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Current treatment strategies still rely on two nitro heterocyclic compounds: benznidazole and nifurtimox. Both agents exhibit limited therapeutic efficacy during the chronic phase of the disease and are often linked to severe adverse effects that frequently lead to treatment discontinuation. This urgent need for safer, more effective oral treatments drives the development of novel chemotypes. Objective: In this study, we advanced the preclinical evaluation of 4-imidazoline-1H-pyrazole derivatives, which have been identified as promising candidates against Trypanosoma cruzi. Methods: The candidate compound identified from the reversibility assay underwent further evaluation for its efficacy using a three-dimensional (3D) culture model and a Transwell co-culture system, in addition to the in vivo assessment. Results: Our findings revealed that compound 3m (3-Cl, 4-CH3) exhibited low cytotoxicity while substantially decreasing the parasite burden in 3Dcardiac spheroid models. The compound effectively permeated Caco-2 cell monolayers and demonstrated the ability to inhibit T. cruzi infection in Vero cell cultures within a co-culture system. Furthermore, the 3m derivative not only controlled parasite resurgence but also showed significant therapeutic benefits in a murine model of acute T. cruzi infection, resulting in marked reductions in parasitemia and tissue parasitism, associated with diminished inflammatory infiltrate and cardiac fibrosis. Treatment with 3m increased the survival rate of infected mice to 40%, comparable to the reference drug benznidazole in several key pathological endpoints. Conclusion: These findings highlight the potential of 4-imidazoline-1H-pyrazole derivatives, particularly compound 3m, in mitigating the pathological effects associated with T. cruzi infection.<\/jats:p>","DOI":"10.3390\/ph18101552","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T07:29:38Z","timestamp":1760599778000},"page":"1552","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pyrazole-Imidazoline Derivative Prevents Cardiac Damage and Mortality in Acute Trypanosoma cruzi Infection"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5962-4163","authenticated-orcid":false,"given":"Lorraine Martins Rocha","family":"Orlando","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz. Av. Brasil 4365, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9391-7664","authenticated-orcid":false,"given":"Leonardo da Silva","family":"Lara","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz. Av. Brasil 4365, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thamyris P\u00e9rez","family":"de Souza","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz. Av. Brasil 4365, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitoria Barbosa","family":"Paes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz. Av. Brasil 4365, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia Magalh\u00e3es","family":"Calvet","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz. Av. Brasil 4365, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliane Batista","family":"de Mesquita","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz. Av. Brasil 4365, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4538-3802","authenticated-orcid":false,"given":"Guilherme Cury","family":"Lechuga","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz. Av. Brasil 4365, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia Nath\u00e1lia","family":"Pereira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de S\u00edntese de Sistemas Heteroc\u00edclicos (LaSSH), Instituto de F\u00edsica e Qu\u00edmica (IFQ), Universidade Federal de Itajub\u00e1, Av. BPS 1303, Pinheirinho, Itajub\u00e1 37500-903, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1075-9059","authenticated-orcid":false,"given":"Maur\u00edcio Silva","family":"dos Santos","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de S\u00edntese de Sistemas Heteroc\u00edclicos (LaSSH), Instituto de F\u00edsica e Qu\u00edmica (IFQ), Universidade Federal de Itajub\u00e1, Av. 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