(10)-triene (SC-7), 12-acetoxyl-(25S)-22N-spirosol-4-en-3-one (SC-8), (25S)-22N-spirosol-1,4-dien-3-one (SC-9), (25S)-22-N-spirosol-4-en-3-one (SC-10), 22,23-epoxy-solanida-1,4-dien-3-one (SC-11), 22,23-epoxy-10-epi-solanida-1,4,9-trien-3-one (SC-12), 12-hydroxy-(25S)-22N-spirosol-4-en-3-one (SC-13), 22,23-epoxy-solanida-4-en-3-one (SC-14) and 22,23-epoxy-solanida-4-en-3-one (SC-15), (E)-N-[8â(4-hydroxyphenyl)ethyl]-22,23-epoxy-solanida-1,4,9-trien-3-imine (SC-16), (E)-N-[8â(4-hydroxyphenyl)ethyl]-22,23-epoxy-solanida-1,4-dien-3-imine (SC-17), (Z)-N-[8â(4-hydroxyphenyl)ethyl]-22,23-epoxy-solanida-1,4,9-trien-3-imine (SC-18) and (Z)-N-[8â(4-hydroxyphenyl)ethyl]-22,23-epoxy-solanida-1,4-dien-3-imine (SC-19). Except the alkaloids SC-9 and SC-10, which are being reported as natural products for the first time, all others are unknowns. The structure of all isolated compounds were elucidated by spectral) methods (IR, HR-ESI-MS, 1H and 13C NMR 1D and 2D and by comparison with literature data. The fragmentation pattern of the alkaloids was established based on MS/MS experiments and the data were used for the dereplication these compounds present in the crude ethanol extract from leaves of S. campaniforme. The cytotoxic potencial of the main alkaloids (SC-5 and SC-7) was evaluated against the human tumor cell lines (HCT8, MDA-MB-435, HL6 and SF295), however, no one showed any activity. The antiophidic properties of the same compounds were also investigated against Bothrops pauloensis venom, showing anti-myotoxic, anti-hemorrhagic and anti-necrosis effects. In addition, was evaluated the effect of tyramine on the metabolism of animals with dyslipidemia and obesity, which exhibited therapeutic effect associated to reduction of the cholesterol levels

Dans les Antilles françaises, une proportion anormalement élevée de parkinsonismes atypiques sporadiques – des tauopathies – est observée. Un lien avec la consommation de plantes de la famille des Annonaceae, en particulier Annona muricata L. (corossol) a été démontré. Les acétogénines d’Annonaceae, des inhibiteurs puissants du complexe I de la chaine respiratoire mitochondriale, sont considérées comme des toxines candidates. L’annonacine, une acétogénine représentative, majoritaire dans A. muricata, est neurotoxique in vitro et in vivo. L’Agence Française de Sécurité Sanitaire des Aliments a exprimé ses doutes quant à ce problème de santé publique. Elle insiste sur l’importance d’évaluer l’exposition des consommateurs d’Annonaceae aux acétogénines, et de déterminer les paramètres pharmacocinétiques de ces molécules. Au cours de cette thèse, nous avons cherché à répondre à ces interrogations, avec l’annonacine pour modèle. Après l’analyse structurale d’acétogénines étalons, une méthode de déréplication puissante et innovante a été mise au point par CLHP-ESI-LTQ-Orbitrap® avec infusion post-colonne de lithium. Les profils complets des acétogénines d’extraits bruts issus d’un nectar d’A. muricata et d’un alcool d’Annona cherimolia Mill. (annone, chérimole) ont été élucidés, mettant en évidence une composition plus complexe et plus variée que celle envisagée dans la littérature. A. cherimolia n’avait pas été identifiée comme une source d’exposition jusqu’à maintenant. Des données quantitatives ont été obtenues par CLHP-DAD-MS, à partir d’une quinzaine d’échantillons de produits commerciaux, confirmant une exposition humaine importante à ces molécules par voie alimentaire, via des produits d’origines géographiques, de statuts et de modes d’obtention variés. Des travaux préliminaires d’étude du passage de l’annonacine à travers des membranes biologiques ont été amorcés (modèles de barrières intestinale – Caco-2 – et hémato-encéphalique – hCMEC/D3). Une étude de métabolisation de phase I de l’annonacine sur microsomes de foie de Rat a permis d'identifier 25 métabolites mono-hydroxylés par CLHP-ESI-LTQ-Orbitrap®. Seuls trois d’entre eux sont observés avec des microsomes humains. Ces métabolites ont été obtenus par hémisynthèse (bioconversion, catalyse par porphyrines) et leur structure a été déterminée. Les résultats montrent que cette étape de métabolisation n’est pas cruciale dans le devenir de l’annonacine, et ne peut expliquer de susceptibilité différentielle aux acétogénines. Après la présentation de rappels concernant les Annonaceae, les parkinsonismes et leurs formes atypiques guadeloupéennes et tropicales, puis d’aspects méthodologiques en spectrométrie de masse, nos travaux de phytochimie analytique, d’analyse métabolique, d’hémisynthèse et de détermination structurale sont présentés, et discutés en regard d’un problème de santé publique potentiellement large et préoccupant. / In the French West Indies, an unusually high proportion of atypical sporadic parkinsonisms - tauopathies - is observed. A link between these atypical parkinsonisms and the consumption of plants of the Annonacea family, Annona muricata L. (soursop) was demonstrated. The Annonaceous acetogenins are potent inhibitors of complex I of mitochondrial respiratory chain and are considered to be in vitro toxins candidate. The major acetogenin in Annona muricata, annonacin, is neurotoxic in in vitro and in vivo models. Afssa (Agence Française de Sécurité Sanitaire des Aliments) expressed its concern regarding this public health problem. The Agency reports the importance of assessing consumers ‘exposure to Annonaceous acetogenins, and of determining the pharmacokinetic of these molecules. In this thesis, we sintended to answer these questions, with annonacine as a model. After the structural analysis of acetogenins standards, a powerful and innovative method of dereplication was developed by HPLC-ESI-LTQ-Orbitrap ® with post-column infusion of lithium. Complete acetogenins profile in crude extracts from nectar of A. muricata and from an alcohol of Annona cherimolia Mill. (Annona, cherimoya) were elucidated, revealing a more complex and more varied composition than that proposed in the literature. A. cherimolia had not been identified as a source of exposure to date. Quantitative data were obtained by HPLC-DAD-MS, from fifteen samples of commercial products, confirming an important human exposure to these molecules through food products of varied geographical origins, status and methods. Preliminary works to study ability of annonacin to cross biological membranes have been initiated (intestinal barrier models - Caco-2 - and blood-brain barrier - hCMEC/D3). A study of phase I metabolism of annonacin in rat liver microsomes allowed the identification of 25 mono-hydroxylated metabolites by HPLC-ESI-LTQ-Orbitrap®. Only three of them were observed with human microsomes. These metabolites were obtained by semisynthesis (bioconversion, porphyrin mediated catalysis) and their structure was determined. The results show that phase metabolism is not critical in the becoming of annonacin, and cannot explain a differential susceptibility of acetogenins. After a presentation of the Annonaceae family, of parkinsonism – including atypical and guadeloupean forms then of and methodological aspects of mass spectrometry, analytical phytochemistry of our work, metabolic analysis, semisynthesis and structure determination are proposed, and discussed in the context of a public health problem and potentially broad concern.

