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Master's Dissertation
DOI
10.11606/D.60.2015.tde-25092015-113957
Document
Author
Full name
Ana Paula Hartmann
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2015
Supervisor
Committee
Carvalho, Ivone (President)
Bernardes, Lilian Sibelle Campos
Silva, João Santana da
Title in Portuguese
Síntese e avaliação de derivados furânicos, tetraidrofurânicos e pirrólicos com potencial atividade  tripanocida
Keywords in Portuguese
derivados furânicos
derivados tetraidrofurânicos
Doença de Chagas
lignanas tetraidrofurânicas
Trypanosoma cruzi
Abstract in Portuguese
A Doença de Chagas é causada pelo Trypanosoma cruzi, e possui duas fases clínicas, sendo o tratamento com o fármaco benznidazol eficaz somente na fase aguda, porém com diversos efeitos adversos ao longo do período do tratamento. Desta forma, consórcios vêm sendo estabelecidos entre "governo - universidade - indústria", com auxilio de capital nacional e estrangeiro para o desenvolvimento de novos fármacos. Apesar de diversas ferramentas disponíveis para o planejamento de novos compostos, a busca por produtos naturais ainda desperta interesse de muitos pesquisadores. Diversos trabalhos vêm descrevendo estudos de síntese e atividade tripanocida de lignanas, as quais merecem destaque, veraguensina (17) e grandisina (18). Devido à falta de tratamento e a alta toxicidade dos agentes disponíveis, este trabalho tem como objetivo sintetizar análogos dessas lignanas, relacionados a derivados de tetraidrofurânicos, furânicos, pirrólicos e de seus intermediários e testa-lasfrente à atividade tripanocida e citotóxica. O planejamento sintético envolveu a geração de derivados 1,4-diaril-2-butino-1,4-diol (28a-t) a partir da reação de condensação entre fenil carbinol (26) e aldeídos arílicos (27a-t) com diferentes padrões de substituiçõescom diversos grupos funcionais. Estes intermediários, obtidos em rendimentos moderados, foram convertidos aos correspondentes 1,4-diaril-1,4-diidroxílicos (30a-g), pela reação de redução em dióxido de platina e, posteriormente, oxidados a 1,4-diaril-1,4-dicetonas (29a-g). A partir da formação dos intermediários 29 e 30, os produtos de interesse, 2,5-diaril-furano (32a-g) e 2,5-diaril-tetraidrofurano (31a-g) foram preparados empregando reações de ciclização na presença de ácidos tríflico e trifluoroacético, respectivamente. Os intermediários e produtos obtidos em rendimentos de moderado a bom, totalizando 48 compostos, foram avaliados em ensaios de atividade tripanocida, envolvendo a cepa Tulahuen de T. cruzi, bem como ensaios de citotoxicidade. Considerando as cinco séries sintetizadas (28, 29, 30, 31 e 32), vale destacar que a maioria apresentou compostos com potente atividade tripanocida, a partir de 1,4 ?M, superior ao fármaco disponível benznidazol (7,9 ?M) e, adicionalmente, não apresentaram citotoxicidade em ensaios realizados por citometria de fluxo.
Title in English
Synthesis and evaluation of furan, tetrahydrofuran and pyrrole derivatives with potential trypanocidal activity
Keywords in English
Chagas disease
furan derivatives
tetrahydrofuran derivatives
tetrahydrofuran lignans
Trypanosoma cruzi
Abstract in English
Chagas' disease is caused by the Trypanosoma cruzi, whichhas two clinical stages. The treatment with the benznidazole is effective only in the acute stage, although with several side effects throughout the treatment period. Therefore, consortia are being established between "government - university - industry", with national and foreign financial support for drug discovery development. In spite of many available tools to design new compounds, the search for natural products still arouse interestfor a great number of researchers. Several papers have described studies of synthesis and trypanocidal activity of lignans, being veraguensin (17) and grandisin (18) worth to mention. Due to the lack of treatment and the high toxicity of the available drugs, this research has the aimto synthesize analogues from the above lignans, such astetrahydrofuran, furanic, pyrrolic derivatives and their intermediates,and test their trypanocidal activity and cytotoxicities. The synthetic strategy was based on the synthesis of 1,4-diarylacetylene-1,4-glycols (28a-t) via condensation reaction between phenyl carbinol (26) and substituted aryl aldehydes (27a-t) with several functional groups at different positionsof the aromatic ring. These intermediates, obtained in moderate yields, were converted to their corresponding 1,4-diaryl-1,4-dihydroxyl derivatives (30a-g) by the reduction reaction using platinum dioxide and, subsequently, oxidized to 1,4-diaryl-1,4-diketones (29a-g). From the synthesis of the intermediates 29 and 30, products of interest, 2,5-diaryl-furan (32a-g) and 2,5-diaryl-tetrahydrofuran (31a-g) were prepared from the cyclization reaction in the presence of the triflic and trifluoracetic acids, respectively. The intermediates and products, obtained in moderate to good yields, in a total of 48 compounds, were assessed in trypanocidal assays, using T. cruzi Tulahuen strain,as well as cytotoxicity assays. Considering the five synthesized series (28, 29, 30, 31 e 32), it is worth noting that the majority of the compounds showed potent trypanocidal activity from 1.4 ?M, higher than the available benznidazole (7,9 ?M) and, additionally, they were not cytotoxicin Flow Cytometry assays.
 
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Release Date
2017-09-24
Publishing Date
2015-11-03
 
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