SÃntese e avaliaÃÃo de tiossemicarbazonas e tiazolinonas como inibidores da protease cruzaÃna do Trypanosoma cruzi

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

Chagas disease is still a specific and impressive problem in Latin America, under many aspects linked to questions related to social inequity and globalization process. The disease, in spite of financial and policies difficulties, has been controlled; however, a period of two or three decades remains necessary for the consolidation of control, surveillance improvement and appropriate therapy for individuals already infected. Since the discovery of Chagas disease, in 1909, the demand for an effective therapy for both stages of the disease, acute and chronic phase, is a challenge for many researchers. Nowadays, only two drugs are being used against Chagas disease, the Nifurtimox and the Benznidazole, known commercially as Lampit  and Rochagan Â, respectively. This therapy, besides causing several adverse effects, is not effective for the chronic stage of the disease. Currently, several studies report that compounds that have the portion thiosemicarbazone have a potential antichagasic activity due to a possible inhibition of the Trypanosoma cruzi cruzain enzyme (TCC). The cruzain enzyme is responsible for replication of intracellular T. cruzi, and due to this function, itâs a target exploited for the development of new drugs potentially antichagasics. The objective of this work was to analyze the synthesis, the studies of "docking" in cruzain and the antichagasic evaluation of thiosemicarbazonics and thiazolinonics derivatives. Initially, aryl-4-oxothiazolilhidrazones were synthesized, resulting in nine different compounds. The obtained products were submitted to in vitro tests of antichagasic activity and to studies of "docking" in the TCC, showing antichagasic activity and TCC interaction. The most promising compound of the group was the N-(4-oxo-5-ethyl-2 -tiazolin-2-yl)-N -phenilthio-(Z)-etilidenehidrazone (6f), which proved to be active in non-cytotoxic concentrations of mammals cells and presented antichagasic activity comparable to that one verified in drugs nowadays, Nifurtimox and Benznidazole. The studies of "docking" revealed that there is an interaction between the compound 6f and the TCC, similarly to that one occurred between benzinidazole binder and the "186". Finally, new Aril-4-Oxothiazolil-hidrazones were synthesized and submitted to review of in vitro antichagasic activity. Fourteen compounds were obtained; the ones that showed the best antichagasics activity were 2 - [(p-metilphenilthio-(Z)-etilidene) hydrazone hydrochlorid]-5-methyl-1, 3-thiazol-4 (5H)-one (3f), 2 - [(p - bromophenilthio-(Z)-etilidene) hydrazone hydrochlorid]-5-ethyl-1 ,3-thiazol-4 (5H)-one (3i) and 2 - [(phenilthio-(Z)-3-butilidene) hydrazone hydrochlorid] -1, 3-thiazol-4 (5H)-one (3j). The compound 3j, in non-cytotoxic concentration to mammalian cells, presented similar activity to the standards used, the Nifurtimox and the Benznidazole

ASSUNTO(S)

doenÃa de chagas âdockingâ thiosemicarbazones and thiazolinones âdockingâ chagas disease tiossemicarbazonas e tiazolinonas cruzain cruzaÃna trypanosoma cruzi trypanosoma cruzi farmacia

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