title: Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978).
abstract: The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand-androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimization of antischistosomal hydantoins.
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Chunkai
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute , Socinstrasse 57, CH-4002 Basel, Switzerland.|University of Basel , CH-4003 Basel, Switzerland.
authors.forename: Mireille
authors.initials: M
authors.lastname: Vargas
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center , Duarte, California 91010, United States.
authors.forename: Jeremy O
authors.initials: JO
authors.lastname: Jones
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Saunders
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Alice C F
authors.initials: AC
authors.lastname: Ng
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Francis C K
authors.initials: FC
authors.lastname: Chiu
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute , Socinstrasse 57, CH-4002 Basel, Switzerland.|University of Basel , CH-4003 Basel, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006827:Hydantoins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D012550:Schistosoma mansoni / Q000187:drug effects*; D012552:Schistosomiasis / Q000188:drug therapy*; D012556:Schistosomicides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D006827:Hydantoins; D012556:Schistosomicides