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 CIDD-066790 (86.7%) against S. japonicum. We have also evaluated the derivatives ability to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150303 demonstrated (100%) of killing for all life stages at a final concentration of 143 µM in vitro and effective reduction in worm burden in vivo. To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150303 and CIDD-0150610 demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg/kg by oral gavage of each PZQ and CIDD-0150303 reduced the worm burden in an animal model by (90.8%). Therefore, we conclude that CIDD-0150303, CIDD-0149830 and CIDD-066790 are the novel drugs that overcome OXA limitation, and CIDD-0150303 can be used with PZQ in combination therapy.