Diaryl Ureas as an Antiprotozoal Chemotype

Abstract

We now describe the physicochemical profiling, in vitro ADME, and antiparasitic activity of eight N,N′-diarylureas to assess their potential as a broad-spectrum antiprotozoal chemotype. Chromatographic LogD7.4 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 N,N′-diarylurea had submicromolar potency against Trypanosoma cruzi, two had submicromolar potencies against Toxoplasma gondii and Trypanosoma brucei rhodesiense, and five had submicromolar potencies against Leishmania donovani. Plasmodium falciparum appeared to be the most susceptible to growth inhibition by this compound series. Most of the N,N′-diarylureas had antiprotozoal selectivities ≥10. One N,N′-diarylurea had demonstrable activity in mouse models of malaria and toxoplasmosis.

Tribute to Jonathan Vennerstrom

“…In collaboration with researchers at the Swiss Tropical and Public Health Institute and Monash University, Jonathan and co-workers discovered his synthetic ozonides were also endowed with potent trematocidal properties showing activity against various Schistosoma species as well as several other important trematodes known to cause disease in the intestine and liver . In parallel efforts, his laboratories have explored a novel series of aryl hydantoins and diarylureas with impressive antischistosomal activity. In addition to his foundational work on malaria and schistosomiasis, Jonathan has developed a novel class of diimidazolines for the treatment of African trypanosomiasis with an improved safety profile compared to the current standard of care pentamidine for the first stage of the disease …”