Current landscape and future perspectives in Chagas disease chemotherapy: From nitroderivatives to new molecular targets

Introduction: Chagas Disease (CD) is an infectious illness caused by the protozoan Trypanosoma cruzi. Despite being endemic in tropical countries, establishing a fully effective treatment remains a challenge due to the limited therapeutic arsenal and the complexity of parasite persistence during the chronic phase. Aim: The present study aimed to conduct a literature review regarding the current approach and future perspectives of the pharmacological treatment of CD. Methodology: This is a narrative review based on articles from the PubMed, SciELO, and LILACS databases. Relevant articles focusing on the mechanisms of action, drug repurposing, and novel therapeutic targets were critically analyzed to compose the results. Results: Standard drugs, benznidazole and nifurtimox, show notable efficacy primarily in the acute phase, while substances such as posaconazole, TAK-187, and ravuconazole demonstrate promising performance in preclinical studies. The review highlights innovative approaches, such as drug repurposing (Flucofuron) and the identification of new targets focused on the collapse of redox homeostasis and mitochondrial dysfunction (apoptosis-like). It was evidenced that the combination of active principles, such as benznidazole associated with the novel compound 1k in 3D cardiac microtissue models, is effective in controlling infection with reduced toxicity. Although challenges persist regarding accessibility and diagnosis, advances in understanding the parasite's cell death mechanisms represent a crucial step. Conclusions: In this context, collaborative work between researchers and governments remains essential to ensure that these new therapeutic candidates advance to clinical practice, improving the quality of life for patients.