Schistosomiasis is a parasitic disease caused by trematodes of the genus Schistosoma. The three main schistosome species parasitizing humans are Schistosoma haematobium, S. mansoni and S. japonicum. In a restricted geographical focus in Cambodia and Laos, S. mekongi occurs. Schistosomiasis is responsible for a global burden of 2.6 million disability-adjusted life years. The standard treatment used against schistosomiasis is praziquantel, a safe and efficacious drug that is, however, not without drawbacks. For instance, praziquantel is active against adult schistosomes, but has no or only very little activity against young developmental stages of the parasite. Additionally, the high drug pressure from the widespread use of praziquantel could lead to drug resistance, which would jeopardize the global control strategy against schistosomiasis, as there are no marketed alternatives to praziquantel. Hence, there is a pressing need to develop novel antischistosomal drugs. Unfortunately though, neglected disease markets are non-commercial, therefore drug companies are not interested in them. Moreover, there are only very few academic research groups working on anthelminthic drug discovery. The single exception in the field of antischistosomal drug development is a consortium that aims to develop a paediatric formulation (oral dispersible tablet (ODT)) of praziquantel based on the enantiomer or the racemate.The aim of my 4-year research project is to identify one or several antischistosomal drug development candidates targeting the haemoglobin degradation pathway and/or other mechanisms with favourable physico-chemical and drug metabolism and pharmacokinetics (DMPK) properties. My proposed research will assist in improving current treatment options for schistosomiasis (and other trematodiases, such as opisthorchiasis). To accomplish this aim, I will pursue four specific objectives:i.To assess the in vitro activity of analogues of selected lead compounds against larval (schistosomula) and adult S. mansoni and assess cytotoxicity and metabolic stability.ii.To elucidate and characterize in vivo efficacy of lead compounds in schistosome-rodent models.iii.To determine pharmacokinetic parameters for the most potent compounds.iv.To determine the activity, safety and pharmacokinetics of escalating dosages of a new ODT of praziquantel in preschool-aged children infected with S. haematobium in Côte d’Ivoire and S. mekongi (and Opisthorchis viverrini) in Laos.Antischistosomal drug discovery suggested in this proposal will be done in close collaboration with Medicines for Malaria Venture (MMV) and Prof. Kelly Chibale in South Africa. We will work with pyrido[1,2-a]benzimidazole-based and benzimidazole compounds synthesized by Prof. Chibale and leads obtained from the MMV Stasis and Pathogen Box. The clinical trials will be conducted in collaboration with Merck and established partners in Côte d’Ivoire and Laos. Our work is of potential public health relevance. The identified leads from this project will be further profiled and optimized as potential preclinical and clinical development candidates for the treatment of schistosomiasis. In addition, this research will generate a deeper understanding of the new praziquantel ODTs against S. haematobium and S. mekongi as well as O. viverrini resulting in optimal treatment schedules for pediatric schistosomiasis. Understanding better the dose versus concentration versus effect profile will be invaluable for improving and guiding clinicians to use a safe and efficacious dose of the new praziquantel formulation in children, which is the demographic that is most affected by schistosomiasis.