Antitrypanosomal Activity of 1,2,3-Triazole-Based Hybrids Evaluated Using In Vitro Preclinical Translational Models

SIMPLE SUMMARY: Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected tropical disease that affects 6–7 million people worldwide. It is a global disease, due to migration from Latin America to other regions of the world, and a recognized worldwide public health problem. Clinical treatment is based on two fifty-year-old drugs, nifurtimox and benznidazole. These drugs have low efficacy in the chronic phase of the disease and have severe adverse effects, making the search for new drugs essential. This study aimed to evaluate the trypanocidal potential of 1,2,3-triazole analogs. Our data highlight three analogs with potent activity against trypomastigotes and similar efficacy to benznidazole, the reference drug, against intracellular parasites. These analogs showed high efficacy in 3D cardiac microtissue. However, despite potentially reducing parasite load, the promising candidates did not inhibit the resurgence of the parasite in the absence of the drug. Newly designed analogs will be screened against T. cruzi to identify potentially active and safe drugs for Chagas disease therapy. ABSTRACT: Chagas disease therapy still relies on two nitroderivatives, nifurtimox and benznidazole (Bz), which have important limitations and serious adverse effects. New therapeutic alternatives for this silent disease, which has become a worldwide public health problem, are essential for its control and elimination. In this study, 1,2,3-triazole analogues were evaluated for efficacy against T. cruzi. Three triazole derivatives, 1d (0.21 µM), 1f (1.23 µM), and 1g (2.28 µM), showed potent activity against trypomastigotes, reaching IC(50) values 10 to 100 times greater than Bz (22.79 µM). Promising candidates are active against intracellular amastigotes (IC(50) ≤ 6.20 µM). Treatment of 3D cardiac spheroids, a translational in vitro model, significantly reduced parasite load, indicating good drug diffusion and efficacy. Oral bioavailability was predicted for triazole derivatives. Although infection was significantly reduced without drug pressure in a washout assay, the triazole derivatives did not inhibit parasite resurgence. An isobologram analysis revealed an additive interaction when 1,2,3-triazole analogs and Bz were combined in vitro. These data indicate a strengthened potential of the triazole scaffold and encourage optimization based on an analysis of the structure–activity relationship aimed at identifying new compounds potentially active against T. cruzi.