Praziquantel is the only widely available drug to treat schistosomiasis. With very few candidates currently in the drug development pipeline, there is an urgent need to discover and develop novel antischistosomal drugs. In this regard, the pyrido-[1,2-a]benzimidazole (PBI) scaffold has emerged as a promising chemotype in hit-to-lead efforts. Here, we report a novel series of antischistosomal PBIs with potent in vitro activity (IC 50 values of 0.08−1.43 μM) against Schistosoma mansoni newly transformed schistosomula and adult worms. Moreover, the current PBIs demonstrated good hepatic microsomal stability (>70% of drug remaining after 30 min) and were nontoxic to the Chinese hamster ovarian and human liver HepG2 cells, though toxicity (selectivity index, SI < 10) against the rat L6 myoblast cell line was observed. The compounds showed a small therapeutic window but were efficacious in vivo, exhibiting moderate to high worm burden reductions of 35.8−89.6% in S. mansoni-infected mice.
In recent years,
N,N’
-diarylureas have emerged as a promising chemotype for the treatment of schistosomiasis, a 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. Low IC
50
values for
Schistosoma mansoni
newly transformed schistosomula (0.6 – 7.7 μM) and adult worms (0.1 – 1.6 μM) were observed. Four selected compounds, highly active in presence of albumin (>70% at 10 μM), endowed with decent cytotoxicity profile (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 SF
5
-containing
N,N’
-diarylureas.
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