Abstract
BackgroundSchistosomiasis is one of the world’s major public health problems. Besides praziquantel (PZQ), there is currently no other effective treatment against schistosomiasis. The development of new antischistosomal agents to curb the emergence of PZQ resistance should be a high priority. Oxadiazole-2-oxides have been identified as potential antischistosomal reagents, with thioredoxin glutathione reductase (TGR) being one of their molecular targets.MethodsTo develop novel treatment reagents against Schistosoma japonicum, 30 novel oxadiazole-2-oxides were synthesised and their antischistosomal activities on juvenile and adult S. japonicum were evaluated in vitro and in vivo. Their inhibitory activities against S. japonicum thioredoxin glutathione reductase (SjTGR) were also analysed.ResultsMost of the oxadiazole-2-oxides showed good juvenile and adult S. japonica killing activities in vitro. However, the antischistosomal effects of these compounds were not positively correlated with either their inhibition of SjTGR, or with nitric oxide (NO) release. Compounds 4a, 4b, 7c, 13, 16 and 20 resulted in 87.7 %, 83.1 %, 87.1 %, 84.6 %, 90.8 % and 69.5 %, respectively, mortality in the adult worms, when used to treat infected mice at schistosomula stage. These mortality rates were similar to or higher than that of artemisinin. Furthermore, compounds 4a and 16 resulted in 66.7 % and 69.4 % reductions in the worm burdens, respectively, when infected mice were treated at the adult worm stage. These treatment effects were similar to PZQ. No differences in activity of the oxadiazole-2-oxides against female and male adult worms were observed. The toxicity of the oxadiazole-2-oxides on mammalian cells appeared to be similar to, or less than, that of PZQ.ConclusionsThe antischistosomal activity of the oxadiazole-2-oxides does not depend on NO production or the inhibition of SjTGR activity. There may be other functional targets of the oxadiazole-2-oxides in S. japonicum. Several of the novel oxadiazole-2-oxides synthesised in this study could be used to develop novel antischistosomal drugs and explore potential molecular targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1301-3) contains supplementary material, which is available to authorized users.
Highlights
Schistosomiasis is one of the world’s major public health problems
The results show that some novel oxadiazole-2oxides had a good killing activity against S. japonicum, but did not inhibit the activity of S. japonicum thioredoxin glutathione reductase (SjTGR), implying that oxadiazole-2-oxides may have other functional targets in S. japonicum
The results showed that compounds 4a, 4b, 4c, 7a, 7b, 7c, 8, 11, 12, 13, 14, 16, 20 and 22 inhibited the activity of SjTGR (Fig. 1 and Table 1), with IC50 values between 0.5 and 37.4 μM
Summary
Schistosomiasis is one of the world’s major public health problems. Besides praziquantel (PZQ), there is currently no other effective treatment against schistosomiasis. The development of new antischistosomal agents to curb the emergence of PZQ resistance should be a high priority. Schistosomiasis is one of the most prevalent parasitic diseases. The infection is caused by trematodes of the genus Schistosoma, among which Schistosoma mansoni, S. haematobium, S. japonicum, S. mekongi and S. intercalatum represent the most important pathogenic species for human beings. The worms (schistosomes) persist in the liver and hepatic portal system or the urinary tract system of humans. In China, the disease caused by S. japonica is a major public health concern, with more than 280 thousand people infected [3]. To cure subtle morbidity and prevent the development of severe chronic stage hepatosplenomegaly, praziquantel (PZQ) is the only choice of chemotherapy. The mechanism by which PZQ works is still undefined [5]
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