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.