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Orientador: Prof. Dr. João Henrique Ghilardi Lago Coorientadora: Profa. Dra. Simone dos Santos Grecco Tese (doutorado) - Universidade Federal do ABC, Programa de Pós-Graduação em Ciência e Tecnologia Química, Santo André, 2020. O genero Baccharis abrange cerca de 400 especies originalmente distribuidas em toda a America, entretanto apenas 30% das especies deste genero foram estudadas quimicamente. Os principais compostos encontrados neste genero sao flavonoides e diterpenos, considerados os metabolitos responsaveis pelas diversas atividades biologicas atribuidas a essas especies. Nesse estudo, os extratos metanolicos de duas especies de Baccharis . B. sphenophylla (BSM) e B. lateralis (BLM), foram submetidos a estudos de desreplicacao molecular via UPLC/DAD/HRMS, visto que nao existe na literatura nenhum estudo concernente a composicao quimica ou atividade biologica destes. Tendo em vista a busca constante de extratos e compostos bioativos frente a doencas negligenciadas por nosso grupo de pesquisa, os potenciais antiparasitarios desses extratos foram investigados contra formas tripomastigotas de Trypanosoma cruzi. A investigacao quimica dos extratos metanolicos de BSM e BLM evidenciou a presenca de 18 e 15 compostos respectivamente, com destaque para sakuranetina (XXIX) e apigenina (XXVII), alem dos acidos 5-metoxissalicilico (VIII) e urocanico (V) em BLM, e da gardenina A (XVIII), da 6-metoxiluteolina (XII) e do acido 5-metoxissalicilico (VIII) em BSM. No que tange a avaliacao da atividade anti-T. cruzi, os valores de CI50 foram definidos como 27,2 ¿Êg/mL e 16,9 ¿Êg/mL, para os extratos de BSM e BLM, respectivamente. Os extratos nao apresentaram toxicidade frente a celulas NCTC, CC50 > 200 ¿Êg/mL, portanto, os indices de seletividade (IS) de ambos foram calculados como > 7,3 para BSM e > 11,8 para BLM. O maior potencial antiparasitario apresentado por BLM, pode ser justificado, pelo menos em parte, pela presenca dos flavonoides XXIX e XXVII, cujo potencial antiparasitario foi previamente descrito. Adicionalmente os extratos hexanicos de ambas as especies apresentaram atividade anti-helmintica in vitro, com 100% de morte parasitaria. A analise por Ressonancia Magnetica Nuclear (RMN) destes extratos indicou a presenca de diterpenos do tipo ent-caureno que foram isolados e identificados como acido ent-caur-16-en-19-oico (I) e acido 15¿À-senecioiloxi-ent-caur-16-en-19-oico (II). Tais compostos, foram testados individualmente frente a vermes adultos de Schistosoma mansoni, gerando valores de CC50 de 108,6 ¿ÊM e 147,2 ¿ÊM e IS de 1,7 e 9,1 respectivamente. Posteriormente foram realizados ensaios in vivo para o composto II, cujos resultados mostraram significativa reducao da carga parasitaria e reducao das lesoes de hepatoesplenomegalia dos animais tratados, sendo, portanto, um produto natural com elevado potencial anti-helmintico. Belonging to Asteraceae, with about 400 species originally distributed throughout America, only 30% of species from the Baccharis genus have been studied chemically. The main compounds found in this genus are flavonoids and diterpenes, which are considered the metabolites responsible for several biological activities attributed to these plant species. In this study, the methanolic extracts of two species of Baccharis - B. sphenophylla (BSM) and B. lateralis (BLM), were subjected to molecular dereplication, through UPLC/DAD/HRMS, since the chemical composition of its extracts or biological activity are still unreported. In view of the constant search for extracts and bioactive compounds for neglected diseases, by our research group, additionally the anti-parasitic potential of BLM and BSM extracts were also investigated against trypomastigote forms of Trypanosoma cruzi. The chemical investigation of BSM and BLM extracts highlighted 18 and 15 compounds, respectively. Among, these were identified sakuranetin (XXIX), apigenin (XXVII) and the 5-methoxysalicylic and urocanic acids (VIII and V), mainly in BLM; and gardenin A (XVIII), 6-methoxyluteolin (XII) and 5-methoxysalicylic acid (VIII) in BSM. Regarding the evaluation of antiparasitic activity, IC50 values were defined as 27.2 ìg/mL and 16.9 ìg/mL, for BSM and BLM, respectively. The