**Abstract**

Schistosomiasis, a parasitic disease caused by infection by helminths of the *Schistosoma* genus, affects over 200 million people, primarily in the developing world. Treatment of this disease largely relies on one drug, praziquantel. Although this drug is cheap, safe, and effective, the looming prospect of drug resistance makes the development of a pipeline of anti-schistosomiasis drugs a priority. Many new drug leads have arisen from screening existing sets of compounds such as the Open Access Boxes developed by the Medicines for Malaria Venture (MMV) in collaboration with the Drugs for Neglected Diseases Initiative (DNDI). Other leads have been found through work focused on druggable targets such as kinases, histone deacetylases, proteases, and others. This chapter will discuss recent work concerning the discovery and development of novel anti-schistosomiasis drug leads from many sources.

**Keywords:** schistosomiasis, drug discovery, praziquantel, antiparasitic medicinal chemistry, drug screening, enzyme inhibitors

### **1. Introduction**

Schistosomiasis is a neglected tropical disease that affects hundreds of millions of people, primarily in the developing world [1, 2]. The disease is caused by blood flukes of the genus *Schistosoma*; the three main infectious species are *S. mansoni* (in Africa and tropical South America), *S. japonicum* (in China and the Philippines), and *S. haematobium* (in Africa) [1]. Infections occur when parasites in their cercariae stage swim from their freshwater snail hosts and penetrate human skin. The cercariae then lose their tails and migrate to the intestinal or urogenital area. There they mature to adult worms, form male-female pairs, and lay eggs prolifically; the host's disease symptoms are due to an immune response to these eggs [3]. Eggs shed into a water source by human defecation hatch and release miracidia, which infect the intermediate snail host and continue the cycle.

Chronic schistosomiasis is associated with diseases of the kidneys, spleen, liver, bladder and intestine [3]. In endemic areas, up to 75% of the incidence of bladder cancer has been attributed to infection with *S. haematobium*; [4, 5] the link between *S. mansoni* infection and cancer is still being investigated [6]. In all, the global burden

**Figure 1.**

*Praziquantel (***PZQ***), its primary metabolite (***1***), and related compounds* **2***–***5***.*

due to schistosomiasis, in terms of disability-adjusted life years (DALYs, which combine premature mortality data with years lived with a disability) has been estimated at 1.7–4.5 million [7].

Current treatment of this disease relies almost exclusively on one drug: praziquantel (**PZQ**, **Figure 1**). While PZQ has so far proven effective against adult *Schistosoma* worms of all species, the specter of drug resistance, as well as PZQ's ineffectiveness against immature parasites, have motivated the search for new antischistosomals. Several excellent reviews have recently been published on these efforts [8–13]. In this chapter, I will briefly discuss current antischistosomals in use, antimalarials with antischistosomiasis potential, and finally, the discovery of novel scaffolds for drug development, by screening for phenotypic changes or against a specific biological target.
