Expanding the Activity Profile of Pyrido[1,2-a]benzimidazoles: Synthesis and Evaluation of Novel N1-1-Phenylethanamine Derivatives against Schistosoma mansoni

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 (IC50 values of 0.08-1.43 mu M) 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.

Automated summary

Praziquantel is currently the main drug for treating schistosomiasis, but there is a need for new antischistosomal drugs. The novel antischistosomal PBIs show potential efficacy and good hepatic microsomal stability, but exhibit some toxicity in vivo.