{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T07:24:39Z","timestamp":1790061879932,"version":"4.0.1"},"reference-count":39,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CSIC (Comisi\u00f3n Sectorial de Investigaci\u00f3n Cient\u00edfica) I+D 2016","award":["ID435"],"award-info":[{"award-number":["ID435"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease\/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of &gt;450 compounds from in-house and\/or \u201cPathogen Box\u201d (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 \u03bcM and had selectivity index values &gt;10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity.<\/jats:p>","DOI":"10.3390\/ph14070644","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T04:18:21Z","timestamp":1625458701000},"page":"644","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Preclinical Studies in Anti-Trypanosomatidae Drug Development"],"prefix":"10.3390","volume":"14","author":[{"given":"Cintya","family":"Perdomo","sequence":"first","affiliation":[{"name":"Laboratorio de Mol\u00e9culas Bioactivas, Departamento de Ciencias Biol\u00f3gicas, CENUR Litoral Norte, Universidad de la Rep\u00fablica, Paysand\u00fa 60000, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1052-687X","authenticated-orcid":false,"given":"Elena","family":"Aguilera","sequence":"additional","affiliation":[{"name":"Grupo de Qu\u00edmica Org\u00e1nica Medicinal, Instituto de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias, Universidad de la Rep\u00fablica, Montevideo 11400, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ileana","family":"Corvo","sequence":"additional","affiliation":[{"name":"Laboratorio de Mol\u00e9culas Bioactivas, Departamento de Ciencias Biol\u00f3gicas, CENUR Litoral Norte, Universidad de la Rep\u00fablica, Paysand\u00fa 60000, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Faral-Tello","sequence":"additional","affiliation":[{"name":"Institut Pasteur de Montevideo, Unidad de Biolog\u00eda Molecular, Montevideo 11400, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elva","family":"Serna","sequence":"additional","affiliation":[{"name":"Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunci\u00f3n, San Lorenzo 2169, Paraguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Robello","sequence":"additional","affiliation":[{"name":"Institut Pasteur de Montevideo, Unidad de Biolog\u00eda Molecular, Montevideo 11400, Uruguay"},{"name":"Departamento de Bioqu\u00edmica, Facultad de Medicina, Universidad de la Rep\u00fablica, Montevideo 11800, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8474-1943","authenticated-orcid":false,"given":"Shane R.","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Queen Mary Pre-Clinical Drug Discovery Group, School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7568-4756","authenticated-orcid":false,"given":"Gloria","family":"Yaluff","sequence":"additional","affiliation":[{"name":"Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunci\u00f3n, San Lorenzo 2169, Paraguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-6100","authenticated-orcid":false,"given":"Guzm\u00e1n","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Laboratorio de Mol\u00e9culas Bioactivas, Departamento de Ciencias Biol\u00f3gicas, CENUR Litoral Norte, Universidad de la Rep\u00fablica, Paysand\u00fa 60000, Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,5]]},"reference":[{"key":"ref_1","unstructured":"WHO (2020). 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