title: Activities of N,N'-Diarylurea MMV665852 analogs against Schistosoma mansoni.
abstract: There is an unmet need to discover and develop novel antischistosomal drugs. As exemplified by MMV665852, N,N'-diarylureas have recently emerged as a promising antischistosomal chemotype. In this study, we evaluated the structure-activity relationships of 46 commercially available analogs of MMV665852 on newly transformed schistosomula (NTS) and adult Schistosoma mansoni worms in vitro. Active compounds were evaluated with a cytotoxicity assay, in silico calculations, metabolic stability studies, and an in vivo assay with mice harboring adult S. mansoni worms. Of the 46 compounds tested at 33.3 μM, 13 and 14 compounds killed NTS and adult worms, respectively, within 72 h. Nine compounds had 90% inhibitory concentrations (IC90s) of ≤10 μM against adult worms, with selectivity indexes of ≥2.8. Their physicochemical properties and permeation through an artificial membrane indicated good to moderate intestinal absorption. Their metabolic stabilities ranged from low to high. Despite satisfactory in vitro results and in silico predictions, only one compound resulted in a statistically significant worm burden reduction (66%) after administration of a single oral dose of 400 mg/kg of body weight to S. mansoni-infected mice. Worm burden reductions of 0 to 43% were observed for the remaining eight compounds tested. In conclusion, several analogs of the N,N'-diarylurea MMV665852 had high efficacy against S. mansoni in vitro and favorable physicochemical properties for permeation through the intestinal wall. To counteract the low efficacy observed in the mouse model, further investigations should focus on identifying compounds with improved solubility and pharmacokinetic properties.
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: Institute of Molecular Pharmacy, University of Basel, Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Dätwyler
authors.affiliation: Institute of Molecular Pharmacy, University of Basel, Basel, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Ernst
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Chunkai
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
authors.affiliation: Medicines for Malaria Venture (MMV), 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 jennifer.keiser@unibas.ch.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
mesh_terms: D000818:Animals; D001822:Body Burden; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D005260:Female; D007408:Intestinal Absorption; D008567:Membranes, Artificial; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012550:Schistosoma mansoni / Q000187:drug effects*; D012555:Schistosomiasis mansoni / Q000188:drug therapy / Q000469:parasitology; D012556:Schistosomicides / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000603509:MMV665852; D008567:Membranes, Artificial; D010671:Phenylurea Compounds; D012556:Schistosomicides