Development of Next-Generation Oxamniquine Derivatives for the Treatment of Human Schistosomiasis

Human schistosomiasis, one of the most important neglected tropical diseases caused by parasitic worms of the genus Schistosoma. It is accompanied by severe clinical symptoms as well as socioeconomic problems, and more than 200,000 deaths per year. According to the WHO, some 229 million people in 78 countries are affected. Although disease transmission is more common in tropical and subtropical areas, a potential shift of schistosomiasis into new habitat like south Europe is anticipated due to climate change. No vaccine is available, only the drug Praziquantel (PZQ) is used for treatment. However, PZQ still having some basic problems as, constant selection pressure that caused a serious concern for the spread of drug-resistance to this monotherapy and the cure rate for PZQ is usually 60-90% but never 100%. In addition, PZQ is active against mature parasites only and not active against juvenile parasites which leads to re-activation since the patient is still harboring juvenile worms. Due to PZQ treatment limitations and constant selection pressure, there is an urgency of developing new therapies for schistosomiasis. Our starting point in drug development was a previous treatment of Schistosoma, Oxamniquine (OXA). OXA is a prodrug that requires activation by an endogenous schistosome sulfotransferase. However, OXA has fallen out of use due to drug resistance and limited efficacy. To overcome these treatment limitations, we have successfully derivatized OXA using structure-function-guided approaches to design a new series of compounds with major advancements over both PZQ and OXA. Guided by data from X-ray crystallography and Schistosoma killing assays, we designed, synthesized, and tested 350 compounds. We have successfully identified CIDD-015610 that has major advancement. In vivo studies demonstrated that CIDD-0150610 can reduced the infection up to 80%. CIDD-015610 is effective against the main clinically important Schistosoma species. and, importantly, they are also effective against juvenile parasite and PZQ-resistant strains. We conclude that CIDD-0150610 is a better that can be used in combination with PZQ to mitigate drug resistance and improve efficacy. National Institute of General Medical Science (2k12GM111726), the National Institute of Allergy and Infectious Diseases (AI27219), Morrison Trust, the National Institutes of Health (P30 CA054174), the NIH-ORIP SIG (S10OD030374), the National Institute of General Medical Sciences (P30 GM124165), and the NIH-ORIP HEI (S10OD021527).