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The extensive use of anthelmintic drugs has led to the emergence of resistant parasite strains, posing a threat to treatment success. The complex life cycle of the liver fluke, coupled with limited funding and research interest, have hindered progress in drug discovery. Our group has been working in drug development against this parasite using cathepsin proteases as molecular targets, finding promising compound candidates with <jats:italic>in\u2005vitro<\/jats:italic> and <jats:italic>in\u2005vivo<\/jats:italic> efficacy. Here, we evaluated hybrid molecules that combine two chemotypes, chalcones and quinoxaline 1,4\u2010di\u2010 <jats:italic>N<\/jats:italic>\u2010oxides, previously found to inhibit <jats:italic>F.\u2005hepatica<\/jats:italic> cathepsin Ls and tested their <jats:italic>in\u2005vitro<\/jats:italic> activity with the isolated targets and the parasites in culture. These molecules proved to be good cathepsin inhibitors and to kill the juvenile parasites at micromolar concentrations. Also, we performed molecular docking studies to analyze the compounds\u2010cathepsins interface, finding that the best inhibitors interact at the active site cleft and contact the catalytic dyad and residues belonging to the substrate binding pockets. We conclude that the hybrid compounds constitute promising scaffolds for the further development of new fasciolicidal compounds.<\/jats:p>","DOI":"10.1002\/cmdc.202400305","type":"journal-article","created":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T22:24:38Z","timestamp":1718317478000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Flavonoid\u2010Quinoxaline Hybrid Compounds as Cathepsin Inhibitors Against Fascioliasis"],"prefix":"10.1002","volume":"19","author":[{"given":"Florencia","family":"Ferraro","sequence":"first","affiliation":[{"name":"Laboratorio de I+D de Mol\u00e9culas Bioactivas Departamento de Ciencias Biol\u00f3gicas CENUR Litoral Norte Universidad de la Rep\u00fablica  Ruta 3\u2005km 363 Paysand\u00fa 60000 Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Merlino","sequence":"additional","affiliation":[{"name":"Laboratorio de Qu\u00edmica Te\u00f3rica y Computacional Facultad de Ciencias Universidad de la Rep\u00fablica  Igu\u00e1 4225 Montevideo 11400 Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Gil","sequence":"additional","affiliation":[{"name":"Laboratorio de Reproducci\u00f3n Animal Producci\u00f3n y Reproducci\u00f3n de Rumiantes Departamento de Ciencias Biol\u00f3gicas CENUR Litoral Norte-Facultad de Veterinaria Universidad de la Rep\u00fablica  Ruta 3\u2005km 363 Paysand\u00fa 60000 Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"P\u00e9rez\u2010Silanes","sequence":"additional","affiliation":[{"name":"ISTUN Institute of Tropical Health Department of Pharmaceutical Sciences Universidad de Navarra IdiSNA (Navarra Institute for Health Research)  Campus Universitario 31009 Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7527-8926","authenticated-orcid":false,"given":"Ileana","family":"Corvo","sequence":"additional","affiliation":[{"name":"Laboratorio de I+D de Mol\u00e9culas Bioactivas Departamento de Ciencias Biol\u00f3gicas CENUR Litoral Norte Universidad de la Rep\u00fablica  Ruta 3\u2005km 363 Paysand\u00fa 60000 Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1709-0474","authenticated-orcid":false,"given":"Mauricio","family":"Cabrera","sequence":"additional","affiliation":[{"name":"Laboratorio de I+D de Mol\u00e9culas Bioactivas Departamento de Ciencias Biol\u00f3gicas CENUR Litoral Norte Universidad de la Rep\u00fablica  Ruta 3\u2005km 363 Paysand\u00fa 60000 Uruguay"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,9]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1111\/pim.12343"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182022000725"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actatropica.2019.105210"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0022149X16000560"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2023.05.009"},{"issue":"11","key":"e_1_2_9_6_1","first-page":"149","volume":"26","author":"Caravedo M. 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