Oxamniquine derivatives overcome praziquantel treatment limitations for schistosomiasis

Human schistosomiasis is a neglected tropical disease caused by S. mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies for schistosomiasis. Previous treatment of S. mansoni included the use of Oxamniquine (OXA), a drug that activated by schistosomes’ sulfotransferase (SULT). Guided by data from Xray crystallography and Schistosoma killing assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150610 and CIDD-0150303 as powerful derivatives in vitro that kill (100%) of all three Schistosoma species at a final concentration of 143 µM. We evaluated the efficacy of the best OXA derivates in an in vivo model after treatment with a single dose of 100 mg/kg by oral gavage. The highest rate of worm burden reduction was achieved by CIDD -150303 (81.8%) against S. mansoni, CIDD-0149830 (80.2%) against S. haematobium and..., ,