In this review, we intend to provide a general view of the evolution of experimental studies in the area of
chemotherapy for
Chagas disease. We can follow the process of
drug development through three phases. The first phase began almost at the same time as the discovery made by Carlos Chagas and proceeds to 1970, during which time an extensive list of compounds was subjected to preclinical and clinical trials. The second phase began with the introduction of
nifurtimox and
benznidazole into the clinical setting, followed with the search for alternative drugs. In this phase, a dichotomy existed between rational and empirical approaches in preclinical studies. The third phase began with the unravelling of the T. cruzi genome. The development of transgenic parasites has allowed the development of solid HTS protocols, and the establishment of bioluminescent T. cruzi has allowed in vivo
drug evaluations using a reduced number of animals. Among the wide variety of compounds subjected to preclinical studies, we have discovered azolic and non-azolic inhibitors of
sterol C14α-demethylase (CYP51) and
nitro compounds. Two compounds evaluated during the second phase, namely,
MK-436 and
allopurinol, could be revisited. Clinical studies of
posaconazole and E1224 yielded disappointing results, and it is critical to understand the reason for their failure as a monotherapy. Currently, the combination and repositioning of drugs with different mechanisms of action are complementary approaches. The use of
drug combinations, particularly those of
nitro compounds with
CYP51 inhibitors, is considered a real alternative for the treatment of
Chagas disease.