O presente projeto de pesquisa teve por objetivo a descoberta de metabólitos secundários potencialmente bioativos contra atividade parasitária e como agentes anti-virais e antibióticos, usando desreplicação como metodologia essencial na seleção e priorização de extratos brutos oriundos de invertebrados, para a descoberta de produtos naturais estruturalmente inéditos.<br /><br />Foram preparados diversos extratos de invertebrados marinhos a partir de um fracionamento inicial. O desenvolvimento e a aplicação de uma metodologia de desreplicação permitiu a seleção de três organismos de estudo, Iotrochota birotulata, Amathia verticillata, e Tedania brasiliensis. Os extratos destes organismos foram submetidos a diferentes metodologias de fracionamento, isolamento e purificação de substâncias, dependendo dos resultados de desreplicação para cada organismo.<br /><br />Como resultado do isolamento e identificação de substancias destes organismos, obteve-se dois compostos já conhecidos na literatura e dezesseis compostos inéditos, dos quais dois são derivados sintéticos. De todos os compostos isolados, a pseudoceratidina, as desbromopseudoceratidinas e as tedamidas A e B apresentaram um índice de seletividade de 243.1, 217.1 e 89.3 respectivamente para Leishmania (L.) infantum, e o composto N12-acetilpseudoceratidina de 23.2 para Trypanosoma cruzi, sendo estes resultados muito promissores para a utilização das estruturas destas moléculas como potenciais modelos para o desenvolvimento de fármacos. / This research project aimed at the discovery of potentially bioactive secondary metabolites against parasitic activity and as antiviral agents and antibiotics, using dereplication as an essential methodology in the selection and prioritization of crude extracts derived from invertebrates, to the discovery of natural products structurally unpublished.<br /><br />Various extracts of marine invertebrates from an initial fractionation were prepared. The development and application of a dereplication methodology allowed the selection of three study organisms, Iotrochota birotulata, Amathia verticillata, and Tedania brasiliensis. The extracts of these organisms were subjected to different methods of fractionation, isolation and purification of substances, depending on the results of dereplication for each organism.<br /><br /> As a result of the isolation and identification of substances of these organisms, it obtained two compounds already known in the literature and unpublished sixteen compounds, two of which are synthetic derivatives. In all isolated compounds, pseudoceratidina, the desbromopseudoceratidinas and tedamidas A and B showed an index of selectivity 243.1, 217.1 and 89.3 respectively for Leishmania (L.) infantum, and the compound N12-acetilpseudoceratidina 23.2 for Trypanosoma cruzi, which are very promising results for the use of these molecules as structures potential models for drug development.

O presente projeto de pesquisa teve por objetivo a descoberta de metabólitos secundários potencialmente bioativos contra atividade parasitária e como agentes anti-virais e antibióticos, usando desreplicação como metodologia essencial na seleção e priorização de extratos brutos oriundos de invertebrados, para a descoberta de produtos naturais estruturalmente inéditos.<br /><br />Foram preparados diversos extratos de invertebrados marinhos a partir de um fracionamento inicial. O desenvolvimento e a aplicação de uma metodologia de desreplicação permitiu a seleção de três organismos de estudo, Iotrochota birotulata, Amathia verticillata, e Tedania brasiliensis. Os extratos destes organismos foram submetidos a diferentes metodologias de fracionamento, isolamento e purificação de substâncias, dependendo dos resultados de desreplicação para cada organismo.<br /><br />Como resultado do isolamento e identificação de substancias destes organismos, obteve-se dois compostos já conhecidos na literatura e dezesseis compostos inéditos, dos quais dois são derivados sintéticos. De todos os compostos isolados, a pseudoceratidina, as desbromopseudoceratidinas e as tedamidas A e B apresentaram um índice de seletividade de 243.1, 217.1 e 89.3 respectivamente para Leishmania (L.) infantum, e o composto N12-acetilpseudoceratidina de 23.2 para Trypanosoma cruzi, sendo estes resultados muito promissores para a utilização das estruturas destas moléculas como potenciais modelos para o desenvolvimento de fármacos. / This research project aimed at the discovery of potentially bioactive secondary metabolites against parasitic activity and as antiviral agents and antibiotics, using dereplication as an essential methodology in the selection and prioritization of crude extracts derived from invertebrates, to the discovery of natural products structurally unpublished.<br /><br />Various extracts of marine invertebrates from an initial fractionation were prepared. The development and application of a dereplication methodology allowed the selection of three study organisms, Iotrochota birotulata, Amathia verticillata, and Tedania brasiliensis. The extracts of these organisms were subjected to different methods of fractionation, isolation and purification of substances, depending on the results of dereplication for each organism.<br /><br /> As a result of the isolation and identification of substances of these organisms, it obtained two compounds already known in the literature and unpublished sixteen compounds, two of which are synthetic derivatives. In all isolated compounds, pseudoceratidina, the desbromopseudoceratidinas and tedamidas A and B showed an index of selectivity 243.1, 217.1 and 89.3 respectively for Leishmania (L.) infantum, and the compound N12-acetilpseudoceratidina 23.2 for Trypanosoma cruzi, which are very promising results for the use of these molecules as structures potential models for drug development.