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 LogD_7.4 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.

Keywords: N,N′-diarylurea; antiprotozoal; chemotype.

Figure 1.

Antiprotozoal N,N′-diarylureas 1–6.

Figure 2.

Survival of mice lethally infected with T. gondii treated with varying doses of 11. Survival of mice lethally infected with T. gondii (n = 10 per treatment) treated with varying doses of 11. CFW mice were infected with 5000 ME49 tachyzoites. Compound 11 was administered via oral gavage at 25, 50, or 75 mg/kg given on days 1, 3, and 7 postinfection. As a positive control, pyrimethamine was given at 5 mg/kg via intraperitoneal injection once per day for 10 days.

Scheme 1.. Synthesis of N,N′-Diarylureas 12–14^a

^aReagents and conditions: (a) THF, rt, 24 h (12); (b) N,N-diisopropylethylamine, THF, rt, 12 h (13); (c) acetone, rt; 24 h (14).