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This work describes the development of a random forests model for the prediction of the bioavailability of cruzain inhibitors that are <jats:italic>Trypanosoma cruzi<\/jats:italic> killers. Some common properties that characterize drug\u2010likeness are poorly represented in many established cruzain inhibitors. This correlates with the evidence that many high\u2010affinity cruzain inhibitors are not trypanocidal agents against <jats:italic>T.\u00a0cruzi<\/jats:italic>. On the other hand, <jats:italic>T.\u00a0cruzi<\/jats:italic> killers that present typical drug\u2010like characteristics are likely to show better trypanocidal action than those without such features. The random forests model was not outperformed by other machine learning methods (such as artificial neural networks and support vector machines), and it was validated with the synthesis of two new trypanocidal agents. Specifically, we report a new lead compound, <jats:bold>Neq0565<\/jats:bold>, which was tested on <jats:italic>T.\u00a0cruzi<\/jats:italic> Tulahuen (\u03b2\u2010galactosidase) with a pEC<jats:sub>50<\/jats:sub> of 4.9. It is inactive in the host cell line showing a selectivity index (SI\u00a0=\u00a0EC<jats:sub>50<\/jats:sub><jats:sup>cyto<\/jats:sup>\/EC<jats:sub>50<\/jats:sub><jats:italic><jats:sup>T.\u00a0cruzi<\/jats:sup><\/jats:italic>) higher than 50.<\/jats:p>","DOI":"10.1111\/cbdd.13663","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T08:08:28Z","timestamp":1602749308000},"page":"948-960","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular design aided by random forests and synthesis of potent trypanocidal agents as cruzain inhibitors for Chagas disease treatment"],"prefix":"10.1111","volume":"96","author":[{"given":"S\u00e9rgio","family":"de Albuquerque","sequence":"first","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Cianni","sequence":"additional","affiliation":[{"name":"Grupo de Qu\u00edmica Medicinal Instituto de Qu\u00edmica de S\u00e3o Carlos Universidade de S\u00e3o Paulo S\u00e3o Carlos\/SP Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"de Vita","sequence":"additional","affiliation":[{"name":"Grupo de Qu\u00edmica Medicinal Instituto de Qu\u00edmica de S\u00e3o Carlos Universidade de S\u00e3o Paulo S\u00e3o Carlos\/SP Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carla","family":"Duque","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana S. 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