Diaryl Ureas as an Antiprotozoal Chemotype.

We now describe the physicochemical profiling, ADME, and antiparasitic activity of eight ,-diarylureas to assess their potential as a broad-spectrum antiprotozoal chemotype. Chromatographic LogD values ranged from 2.5 to 4.5; kinetic aq. solubilities were ≤6.3 μg/mL, and plasma protein binding ranged from 95 to 99%. All of the compounds had low intrinsic clearance values in human, but not mouse, liver microsomes. Although no ,-diarylurea had submicromolar potency against , two had submicromolar potencies against and , and five had submicromolar potencies against . appeared to be the most susceptible to growth inhibition by this compound series. Most of the ,-diarylureas had antiprotozoal selectivities ≥10. One ,-diarylurea had demonstrable activity in mouse models of malaria and toxoplasmosis.