Resumo:
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.