title: Aryl hydantoin Ro 13-3978, a broad-spectrum antischistosomal.
abstract: OBJECTIVE
  Praziquantel is the only drug available for the treatment of schistosomiasis and the state of the exhausted drug discovery pipeline is alarming. We restarted investigations on the abandoned antischistosomal Ro 13-3978, an aryl hydantoin discovered in the early 1980s by Hoffmann La-Roche.
  
  
  METHODS
  Newly transformed schistosomula and adult Schistosoma mansoni were studied in the presence of Ro 13-3978 in vitro. The metabolic stability of Ro 13-3978 was determined in vitro using human and mouse liver S9 fractions. Dose-response relationship, stage specificity, hepatic shift and scanning electron microscopy studies were carried out in S. mansoni-infected mice. In addition, efficacy experiments were conducted in rodents infected with Echinostoma caproni and Fasciola hepatica as well as in S. mansoni-infected immunocompromised nude (Foxn1(nu)) mice.
  
  
  RESULTS
  Ro 13-3978 showed minor in vitro activity and no damage to the tegument was found. No cytotoxicity was detected for Ro 13-3978. Ro 13-3978 was metabolically stable. ED50 values of 138.9 and 14.6 mg/kg were calculated for the treatment of juvenile and adult S. mansoni infections, respectively, with a single oral dose of Ro 13-3978. SEM studies revealed severe damage to the worms 48 h post-treatment of infected mice. A single oral dose of Ro 13-3978 (100 mg/kg) administered to S. mansoni-infected (Foxn1(nu)) mice reduced the worm burden by 88%. Ro 13-3978 was not active against E. caproni and F. hepatica in vivo.
  
  
  CONCLUSIONS
  Ro 13-3978 has excellent antischistosomal properties in vivo. Structure-activity relationship studies with the aryl hydantoins have been launched in order to elucidate active pharmacophores, further investigate the mechanism of action and to identify a derivative with minimal antiandrogenic effects.
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland University of Basel, CH-4003 Basel, Switzerland jennifer.keiser@unibas.ch.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland University of Basel, CH-4003 Basel, Switzerland.
authors.forename: Gordana
authors.initials: G
authors.lastname: Panic
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland University of Basel, CH-4003 Basel, Switzerland.
authors.forename: Mireille
authors.initials: M
authors.lastname: Vargas
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Chunkai
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dong
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Nagsen
authors.initials: N
authors.lastname: Gautam
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004449:Echinostoma / Q000187:drug effects / Q000648:ultrastructure; D004451:Echinostomiasis / Q000188:drug therapy / Q000469:parasitology; D005210:Fasciola hepatica / Q000187:drug effects / Q000648:ultrastructure; D005211:Fascioliasis / Q000188:drug therapy / Q000469:parasitology; D005260:Female; D006827:Hydantoins / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D051381:Rats; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000648:ultrastructure; D012555:Schistosomiasis mansoni / Q000188:drug therapy / Q000469:parasitology; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
chemical_list: D000871:Anthelmintics; D006827:Hydantoins; C000591057:Ro 13-3978
keywords: Schistosoma mansoni; chemotherapy; drug discovery; schistosomiasis