{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:28:00Z","timestamp":1785421680426,"version":"3.56.0"},"reference-count":49,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002848","name":"FONDECYT","doi-asserted-by":"publisher","award":["1240129"],"award-info":[{"award-number":["1240129"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1240129"],"award-info":[{"award-number":["1240129"]}],"id":[{"id":"https:\/\/ror.org\/016nafs32","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National System of Researchers (SISNI) of the National Council of Science and Technology"},{"name":"Fund for Structural Convergence of the Mercosur","award":["COF 03\/11"],"award-info":[{"award-number":["COF 03\/11"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Jatrophone is a bioactive diterpenoid with reported antitrypanosomal activity; however, its development as a lead compound is limited by pronounced cytotoxicity toward mammalian cells. This study aimed to explore the structural modification of jatrophone through triazole functionalization to modulate its antiparasitic activity and improve selectivity against Trypanosoma cruzi. Methods: A series of mono- and bis-triazole jatrophone derivatives was semi-synthesized via Cu(I)-catalyzed azide\u2013alkyne cycloaddition (CuAAC) from a stereoselectively prepared diazido intermediate. Jatrophone, its azido precursor, and the synthesized triazole derivatives were evaluated in vitro against T. cruzi epimastigotes and intracellular amastigotes. Cytotoxicity toward mammalian host cells was assessed in parallel to determine selectivity indices. Results: Jatrophone exhibited potent activity against epimastigotes but showed poor selectivity due to significant mammalian cell toxicity. Introduction of azide and triazole functionalities altered the biological profile of the parent scaffold, leading to derivatives with reduced cytotoxicity and improved selectivity in extracellular assays. Among the evaluated compounds, a mono-triazole derivative bearing a methylene-linked cycloalkyl substituent retained antiparasitic activity while displaying markedly lower toxicity toward mammalian cells. However, in the intracellular amastigote model, most derivatives demonstrated a substantial reduction in selectivity, indicating limited translation of extracellular activity to the intracellular parasite stage. Conclusions: Triazole functionalization of the jatrophone scaffold represents a viable strategy to modulate its biological properties and reduce host-cell toxicity. Nevertheless, the reduced efficacy observed in intracellular assays underscores the limitations of epimastigote-based screening and highlights the challenges in developing selective intracellular antitrypanosomal agents from the jatrophone scaffold.<\/jats:p>","DOI":"10.3390\/ph19050801","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T02:32:28Z","timestamp":1779676348000},"page":"801","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Triazole-Functionalized Jatrophone Derivatives as Antiprotozoal Agents Against Trypanosoma cruzi: Synthesis, Biological Evaluation and Structure\u2014Activity Relationships"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0203-4891","authenticated-orcid":false,"given":"Mariano Walter","family":"Pertino","sequence":"first","affiliation":[{"name":"Instituto de Qu\u00edmica de Recursos Naturales, Universidad de Talca, Campus Lircay, Talca 3480094, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricio","family":"Carre\u00f1o Gonzalez","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica de Recursos Naturales, Universidad de Talca, Campus Lircay, Talca 3480094, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Venegas Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Escuela de Ingenier\u00eda en Biotecnolog\u00eda, Facultad de Ciencias Agrarias y Forestales, Universidad Cat\u00f3lica del Maule, Talca 3480112, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9228-5378","authenticated-orcid":false,"given":"Guillermo","family":"Schmeda-Hirschmann","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica de Recursos Naturales, Universidad de Talca, Campus Lircay, Talca 3480094, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6291-4316","authenticated-orcid":false,"given":"Celeste","family":"Vega G\u00f3mez","sequence":"additional","affiliation":[{"name":"Centro para el Desarrollo de la Investigaci\u00f3n Cient\u00edfica (CEDIC), Manduvir\u00e1 635, Asunci\u00f3n 1255, Paraguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8123-4260","authenticated-orcid":false,"given":"Miriam","family":"Rol\u00f3n","sequence":"additional","affiliation":[{"name":"Centro para el Desarrollo de la Investigaci\u00f3n Cient\u00edfica (CEDIC), Manduvir\u00e1 635, Asunci\u00f3n 1255, Paraguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6207-1870","authenticated-orcid":false,"given":"Antonieta","family":"Rojas de Arias","sequence":"additional","affiliation":[{"name":"Centro para el Desarrollo de la Investigaci\u00f3n Cient\u00edfica (CEDIC), Manduvir\u00e1 635, Asunci\u00f3n 1255, Paraguay"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2026, February 06). 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