In Vitro, In Vivo, And Absorption, Distribution, Metabolism, And Excretion Evaluation Of Sf5-Containing N,N'-Diarylureas As Antischistosomal Agents

In recent years, N,N'-diarylureas have emerged as a promising chemotype for the treatment of schistosomiasis, a parasite-caused disease that poses a considerable health burden to millions of people worldwide. Here, we report a novel series of N,N'-diarylureas featuring the scarcely explored pentafluorosulfanyl group (SF5). Low 50% inhibitory concentration (IC50) values for Schistosoma mansoni newly transformed schistosomula (0.6 to 7.7 mu M) and adult worms (0.1 to 1.6 mu M) were observed. Four selected compounds that were highly active in the presence of albumin (>70% at 10 mu M), endowed with decent cytotoxicity profiles (selectivity index [SI] against L6 cells >8.5), and good microsomal hepatic stability (>62.5% of drug remaining after 60 min) were tested in S. mansoni-infected mice. Despite the promising in vitro worm-killing potency, none of them showed significant activity in vivo. Pharmacokinetic data showed a slow absorption, with maximal drug concentrations reached after 24 h of exposure. Finally, no direct correlation between drug exposure and in vivo activity was found. Thus, further investigations are needed to better understand the underlying mechanisms of SF5-containing N,N'-diarylureas.