BackgroundAs plans to expand mass drug treatment campaigns to fight schistosomiasis form, worries about reliance on praziquantel as the sole available treatment motivate the investigation for novel antischistosomal compounds. Drug repurposing might be an inexpensive and effective source of novel antischistosomal leads.Methodology1600 FDA approved compounds were first assayed against Schistosoma mansoni schistosomula at a concentration of 10 µM. Active compounds identified from this screen were advanced to the adult worm screen at 33.33 µM, followed by hit characterization. Leads with complementary pharmacokinetic and toxicity profiles were then selected for in vivo studies.Principal FindingsThe in vitro screen identified 121 and 36 compounds active against the schistosomula and adult stage, respectively. Further, in vitro characterization and comparison with already available pharmacokinetic and toxicity data identified 11 in vivo candidates. Doramectin (10 mg/kg) and clofazimine (400 mg/kg) were found to be active in vivo with worm burden reductions of 60.1% and 82.7%, respectively.Conclusions/SignificanceThe work presented here expands the knowledge of antischistosomal properties of already approved compounds and underscores variations observed between target-based and phenotypic approaches and among laboratories. The two in vivo-active drugs identified in this study, doramectin and clofazimine are widely available and present as novel drug classes as starting points for further investigation.

BackgroundWorldwide 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.MethodologyWe 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.Principal FindingsPromising 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.Conclusions/SignificanceThe 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.

We evaluated the in vivo antischistosomal activities of 11 structurally diverse synthetic peroxides. Of all compounds tested, ozonide (1,2,4-trioxolane) OZ418 had the highest activity against adult Schistosoma mansoni, with total and female worm burden reductions of 80 and 90% (P < 0.05), respectively. Furthermore, treatment of S. haematobium-infected mice with OZ418 reduced the total worm burden by 86%. In conclusion, OZ418 is a promising antischistosomal lead compound. S chistosomiasis, caused by blood flukes of the genus Schistosoma, is an important cause of morbidity and mortality, mainly among the rural poor in sub-Saharan Africa (5, 16). The need for new antischistosomal drugs is quite evident, given that praziquantel is the only drug available and is in widespread use in population-based morbidity control programs (16).Various classes of synthetic peroxides, including trioxaquines (1,2,4-trioxanes) (1, 12), the tetraoxaspirononadecane N-89 (15), and ozonides (1,2,4-trioxolanes) (19), have been studied for their antischistosomal properties. Our previous data demonstrate that, like the artemisinins, ozonides possess promising antischistosomal properties (10, 19). We investigated three representative ozonides, namely, carboxylic acid OZ78, amine OZ209, and phenol OZ288 (Fig. 1). Of these, 8=-aryl ozonide OZ288 had the highest antischistosomal activity; this ozonide reduced the total worm burden by 95% (200 mg/kg body weight) in mice harboring juvenile Schistosoma mansoni and by 52% (400 mg/kg) in mice harboring adult worms (19). Although 8=-alkyl ozonides OZ78 and OZ209 had activities greater than 80% against juvenile worms, lower activities (0 and 17%, respectively) were observed for these two ozonides against adult worms. We suggest that the increased iron(II) stabilities of 8=-aryl ozonides compared to those of 8=-alkyl ozonides (2) might contribute to the superior antischistosomal efficacy of OZ288.The aim of the present study was to evaluate in a first step the in vivo antischistosomal activities of nine structurally diverse OZ288 analogs (Fig. 2), including antimalarial drug candidate OZ439, currently in phase II clinical testing (2). Since schistosomiasis and malaria are coendemic in many parts of the world, it is important to assess the potential auxiliary effects of antimalarial drug candidates such as OZ439 on Schistosoma species.Our animal studies were carried out following national and cantonal regulations on animal welfare (permission no. 2070). All compounds were synthesized as described in previous publications and patents (3,4,17,18). Compounds were freshly prepared in homogenous aqueous suspensions in 7% Tween 80 and 3% ethanol.Female NMRI mice (n ϭ 147; age, 4 weeks; weight, ϳ20 g) were purchased from Charles River (Sulzfeld, Germany) and Harlan Laboratories (Blackthorn, United Kingdom). Mice were maintained in groups of 10 in Makrolon cages under environmentally controlled conditions (temperature, ϳ25°C; humidity, ϳ50%; 12-h light and 12-h dark cycle) with free access to water and food. Mi...