Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is a serious public health problem. Current treatment is restricted to two drugs, benznidazole and nifurtimox, displaying serious efficacy and safety drawbacks. Nucleoside analogues represent a promising alternative as protozoans do not biosynthesize purines and rely on purine salvage from the hosts. Protozoan transporters often present different substrate specificities from mammalian transporters, justifying the exploration of nucleoside analogues as therapeutic agents. Previous reports identified nucleosides with potent trypanocidal activity; therefore, two 7-derivatized tubercidins (FH11706, FH10714) and a 3′-deoxytubercidin (FH8513) were assayed against T. cruzi. They were highly potent and selective, and the uptake of the tubercidin analogues appeared to be mediated by the nucleoside transporter TcrNT2. At 10 μM, the analogues reduced parasitemia >90% in 2D and 3D cardiac cultures. The washout assays showed that FH10714 sterilized the infected cultures. Given orally, the compounds did not induce noticeable mouse toxicity (50 mg/kg), suppressed the parasitemia of T. cruzi-infected Swiss mice (25 mg/kg, 5 days) and presented DNA amplification below the limit of detection. These findings justify further studies with longer treatment regimens, as well as evaluations in combination with nitro drugs, aiming to identify more effective and safer therapies for Chagas disease.

Chagas disease is a relevant public health threat that affects over 6 million people worldwide, resulting in devastating social and economic consequences. Moreover, the therapeutic options are limited, highlighting the urgency in searching for novel active antitrypanosomal molecules. Compounds with either thiazole or biaryl units have been described as possessing anti-Trypanosoma cruzi activities. Therefore, here, we describe the synthesis of nine arylated and diarylated thiazole derivatives and the evaluation of their in vitro toxicity on mammalian cells as well as their anti-T. cruzi activity. The compounds were prepared in straightforward synthetic routes, using Hantzsch thiazole synthesis and cross-coupling reactions as key steps. A pyridylphenyl-thiazole (PPT) derivative (4c) presented 76% of T. cruzi growth inhibition in preliminary tests using a fixed concentration of 20 µM. This compound was used as a scaffold for the synthesis of two novel PPT analogs (4g and 4h). Dose-response assays on intracellular forms of T. cruzi demonstrated that these three compounds presented high antiparasitic potency (half maximal effective concentration (EC50) values ranging from 1.15 to 2.38 μM) and low toxic profile against L929 cell lines. Hence, these findings highlight the pyridyl-phenyl-thiazole backbone as a novel privileged scaffold in the search for active molecules against T. cruzi.