{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:12:23Z","timestamp":1788541943158,"version":"build-2803163510"},"reference-count":27,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UNR","award":["80020230200019UR"],"award-info":[{"award-number":["80020230200019UR"]}]},{"DOI":"10.13039\/501100002923","name":"CONICET","doi-asserted-by":"publisher","award":["PIP 2021-2023 11220200101045CO"],"award-info":[{"award-number":["PIP 2021-2023 11220200101045CO"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002923","name":"CONICET","doi-asserted-by":"publisher","award":["PIBAA 28720210100409"],"award-info":[{"award-number":["PIBAA 28720210100409"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003074","name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"crossref","award":["ANPCyT PICT 2021-I-A-00512"],"award-info":[{"award-number":["ANPCyT PICT 2021-I-A-00512"]}],"id":[{"id":"10.13039\/501100003074","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003074","name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"crossref","award":["2018-1801"],"award-info":[{"award-number":["2018-1801"]}],"id":[{"id":"10.13039\/501100003074","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003074","name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"crossref","award":["2019-02622"],"award-info":[{"award-number":["2019-02622"]}],"id":[{"id":"10.13039\/501100003074","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"crossref","award":["MR\/P027989\/1"],"award-info":[{"award-number":["MR\/P027989\/1"]}],"id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Introduction: Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a major public health concern due to the limited effectiveness of current treatments, especially in the chronic stage. Objective: Here, we wanted to advance a library of 30 N,N\u2032-disubstituted diamines as promising antichagasic agents and gain insight into the mechanism of action. Methods: The library was evaluated for activity against the T. cruzi amastigote stage and trypanocidal efficacy. In addition, selected compounds were tested as potential polyamine transport inhibitors, and a fluorescent analog was employed to investigate compound internalization. Results: Five compounds exhibited potent activity (pIC50 &gt; 6.0), particularly those with short aliphatic linkers (3\u20136 carbon atoms), suggesting a structure\u2013activity relationship favouring shorter chains. Mechanistic studies showed that compound 3c strongly inhibited polyamine transport, a vital pathway in T. cruzi, though this was not a universal mechanism among active hits, indicating the potential for multiple targets. A fluorescent analog confirmed intracellular uptake in amastigotes but lacked antiparasitic activity, likely due to disrupted pharmacophoric features. Importantly, none of the compounds demonstrated trypanocidal activity in long-term assays, and some showed cytotoxicity, particularly in the benzyloxy-substituted series. Conclusions: These findings position N,N\u2032-disubstituted diamines as a viable scaffold for Chagas disease drug discovery. However, further optimization is required to enhance selectivity, achieve trypanocidal effects, and better understand the underlying mechanisms of action.<\/jats:p>","DOI":"10.3390\/ph19010119","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T14:15:50Z","timestamp":1767968150000},"page":"119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanistic Exploration of N,N\u2032-Disubstituted Diamines as Promising Chagas Disease Treatments"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9688-4589","authenticated-orcid":false,"given":"Alejandro I.","family":"Recio-Balsells","sequence":"first","affiliation":[{"name":"Instituto de Qu\u00edmica Rosario (IQUIR-CONICET-UNR), Suipacha 531, Rosario 2000, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8844-8517","authenticated-orcid":false,"given":"Chantal","family":"Reigada","sequence":"additional","affiliation":[{"name":"Facultad de Medicina, Instituto de Investigaciones M\u00e9dicas A. Lanari, Universidad de Buenos Aires, Buenos Aires 1113, Argentina"},{"name":"Laboratorio de Parasitolog\u00eda Molecular, Instituto de Investigaciones M\u00e9dicas (IDIM), Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Universidad de Buenos Aires, Buenos Aires 1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Gabriela","family":"Mediavilla","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario (IBR-CONICET-UNR), Ocampo y Esmeralda, Rosario 2000, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esteban","family":"Panozzo-Z\u00e9nere","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica Rosario (IQUIR-CONICET-UNR), Suipacha 531, Rosario 2000, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Villarreal Parra","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica Rosario (IQUIR-CONICET-UNR), Suipacha 531, Rosario 2000, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia S.","family":"Doyle","sequence":"additional","affiliation":[{"name":"Department of Pathology, Sandler Center for Drug Discovery, University of California San Francisco, San Francisco, CA 94158-2330, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan C.","family":"Engel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Sandler Center for Drug Discovery, University of California San Francisco, San Francisco, CA 94158-2330, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio A.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Facultad de Medicina, Instituto de Investigaciones M\u00e9dicas A. Lanari, Universidad de Buenos Aires, Buenos Aires 1113, Argentina"},{"name":"Laboratorio de Parasitolog\u00eda Molecular, Instituto de Investigaciones M\u00e9dicas (IDIM), Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Universidad de Buenos Aires, Buenos Aires 1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8993-3880","authenticated-orcid":false,"given":"Julia A.","family":"Cricco","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario (IBR-CONICET-UNR), Ocampo y Esmeralda, Rosario 2000, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2467-1573","authenticated-orcid":false,"given":"Guillermo R.","family":"Labadie","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica Rosario (IQUIR-CONICET-UNR), Suipacha 531, Rosario 2000, Argentina"},{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Ciencias Bioqu\u00edmicas y Farmac\u00e9uticas, Universidad Nacional de Rosario, Suipacha 531, Rosario 2000, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"ref_1","unstructured":"WHO (2021). 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