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We revisited the 9-acridanone hydrazone, Ro 15-5458, a largely forgotten antischistosomal lead compound.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Ro 15-5458 was evaluated in juvenile and adult Schistosoma mansoni-infected mice. We studied dose\u2013response, hepatic shift and stage specificity. The metabolic stability of Ro 15-5458 was measured in the presence of human and mouse liver microsomes, and human hepatocytes; the latter also served to identify metabolites. Pharmacokinetic parameters were measured in naive mice. The efficacy of Ro 15-5458 was also assessed in S. haematobium-infected hamsters and S. japonicum-infected mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Ro 15-5458 had single-dose ED50 values of 15 and 5.3\u2009mg\/kg in mice harbouring juvenile and adult S. mansoni infections, respectively. An ED50 value of 17\u2009mg\/kg was measured in S. haematobium-infected hamsters; however, the compound was inactive at up to 100\u2009mg\/kg in S. japonicum-infected mice. The drug-induced hepatic shift occurred between 48 and 66\u2009h post treatment. A single oral dose of 50\u2009mg\/kg of Ro 15-5458 had high activity against all tested S. mansoni stages (1-, 7-, 14-, 21- and 49-day-old). In vitro, human hepatocytes produced N-desethyl and glucuronide metabolites; otherwise Ro 15-5458 was metabolically stable in the presence of microsomes or whole hepatocytes. The maximum plasma concentration was approximately 8.13\u2009\u03bcg\/mL 3\u2009h after a 50\u2009mg\/kg oral dose and the half-life was approximately 4.9\u2009h.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Ro 15-5458 has high activity against S. mansoni and S. haematobium, yet lacks activity against S. japonicum, which is striking. This will require further investigation, as a broad-spectrum antischistosomal drug is desirable.<\/jats:p><\/jats:sec>","DOI":"10.1093\/jac\/dkaa247","type":"journal-article","created":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T11:07:20Z","timestamp":1590059240000},"page":"2925-2932","source":"Crossref","is-referenced-by-count":6,"title":["Efficacy, metabolism and pharmacokinetics of Ro 15-5458, a forgotten schistosomicidal 9-acridanone hydrazone"],"prefix":"10.1093","volume":"75","author":[{"given":"Alexandra","family":"Probst","sequence":"first","affiliation":[{"name":"Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, PO Box, CH-4002, Basel, Switzerland"},{"name":"University of Basel, PO Box, CH-4003, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"H\u00e4berli","sequence":"additional","affiliation":[{"name":"Department of Medical Parasitology and Infection Biology, 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