Síntese e caracterização de sistemas híbridos pirazol-tiadiazol com potencial atividade tripanocida

Abstract

Chagas Disease (CD) was discovered in 1909 by Dr. Carlos Chagas and it is, until today, a public health problem. According to WHO, CD is one of the 20 Neglected Tropical Disease and affects the poorest people who live in Latin American, where the disease is endemic. It is caused by Trypanosoma cruzi, transmitted to humans by the triatomine bugs. The treatment of CD is based on two drugs, benznidazole and nifurtimox, both were developed more than 50 years ago. They have limited efficacy on chronic phase and cause many side effects. Thus, there is an urgent need to develop new compounds more active against T. cruzi, in both phases of the disease, and with less side effects. In this sense, heterocycles are an attractive class to design new drugs, because they are present in a plethora of bioactive compounds. Especially, azolic heterocycles 1H-pyrazole and 1,3,4-thiadiazole have gained considerable attention in the development of antiparasitic agents. Thus, in this work two new series of pyrazole-thiadiazole hybrids 1(a-l) and 2(a-l) have been planned with potential trypanocidal activity. The final products were synthesized using the key intermediates 3(a-l) and 4(a-l). Initially, two alternative methodologies to the final products synthesis were investigated. The carbonitriles 4(a,c,g,i,j) and the carboxamides 5(a,f,j) were used as raw materials in the first and second attempt, respectively. However, the desired products could not be obtained and the unexpected products 5(a,c,g,i,j) were formed in the first case and 6(a,f,j) in the second one. Finally, employing thiosemicarbazide and trifluoroacetic acid, the intermediates 3(a-l) and 4(a-l) were successfully converted into 1(a-l) and 2(a-l), respectively, in yields of 26 to 72% and 20 to 91%, in this order. All the compounds were characterized by FT-IR and the 6(a,f,j), 1(a-l) and 2(a-l) were also analyzed by HRMS, 1H and 13C NMR. So far, the majority of the tested derivatives, 1(a-k) e 2(a,b,d,f-l), did not exhibit toxicity against Vero cells, with CC50 >500 M, except for 1(c,d), which presented a CC50 in 118,77 and 341,65 M, respectively.