Jennifer Keiser1, Gordana Panic2, Mireille Vargas2, Chunkai Wang3, Yuxiang Dong3, Nagsen Gautam3, Jonathan L Vennerstrom3. 1. 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. 2. Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland University of Basel, CH-4003 Basel, Switzerland. 3. College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
Abstract
OBJECTIVES: 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.
OBJECTIVES: 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: 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 Journal: J Antimicrob Chemother Date: 2020-10-01 Impact factor: 5.790
Authors: Jianbo Wu; Chunkai Wang; Cécile Häberli; Karen L White; David M Shackleford; Gong Chen; Yuxiang Dong; Susan A Charman; Jennifer Keiser; Jonathan L Vennerstrom Journal: Bioorg Med Chem Lett Date: 2018-10-25 Impact factor: 2.823
Authors: Chunkai Wang; Qingjie Zhao; Mireille Vargas; Jeremy O Jones; Karen L White; David M Shackleford; Gong Chen; Jessica Saunders; Alice C F Ng; Francis C K Chiu; Yuxiang Dong; Susan A Charman; Jennifer Keiser; Jonathan L Vennerstrom Journal: J Med Chem Date: 2016-11-28 Impact factor: 7.446
Authors: Manu De Rycker; David Horn; Bree Aldridge; Richard K Amewu; Clifton E Barry; Frederick S Buckner; Sarah Cook; Michael A J Ferguson; Nathalie Gobeau; Jennifer Herrmann; Paul Herrling; William Hope; Jennifer Keiser; Maria Jose Lafuente-Monasterio; Paul D Leeson; Didier Leroy; Ujjini H Manjunatha; James McCarthy; Timothy J Miles; Valerie Mizrahi; Olena Moshynets; Jacquin Niles; John P Overington; John Pottage; Srinivasa P S Rao; Kevin D Read; Isabela Ribeiro; Lynn L Silver; Jen Southern; Thomas Spangenberg; Shyam Sundar; Caitlin Taylor; Wes Van Voorhis; Nicholas J White; Susan Wyllie; Paul G Wyatt; Ian H Gilbert Journal: ACS Infect Dis Date: 2019-12-06 Impact factor: 5.084