Efficacy, metabolism and pharmacokinetics of Ro 15-5458, a forgotten schistosomicidal 9-Acridanone hydrazone

Alexandra Probst, Cécile Häberli, Dionicio Siegel, Jianbo Huang, Seth Vigneron, Anh P. Ta, Danielle E. Skinner, Nelly El-Sakkary, Jeremiah D. Momper, Jon Gangoiti, Yuxiang Dong, Jonathan L. Vennerstrom, Susan A. Charman, Conor R. Caffrey, Jennifer Keiser

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Treatment of schistosomiasis, a neglected disease, relies on just one partially effective drug, praziquantel. We revisited the 9-Acridanone hydrazone, Ro 15-5458, a largely forgotten antischistosomal lead compound. Methods: Ro 15-5458 was evaluated in juvenile and adult Schistosoma mansoni-infected mice. We studied dose-response, 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. Results: Ro 15-5458 had single-dose ED50 values of 15 and 5.3 mg/kg in mice harbouring juvenile and adult S. mansoni infections, respectively. An ED50 value of 17 mg/kg was measured in S. haematobium-infected hamsters; however, the compound was inactive at up to 100 mg/kg in S. japonicum-infected mice. The drug-induced hepatic shift occurred between 48 and 66 h post treatment. A single oral dose of 50 mg/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 maximumplasma concentration was approximately 8.13 lg/mL 3 h after a 50 mg/kg oral dose and the half-life was approximately 4.9 h. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)2925-2932
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume75
Issue number10
DOIs
StatePublished - Oct 1 2020

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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