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Master's Dissertation
DOI
Document
Author
Full name
Thiago Kelvin Brito Matos
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Carlos, 2019
Supervisor
Committee
Leitão, Andrei (President)
Porto, André Luiz Meleiro
Miranda, Paulo Cesar Muniz de Lacerda
Schwab, Ricardo Samuel
Title in Portuguese
Síntese de Inibidores Reversíveis de Cisteíno Proteases para Avaliação da Atividade Antileishmaniose
Keywords in Portuguese
dipeptidil-nitrilas
leishmaniose
síntese de inibidores
Abstract in Portuguese

Dentre os diversos tipos de patologias, as doenças negligenciadas apresentam grande prevalência na população em países tropicais. A leishmaniose é uma doença negligenciada endêmica no Brasil, com incidência em áreas urbanas e rurais. A ineficácia e elevados efeitos colaterais de fármacos como a Anfotericina B, que é atualmente empregada, tem levado a pesquisa e desenvolvimento de substâncias bioativas antileishmaniose. Um alvo macromolecular de interesse terapêutico é a cisteíno protease B (CPB) devido a sua atuação e importância em diversas etapas do ciclo de vida da Leishmania. Assim, o Grupo de Química Medicinal (NEQUIMED) estuda inibidores covalentes reversíveis da cisteíno protease CPB com potencial atividade antileishmaniose. Neste projeto, a síntese de derivados de dipeptidil-nitrilas é realizada para que com potencial atividade inibidora da CPB e antileishmaniose seja acessado por meio dos ensaios biológicos correspondentes. Neste projeto, derivados e estereoisômeros do composto N-(1-cianociclopropil)-3-fenil-2-((-2,2,2-trifluoro-1-fenil-etil)amino) propanamida foram produzidos e caracterizados. 15 substâncias foram produzidas e purificadas por HPLC e sua pureza determinada por medição de ponto de fusão e HPLC-MS, com caracterização por RMN (1H e 13C) e FT-IR. A partir desta série, a estereosseletividade enzimática para a CPB será acessada por meio de ensaios bioquímicos e biofísicos e também por ensaios celulares a serem realizados por outros membros do grupo.

Title in English
Synthesis of Reversible Inhibitors of Cysteine Proteases to Biological Assays
Keywords in English
dipeptidyl nitriles
inhibitors synthesis
leishmaniasis
Abstract in English

Among several types of pathologies, neglected tropical diseases present high prevalence in the population in tropical countries. Leishmaniasis is a neglected disease which endemic in Brazil, with incidence in urban and rural areas. The ineffectiveness and numerous side effects of drugs such as amphotericin B, which is currently used for treatment has led to the research and development of bioactive antileishmanial substances. A macromolecular target of therapeutic interest is the enzyme cysteine protease B (CPB) because of its performance and importance at various stages of the Leishmania life cycle. Thus, the Medicinal Chemistry Group (NEQUIMED) studies covalent inhibitors of cysteine protease CPB with potential antileishmanial activity. In this study, the synthesis of dipeptidyl nitrile derivatives is performed so that with potential inhibitory activity for CPB and antileishmaniasis is accessed through the corresponding biological assays. In this project, it was produced and characterized derivatives and stereoisomers of the compound N-(1-cyanocyclopropyl)-3-phenyl-2-((2,2,2-trifluoro-1-phenyl-ethyl)amino)propanamide. 15 substances were produced and purified by HPLC and determined purity by melting point measurement and HPLC-MS, characterizing by NMR (1H and 13C) and FT-IR. From this series, the enzymatic stereoselectivity for CPB will be accessed through biochemical and biophysical assays and by cellular assays to be performed by other members of the group.

 
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Publishing Date
2019-05-21
 
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