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Currently, only two drugs, nifurtimox and benznidazole (BNZ), are approved for its treatment. However, both are ineffective during the chronic phase, show toxicity, and produce serious side effects. This work aimed to obtain and evaluate novel 2\u2010nitroimidazole\u2010<jats:italic>N<\/jats:italic>\u2010acylhydrazone derivatives analogous to BNZ. The design of these compounds used the two important pharmacophoric subunits of the BNZ prototype, the 2\u2010nitroimidazole nucleus and the benzene ring, and the bioisosterism among the amide group of BNZ and <jats:italic>N<\/jats:italic>\u2010acylhydrazone. The 27 compounds were obtained by a three\u2010step route in 57%\u201398% yields. The biological results demonstrated the potential of this new class of compounds, since eight compounds were potent and selective in the in vitro assay against <jats:italic>T. cruzi<\/jats:italic> amastigotes and trypomastigotes using a drug\u2010susceptible strain of <jats:italic>T. cruzi<\/jats:italic> (Tulahuen) (IC<jats:sub>50<\/jats:sub>\u2009=\u20094.3\u20136.25\u2009\u00b5M) and proved to be highly selective with low cytotoxicity on L929 cells. The type I nitroreductase (TcNTR) assay suggests that the new compounds may act as substrates for this enzyme.<\/jats:p>","DOI":"10.1002\/ardp.202400059","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T03:05:19Z","timestamp":1713323119000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["New 2\u2010nitroimidazole\u2010<i>N<\/i>\u2010acylhydrazones, analogs of benznidazole, as anti\u2010<i>Trypanosoma cruzi<\/i> agents"],"prefix":"10.1002","volume":"357","author":[{"given":"Marcelly C. S. R.","family":"Pitombeira","sequence":"first","affiliation":[{"name":"Laboratorio de Sintese de Farmacos LASFAR, Instituto de Tecnologia em Farmacos, Farmanguinhos\u2014FIOCRUZ Fundacao Oswaldo Cruz Rio de Janeiro Brazil"},{"name":"Programa de Pos \u2010Gradua\u00e7\u00e3o em Farmacologia e Qu\u00edmica Medicinal do Instituto de Ci\u00eancias Biom\u00e9dicas\u2014ICB\u2014UFRJ, Centro de Ci\u00eancias da Sa\u00fade\u2014CCS, Bloco J, Ilha do Fund\u00e3o Rio de Janeiro Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Policarpo A. S.","family":"J\u00fanior","sequence":"additional","affiliation":[{"name":"Grupo de Gen\u00f4mica Funcional e Prote\u00f4mica de Leishmania spp e Trypanosoma cruzi, Instituto Ren\u00e9 Rachou (FIOCRUZ\u2010Minas) Belo Horizonte Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvane Maria Fonseca","family":"Murta","sequence":"additional","affiliation":[{"name":"Grupo de Gen\u00f4mica Funcional e Prote\u00f4mica de Leishmania spp e Trypanosoma cruzi, Instituto Ren\u00e9 Rachou (FIOCRUZ\u2010Minas) Belo Horizonte Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alvaro","family":"Romanha","sequence":"additional","affiliation":[{"name":"Grupo de Gen\u00f4mica Funcional e Prote\u00f4mica de Leishmania spp e Trypanosoma cruzi, Instituto Ren\u00e9 Rachou (FIOCRUZ\u2010Minas) Belo Horizonte Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro H.","family":"Luccas","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Cristalografia de Prote\u00ednas, Departamento de Ci\u00eancias BioMoleculares, Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo Ribeir\u00e3o Preto Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Cristina","family":"Nonato","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Cristalografia de Prote\u00ednas, Departamento de Ci\u00eancias BioMoleculares, Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo Ribeir\u00e3o Preto Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael E. 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