title: Orally active antischistosomal early leads identified from the open access malaria box.
abstract: BACKGROUND
  Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs.
  
  
  METHODS
  We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo.
  
  
  RESULTS
  Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively.
  
  
  CONCLUSIONS
  The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development.
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland ; University of Basel, Basel, Switzerland.
authors.forename: Katrin
authors.initials: K
authors.lastname: Ingram-Sieber
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland ; University of Basel, Basel, Switzerland.
authors.forename: Noemi
authors.initials: N
authors.lastname: Cowan
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland ; University of Basel, 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, Basel, Switzerland ; University of Basel, Basel, Switzerland.
authors.forename: Mireille
authors.initials: M
authors.lastname: Vargas
authors.affiliation: Department of Infection and Immunity, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Nuha R
authors.initials: NR
authors.lastname: Mansour
authors.affiliation: Department of Infection and Immunity, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Quentin D
authors.initials: QD
authors.lastname: Bickle
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Timothy N C
authors.initials: TN
authors.lastname: Wells
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Spangenberg
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland ; University of Basel, Basel, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D020128:Inhibitory Concentration 50; D051379:Mice; D059208:Parasite Load; D021261:Parasitic Sensitivity Tests; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology*; D012550:Schistosoma mansoni / Q000187:drug effects*; D012555:Schistosomiasis mansoni / Q000188:drug therapy*; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D000871:Anthelmintics; D011810:Quinoxalines; D014508:Urea