**2. Praziquantel**

In 1972, Merck and Bayer tested **PZQ** among 400 other drugs, in efforts to develop a commercialized treatment against schistosomiasis [14]. It was first approved and used as a veterinary treatment against the disease, but in the 1980s, it was transitioned into treatment against infections in humans [15]. It is regarded as a safe and highly effective drug against all adult *Schistosoma* worms [16]. **PZQ**'s main metabolite is its 4-*trans*-cyclohexanol derivative **1**, which is 4 to 10 times less effective against *S. mansoni* than **PZQ** itself [17, 18].

**PZQ** analogs derivatized with ferrocenyl groups at various positions, including **2**, were determined to have only moderate *in vitro* activity against *S. mansoni* [19]. Tricarbonylchromium **PZQ** derivatives such as **3**, however, have demonstrated *in vitro* anti-schistosomiasis activity on par with that of **PZQ** itself [20]. Further work established that chromium derivatives of *R*-**PZQ** were more effective than derivatives of *S*-**PZQ**, but still only effected low worm burden reductions (WBRs) *in vivo* [21].

**PZQ** appears to owe its activity to its activation of a Ca2+-permeable ion channel in *S. mansoni* that belongs to a family of transient receptor potential (TRP) channels, which are non-selective cation channels [22, 23]. This target has been widely exploited by other antihelmintics [24, 25] as well as therapies for respiratory diseases, cancer and other conditions [26–28]. By activating this ion channel, **PZQ** effects a rapid calcium uptake across the ion channel, with deleterious effect to the parasite's morphology [29].

Since **PZQ** has been found to target a TRP channel, TRP channels have been further studied as druggable targets for schistosomiasis. A high-throughput screen of about 16,000 compounds against a TRP channel in the melastatin family yielded **4** as a strong receptor agonist (EC50 = 1.6 ± 0.3 μM) and 32 potential receptor antagonists, including **5** [22].

*Recent Advances in Anti-Schistosomiasis Drug Discovery DOI: http://dx.doi.org/10.5772/intechopen.103056*

#### **Figure 2.**

*Oxamniquine (***OXA***) and related compounds (***6***–***11***).*

### **3. Oxamniquine**

The development of oxamniquine (**OXA**, **Figure 2**) as an anti-schistosomiasis drug began with the study of Pfizer compound UK 3883 (**6**) [30, 31], a conformationally restricted analog of Mirasan (**7**), which was itself a simplified version of the early anti-schistosomiasis drug lucanthone (**8**). Mirasan proved effective against *S. mansoni* in mice but not in primates, suggesting that it and its analogs were acting as prodrugs activated by metabolic oxidation at their benzylic positions. The hydroxymethyl metabolite of **6**, **OXA**, has showed excellent anti-schistosomiasis activity in both mice and humans [32].

Although **OXA** can be easily absorbed orally, is active against both intestinal and liver infections, and has a lower cost than **PZQ** [18], it remains the second choice when compared to **PZQ** for a variety of reasons. **OXA** is only effective against *S. mansoni*, whereas **PZQ** is effective against all major forms that manifest in humans [33]. **OXA** also can cause a wide variety of side effects, such as nausea, dizziness, drowsiness, and headache [18]. **OXA** is a prodrug, converted into its reactive sulfate ester form by an *S. mansoni* sulfotransferase enzyme (Smp089320, or *Sm*SULT-OR) [34, 35]. Recent work guided by the crystal structure of this enzyme has led to the development of **OXA** derivatives with greater efficacy not only against *S. mansoni*, but *S. japonium* and *S. hematobium* as well [36].

Ferrocenyl and ruthenocenyl derivatives of **OXA** (**9**–**10**) were also synthesized and found to be roughly as active as the parent **OXA** against *S. mansoni*, but significantly more active in *in vitro* testing than **OXA** against *S. haematobium* and *S. japonicum* [37–39]. Notably, this work also found a benzylated **OXA**, **11**, to be effective against all three parasites *in vitro* [37]. However, the *in vivo* efficacy against the parasites was limited, in part due to their instability in acidic media [39].

