Progress in antischistosomal N,N'-diaryl urea SAR

Abstract

N,N'-Diaryl ureas have recently emerged as a new antischistosomal chemotype. We now describe physicochemical profiling, in vitro ADME, plasma exposure, and ex vivo and in vivo activities against Schistosoma mansoni for twenty new N,N'-diaryl ureas designed primarily to increase aqueous solubility, but also to maximize structural diversity. Replacement of one of the 4-fluoro-3-trifluoromethylphenyl substructures of lead N,N'-diaryl urea 1 with azaheterocycles and benzoic acids, benzamides, or benzonitriles decreased lipophilicity, and in most cases, increased aqueous solubility. There was no clear relationship between lipophilicity and metabolic stability, although all compounds with 3-trifluoromethyl-4-pyridyl substructures were metabolically stable. N,N'-diaryl ureas containing 4-fluoro-3-trifluoromethylphenyl, 3-trifluoromethyl-4-pyridyl, 2,2-difluorobenzodioxole, or 4-benzonitrile substructures had high activity against ex vivo S. mansoni and relatively low cytotoxicity. N,N-diaryl ureas with 3-trifluoromethyl-4-pyridyl and 2,2-difluorobenzodioxole substructures had the highest exposures whereas those with 4-fluoro-3-trifluoromethylphenyl substructures had the best in vivo antischistosomal activities. There was no direct correlation between compound exposure and in vivo activity.

Keywords: Antischistosomal; N,N′-Diaryl urea; SAR.

Figure 1

Figure 2

Plasma concentration versus time profiles following oral administration of 100 mg/kg to non-infected male Swiss outbred mice. Symbols represent the mean of n=2 mice at each time point. Panel A shows the profiles for 1, 2, 15, 18, and 19. Panel B shows the profiles for 5, 17, and 20.

Scheme 1

Reagents and conditions: (a) N,N-diisopropylethylamine, CH₂Cl₂, rt, 12 h (2, 17, 18); (b) THF, 25–80 °C; 12 h (6–9, 19, 20); (c) CH₃CN, 80 °C, 12 h (10–16); (d) CDI, THF, rt, 48 h (3, 4); (e) CDI, 1,2-dimethoxyethane, reflux, 16 h (5).