extracts also showed no toxicity against mammalian cells (NCTC) at the maximum tested concentrations (CC50 > 200 ìg/mL), therefore, the selectivity index (SI) of both extracts were calculated as > 7.3 for BSM and >11.8 for BLM. The greater antiparasitic potential presented by BLM, when compared to BSM, may be due to the presence of sakuranetin and apigenin flavonoids, since previous studies attribute anti-T. cruzi activity to these compounds. The n-hexane extracts of both plant species showed anthelmintic activity, with 100% of parasite death. The analysis by Nuclear Magnetic Resonance (NMR) of these extracts indicated the presence of ent-kaurene diterpenes, that were isolated and identified as ent-kaur-16-en- 19-oic and ent-15â-senecioyloxy-kaur-16-en-19-oic acids (I and II), being tested against adult Schistosoma mansoni worms, displaying CC50 values of 108.6 ìM and 147.2 ìM and IS of 1.7 and 9.1 respectively. In vivo tests were performed for compound II, whose results showed a significant reduction in the parasitic load and a reduction in the hepatosplenomegaly lesions of the treated animals, being, therefore, a natural product with high anthelmintic potential.

Significance Self-replication is an important property of life, yet no one knows how it arose, and the machinery found in modern cells is far too complex to have formed by chance. One suggestion is that simple networks may become able to cooperate and hence replicate together forming autocatalytic sets, but no simple systems have been found. Here we present an inorganic autocatalytic, based on molybdenum blue, that is formed spontaneously when a simple inorganic salt of sodium molybdate is reduced under acidic conditions. This study demonstrates how autocatalytic sets, based on simple inorganic salts, can lead to the spontaneous emergence of self-replicating systems and solves the mystery of how gigantic molecular nanostructures of molybdenum blue can form in the first place., Here we show how a simple inorganic salt can spontaneously form autocatalytic sets of replicating inorganic molecules that work via molecular recognition based on the {PMo12} ≡ [PMo12O40]3– Keggin ion, and {Mo36} ≡ [H3Mo57M6(NO)6O183(H2O)18]22– cluster. These small clusters are able to catalyze their own formation via an autocatalytic network, which subsequently template the assembly of gigantic molybdenum-blue wheel {Mo154} ≡ [Mo154O462H14(H2O)70]14–, {Mo132} ≡ [MoVI72MoV60O372(CH3COO)30(H2O)72]42– ball-shaped species containing 154 and 132 molybdenum atoms, and a {PMo12}⊂{Mo124Ce4} ≡ [H16MoVI100MoV24Ce4O376(H2O)56 (PMoVI10MoV2O40)(C6H12N2O4S2)4]5– nanostructure. Kinetic investigations revealed key traits of autocatalytic systems including molecular recognition and kinetic saturation. A stochastic model confirms the presence of an autocatalytic network involving molecular recognition and assembly processes, where the larger clusters are the only products stabilized by the cycle, isolated due to a critical transition in the network.

Fundo Mackenzie de Pesquisa Molecular replication was introduced as a possible theory to explain the origin of life. Since their proposal they have been extensively studied from a biochemical perspective. This work proposes a taxonomy for the main properties of replicators that are important for building computational tools to solve complex problems as well as introduces two computational models for these entities in order to observe and analyze the behavior of these models in light of the natural properties of replicators introduced. A replicação molecular foi introduzida como uma possível teoria para explicar a origem da vida. Desde sua proposição, ela vem sendo estudada extensivamente a partir de uma perspectiva bioquímica. Baseado na literatura de replicadores moleculares, esta dissertação organiza e propõe uma taxonomia para as principais propriedades dos replicadores que sejam interessantes para a construção de ferramentas computacionais voltadas para a solução de problemas complexos na engenharia e na computação, bem como introduz dois modelos computacionais baseado nessas entidades a fim de observar e analisar o comportamento destes modelos sob a luz das propriedades dos replicadores naturais discutidas nesta dissertação.