### **4. Antischistosomal antimalarials**

#### **4.1 Artemisinins**

Artemisinin (**12**, **Figure 3**) and its congeners are the active ingredients in the extracts of *Artemisia annua*, which have been used as traditional Chinese medicine for a variety

**Figure 3.** *Artemisinin derivatives (***12–13***) and synthetic endoperoxides with antischistosomal potential (***14***–***17***).*

of ailments for thousands of years [40]. The disclosure of the artemisinins' antimalarial potential in 1979 [41] was followed closely by a 1980 report on their antischistosomal activity [42]. The schistosomicidal activity of **12** and similar antimalarials may stem from their ability to interfere with the blood-feeding parasite's ability to detoxify heme [43].

Artemisinins such as **12** and artesunate (**13**) have demonstrated high *in vivo* efficacy against juvenile schistosomes and moderate *in vivo* efficacy against adult schistosomes [43], suggesting that simultaneous treatment with artemisinins and **PZQ** may prove complementary [40]. Although one study did find synergistic effects when artemisinins were combined with **PZQ**, this treatment method would have to be administered repeatedly to prevent reinfection [44].

#### **4.2 Trioxolanes**

The success of artemisinins as antiparasitic agents has motivated the development of fully synthetic derivatives [45]. OZ78 (**14**, **Figure 3**) is a carboxylic acid trioxolane that achieves high WBRs (greater than 80%) against juvenile *S. mansoni* in mice [46]. Its endoperoxide moiety appears to be necessary for its antischistosomal activity, as non-peroxidic analogs showed no activity. Another trioxolane, OZ418 (**15**), is orally active and targets multiple developmental stages of *S. mansoni*. With a single oral dose of 200 mg/kg, infections of juvenile *S. mansoni* were completely cured, and an 80% WBR was achieved [43]. Antimalarial hybrids of trioxolanes with quinine derivatives (e.g. the "trioxaquine" **16**) have also demonstrated promising antischistosomal activity [8, 43], as have similar trioxolane-PZQ hybrids (e.g., the "trioxaquantel" **17**) [47].

#### **4.3 Other antimalarials**

Other antimalarials, including mefloquine (**18**, **Figure 4**), have also shown broad antischistosomal activity [48]. Recent work has added pyronaridine (**19**) and methylene blue (**20**) to the list of antimalarial compounds that show promise against schistosomiasis; both demonstrated sub-micromolar IC50 values against schistosomula, as well as complete killing of adult worms at 30 μM [49]. Pyronaridine was found to be active against juvenile *S. mansoni* but not the adult parasite [48], while methylene blue showed good activity against adult worms *in vivo*. In a small observational trial in Gabon, three out of four children with an *S. haematobium* infection were cured with Pyramax, a combination of pyronaridine and artesunate (**13**) [49].

*Recent Advances in Anti-Schistosomiasis Drug Discovery DOI: http://dx.doi.org/10.5772/intechopen.103056*

**Figure 4.** *Antimalarials/antiparasitics with anti-schistosomiasis activity (***18***–***22***).*

Many natural products have demonstrated anti-schistosomiasis activity [10, 50–52]. The aurone scaffold is another source of antimalarial compounds [53, 54] that has been investigated for anti-schistosomiasis potential [55, 56]. Aurone **21** proved efficacious against *S. mansoni* in an *in vivo* mouse model (against both juvenile (21-dayold) and adult (49-day-old) parasites) and caused a marked decrease in both immature and mature eggs eliminated in feces by infected mice [55].

Cryptolepines, isolated from the roots of *Cryptolepis sanguinolenta,* have been used as traditional medicine in Central and West Africa, and more recently have studies as an antimalarial treatment [57]. Piperazinyl-substituted norneocryptolepines such as **22** have been shown to have high antischistosomal activity (IC50 < 5 μM against adult *S. mansoni*); six out of sixteen neocryptolepines showed 100% worm mortality at a concentration of 5 μg/mL after five days [58].
