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Título: SYNTHESIS OF ARYLATED THIAZOLE DERIVATIVES AND PRELIMINARY EVALUATION OF THEIR TOXICITY AND ANTI T. CRUZI ACTIVITY
Autor: KELLY LOPES FIGUEIRA
Instituição: PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIRO - PUC-RIO
Colaborador(es):  JONES LIMBERGER - ADVISOR
Nº do Conteudo: 56355
Catalogação:  02/12/2021 Idioma(s):  PORTUGUESE - BRAZIL
Tipo:  TEXT Subtipo:  THESIS
Natureza:  SCHOLARLY PUBLICATION
Nota:  Todos os dados constantes dos documentos são de inteira responsabilidade de seus autores. Os dados utilizados nas descrições dos documentos estão em conformidade com os sistemas da administração da PUC-Rio.
Referência [pt]:  https://www.maxwell.vrac.puc-rio.br/colecao.php?strSecao=resultado&nrSeq=56355@1
Referência [en]:  https://www.maxwell.vrac.puc-rio.br/colecao.php?strSecao=resultado&nrSeq=56355@2
Referência DOI:  https://doi.org/10.17771/PUCRio.acad.56355

Resumo:
Neglected diseases are mainly caused by infectious agents or parasites, generating high morbidity and mortality rates worldwide. The investments from developed countries in research, production of drugs/medicines and control of these diseases are small, since they mainly affect populations with low Human Development Index. One of these illnesses is Chagas disease, caused by Trypanosoma cruzi. It presents as a chronic and highly debilitating parasitic infection, affecting more than 6 million people only in Latin America with a perspective of increasing approximately 25 percent in few years. The reference drug for the treatment of Chagas disease in Brazil is benznidazole, which is extremely effective in the acute phase of the disease, but its efficacy in the chronic phase is limited, which makes essential the search for new compounds that also act in this phase. In the present work, synthetic routes were developed for a series of 12 thiazole derivatives, from which eight have been described for the first time. These molecules had their preliminary trypanocidal activity and toxicity evaluated in in vitro models. The compounds with the thiazole ring were structurally planned, based on the bibliographic review, where it was found that certain compounds with this heterocycle display trypanocidal properties. In the synthesis, 1-(4- bromophenyl)ethenone (54) was used as a starting material to obtain the thiazole intermediates 4-(4-bromophenyl)-2-methylthiazole (56) and 4-(4-bromophenyl)thiazol-2- amine (57). Several modifications were performed on these intermediates to produce the target molecules. The structural elucidation of the compounds was performed by 1H NMR and 13C NMR. Preliminary evaluation of trypanocidal activity was performed in the amastigotes intracellular form of the Tulahuen strain and the acute toxicity (LC50) was tested in vitro in mammalian host cells (cell line L929). Among the synthesized compounds, most of them presented low toxicity, with LC50 values greater than 400 (micro)mol/mol.L-1. The thiazole compound pyridil-substituted 59c showed the best results in terms of trypanocidal activity, reducing 76 percent of the infection in host cells in a concentration of 20 (micro)mol/mol.L-1. This thia\ole derivative will be used as a lead compound for structural optimizations aiming at improving trypanocidal activity.

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