Síntese e caracterização de tiossemicarbazonas, carbimidotioatos e derivados benzotriazocínicos avaliação da atividade antiparasitária de tiossemicarbazonas derivadas do núcleo 3,4-metilenidioxila

Abstract

Diseases caused by parasites of the species of Trypanosoma and Leishmania affect hundreds of thousands of people in more than ninety countries on five continents. Thousands of people suffer from Chagas and Leishmaniasis disease in Brazil. People infected by these parasites are generally poor. The treatments available are old, aggressive, expensive and ineffective, and this is explained in part by the lack of sensitivity of the pharmaceutical industry, who are unwilling to invest in drugs for low-income populations. What led these parasites, among other diseases, to compose the list of diseases called "neglected”. This work presents the synthesis of twenty-two thiosemicarbazones, including twelve 3,4-metilenodioxil derived and ten benzo-fluorinateds derived. Fourteen of these are new thiosemicarbazones. Although six compounds were synthesized from the class of hydrazine-carbimidothioates and two were synthesized from the class of benzotriazocin-6(5H)-2-one, all never reported. The compounds were structurally characterized by IV and RMN 1H, 13C, DEPT Q e DEPT 135º. Different synthetic methodologies were employed as alternative means for the reactions of Sandmayer, aiming good results for the core 3.4-metilenodioxil. The chlorination reaction of piperonal with trichloroisocyanuric acid is reported in this study originally. The synthesis reactions of thiosemicarbazones showed yields between 91.0% and 98.5%. Was made a review about enzymes, biosynthetic and metabolic pathways of trypanosomatids, that could be chemotherapeutic targets of these synthesized compounds. Antitripanosomic assessing experiments, in vitro, with epimastigogas T. cruzi and promastigotes of L. amazonensis, was performed with ten synthesized thiosemicarbazones. Five substances have shown trypanomicidal activity below 100 μM, three of which with very promising IC50 values ie, the iodine-substituted IC50 = 7,00 μM, the amino-substituted with IC50 = 7,62 μM and the dicloroaceacetilamino-substituted with IC50 = 9,00 μM. Assays were performed against the macrophage cell line J774-A1 to evaluate the cytotoxicity and selectivity index was calculated from the values obtained in the IC50 trypanomicidal activity. The results indicated the iodine-substituted thiosemicarbazone with the best selectivity index, ie, a low cytotoxicity (279 IC50 μM) and high trypanocidal action (7,0 μM), revealed itself as very promising for in vivo testing. Tests carried forward to murine macrophages infected with amastigote L. amazonensis showed very promising results with IC50 = 10.37 M to the cyano-substituted thiosemicarbazone and IC50 = 9.45 M for iodine-substituted thiosemicarbazone. In this context, appears as a very important way of iron ions sequestration, since the superoxide dismutase enzyme of trypanosomes are dependent on these ions, while in the human host the homologous superoxide dismutase enzyme has atoms of zinc or manganese like central metal. Thus, evaluation of chelating activity against the Fe+2 and Zn+2 ions was performed. The results were very interesting showing the greatest effect of chelating substances tested for Fe+2 when compared to Zn+2 , and greater intensity for the iodine-substituted thiosemicarbazone that showed the best leishmanicidal and trypanomicidal activity. The high selectivity shown by the 6-iodo-1,3-benzodioxole-5-carbaldehyde-thiosemicarbazone on the ion Fe+2, compared with the same capacity on the ion Zn+2, suggests the impossibility of metalloenzyme superoxide dismutase of parasites through the hardship of a vital element for this enzyme.