Synthesis and evaluation of the biological activity of mesoionic compounds of the 1,3,4-thiadiazolium-2-arylaminides class

Autor: Lopes, Nat?lia Drumond
Přispěvatelé: Lima, Aurea Echevarria Aznar Neves, Oliveira, M?rcia Cristina Campos de, Pissinate, Kenia, Simas, Alessandro Bolis Costa, Silva, Edson Ferreira da, Graebin, Cedric Stephan
Jazyk: portugalština
Rok vydání: 2018
Předmět:
Zdroj: Biblioteca Digital de Teses e Dissertações da UFRRJ
Universidade Federal Rural do Rio de Janeiro (UFRRJ)
instacron:UFRRJ
Popis: Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2021-07-27T22:22:12Z No. of bitstreams: 1 2018 - Nat?lia Drumond Lopes.pdf: 4417673 bytes, checksum: 3a56b29265fc2b84f88130b713d9468a (MD5) Made available in DSpace on 2021-07-27T22:22:12Z (GMT). No. of bitstreams: 1 2018 - Nat?lia Drumond Lopes.pdf: 4417673 bytes, checksum: 3a56b29265fc2b84f88130b713d9468a (MD5) Previous issue date: 2018-06-26 Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES, Brasil) Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq, Brasil) Funda??o Carlos Chagas Filho de Amparo ? Pesquisa do Estado do Rio de Janeiro (FAPERJ, Brasil) PETROBRAS Cancer is a public health problem, being considered the second largest cause of death in Brazil. Currently, the therapeutic methods used against cancer are based on surgery, radiotherapy and chemotherapy. Although chemotherapy has been being improved recently, several types of cancer still do not have systemic and adequate treatment, such as melanoma and leukemia adult T-cell lymphoma, making it necessary to find new, more efficient and less toxic antineoplastic agents for healthy cells in order to improve the effectiveness of treatment of these diseases. Considering this scenery, heterocyclic compounds are shown to be promising substances for antitumor activity, including mesoionic compounds. In this work the synthesis of 4 series of mesoionic compounds of the class 1,3,4-thiadiazolium-2-arylaminide in the form of hydrochlorides is presented, resulting in 24 compounds in total, of which 20 are unpublished. The synthesis methodology for the serie I was oriented from the principles of Green Chemistry, performing reactions in absence of solvent and use of microwaves from piperonal derivatives and substituted thiosemicarbazides in yields between 60 and 95%. The compounds of series II, III and IV were obtained from chlorides of substituted cinnamic acids and thiosemicarbazides also substituted in 1,4-dioxane under reflux in satisfactory yields. All synthesized compounds were characterized by IR, 1H and 13C NMR spectroscopic techniques confirming the proposed structures. The compounds of series I were evaluated for inhibition of the enzyme tyrosinase, a biological marker for melanomas. The results obtained were promising for tyrosinase inhibitory activity for derivatives 16 (IC50 = 124 ?mol L-1) and 17 (IC50 = 358 ?mol L-1). The study of interaction with human serum albumin, as well as molecular modeling studies, were performed for these compounds justifying the results obtained in vitro. The compounds of series II were evaluated for cytotoxic activity against three human leukemia lines (Jurkat, MT2 and K562) showing good results for compounds 18 and 22, whereas the assays for the other compounds are in progress with promising preliminary results. The results obtained in this thesis indicate that mesoionic compounds can be used as prototypes for new agents in cancer chemotherapy. O c?ncer ? um problema de sa?de p?blica, sendo considerado a segunda maior causa de morte no Brasil e no mundo. Atualmente, os m?todos terap?uticos empregados contra o c?ncer baseiam-se em cirurgia, radioterapia e quimioterapia. Embora a quimioterapia tenha avan?ado recentemente, v?rios tipos de c?nceres ainda n?o disp?em de tratamento sist?mico e adequado, como o melanoma e a leucemia linfoma de c?lulas T de adulto, tornando-se necess?rio a procura de novos agentes antineopl?sicos mais eficientes e menos t?xicos para as c?lulas sadias, a fim de aprimorar a efic?cia de tratamento dessas doen?as. Diante deste panorama, compostos heteroc?clicos se mostram como subst?ncias promissoras para a atividade antitumoral, incluindo os compostos mesoi?nicos. Neste presente trabalho ? apresentado a s?ntese de 4 s?ries de compostos mesoi?nicos da classe 1,3,4-tiadiaz?lio-2-arilaminida, na forma de cloridratos, resultando em 24 compostos no total, sendo 20 in?ditos. A metodologia de s?ntese para a s?rie I foi orientada a partir dos princ?pios da Qu?mica Verde, realizando rea??es em aus?ncia de solvente e uso de micro-ondas a partir de derivados do piperonal e de tiossemicarbazidas substitu?das em rendimentos entre 60 e 95%. Os compostos das s?ries II, III e IV foram obtidos a partir dos cloretos de ?cidos cin?micos substitu?dos e tiossemicarbazidas tamb?m substitu?das em 1,4-dioxano sob refluxo em rendimentos satisfat?rios. Todos os compostos sintetizados foram caracterizados por t?cnicas espectrosc?picas de IV, RMN 1H e 13C confirmando as estruturas propostas. Os compostos da s?rie I foram avaliados quanto a inibi??o da enzima tirosinase, marcador biol?gico para melanomas. Os resultados obtidos se mostraram promissores quanto ? atividade inibit?ria da tirosinase para os derivados 16 (IC50=124 ?mol L-1) e 17 (IC50=358 ?mol L-1). O estudo da intera??o com a soro albumina humana, bem como, estudos de modelagem molecular, foram realizados para esses compostos justificando os resultados obtidos in vitro. Os compostos da s?rie II foram avaliados quanto a atividade citot?xica frente a tr?s linhagens de leucemias humanas (Jurkat, MT2 e K562) mostrando bons resultados para os compostos 18 e 22, enquanto que os ensaios para os demais compostos est?o em andamento apresentando resultados preliminares promissores. Os resultados obtidos neste trabalho de tese indicam que os compostos mesoi?nicos podem ser utilizados como prot?tipos para novos agentes na quimioterapia do c?ncer.
Databáze: OpenAIRE
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