Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs.
We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo.
Promising antischistosomal activity (IC50: 1.4–9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N′-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively.
The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development.
To date, praziquantel is the only available drug for the treatment of the tropical neglected disease schistosomiasis and is widely used in morbidity control programs. To discover new chemical scaffolds for the treatment of schistosomiasis, we investigated the Medicines for Malaria Venture malaria box containing 200 diverse drug-like and 200 probe-like compounds with known antimalarial activity against Schistosoma mansoni. Compounds were first investigated on the larval stage of S. mansoni, followed by testing against adult worms in vitro and by in vivo studies of lead candidates. We identified two entirely new chemical scaffolds: the N,N′-diarylurea and 2,3-dianilinoquinoxaline derivatives with antischistosomal in vitro activity in the sub micromolar range and significant activity in the mouse model. Since both compounds offer a good pharmacokinetic profile, low cytotoxic potential and easy chemistry, structure-activity relationship studies should be launched.