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In this study, we developed 13 novel pyrazole-imidazoline derivatives, inspired by a previously identified cysteine protease inhibitor, and evaluated their antiparasitic activity. Our in silico analyses predicted favorable physicochemical profiles and promising oral bioavailability for these derivatives. Upon phenotypic screening, we observed that these new derivatives exhibited low cytotoxicity (CC50 &gt; 100 \u00b5M) and marked efficacy against intracellular amastigotes. Derivative 1k showed high activity (IC50 = 3.3 \u00b1 0.2 \u00b5M), selectivity (SI = 73.9), and potency (pIC50 = 5.4). In a 3D cardiac microtissue model, 1k significantly reduced parasite load, matching the efficacy of benznidazole (Bz) even at lower concentrations. Both 1k and Bz effectively prevented parasite recrudescence; however, neither resulted in parasite sterility under the experimental conditions employed. The combination of 1k\u2013Bz yielded an additive interaction, highlighting its potential for in vivo combination therapy. While structural changes abolished cysteine protease inhibition, incorporating a CF3 substituent at the para position and excluding the amino group enhanced antiparasitic activity. These findings reinforce the promise of the pyrazole-imidazoline scaffold and support further structural optimizations to develop innovative candidates for treating Chagas disease.<\/jats:p>","DOI":"10.3390\/molecules30153082","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T11:52:47Z","timestamp":1753271567000},"page":"3082","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Anti-Trypanosoma cruzi Potential of New Pyrazole-Imidazoline Derivatives"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3545-4269","authenticated-orcid":false,"given":"Edinaldo Castro","family":"de Oliveira","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. 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Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Carolina","family":"Mazzochi","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, Avenida BPS, 1303, Pinheirinho, Itajub\u00e1, Minas Gerais 37500-903, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro Henrique Myra","family":"Fernandes","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, Avenida BPS, 1303, Pinheirinho, Itajub\u00e1, Minas Gerais 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, Avenida BPS, 1303, Pinheirinho, Itajub\u00e1, Minas Gerais 37500-903, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2223-3289","authenticated-orcid":false,"given":"Mirian Claudia de Souza","family":"Pereira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,23]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2025, March 27). Chagas Disease (Also Known as American Trypanosomiasis). Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/chagas-disease-(american-trypanosomiasis)."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ejim.2017.05.001","article-title":"Chagas disease in Europe: A review for the internist in the globalized world","volume":"43","author":"Antinori","year":"2017","journal-title":"Eur. J. Intern. 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