Antischistosomal Activity of Trioxaquines: In Vivo Efficacy and Mechanism of Action on Schistosoma mansoni

Abstract

Schistosomiasis is among the most neglected tropical diseases, since its mode of spreading tends to limit the contamination to people who are in contact with contaminated waters in endemic countries. Here we report the in vitro and in vivo anti-schistosomal activities of trioxaquines. These hybrid molecules are highly active on the larval forms of the worms and exhibit different modes of action, not only the alkylation of heme. The synergy observed with praziquantel on infected mice is in favor of the development of these trioxaquines as potential anti-schistosomal agents.

Author Summary

Schistosomiasis is a tropical disease affecting more than 200 million people throughout the sub-tropical and tropical world. The treatment and control of schistosomiasis rely on the use of a single drug, the praziquantel and no vaccine is available. However, schistosome species with low sensitivity or resistance to praziquantel have been identified in several countries. It is an urgent need to develop new drugs against this parasite. In this context, our study reports the activity the trioxaquine PA1259. PA1259 is an hybrid drug containing two pharmacophores within a single molecule: a trioxane and an aminoquinoline. Initially developed against malaria, the trioxaquines target the heme a disposal product resulting from the digestion of the hemoglobin. The first action of the trioxaquine is an alkylation of the heme with the trioxane entity, and the second action is stacking with the heme due to the aminoquinoline moiety. In this study we show that this new drug is active in vitro against all schistosome stages (cercariae, schistosomule and adult). The PA1259 is also active in vivo and shows synergistic action in association with praziquantel. This opens the route to an efficient bitherapy of a highly neglected disease.