Oxadiazole-2-oxides may have other functional targets, in addition to SjTGR, through which they cause mortality in Schistosoma japonicum

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.

Comparative Evaluation of Anthelmintic Activity of Edible and Ornamental Pomegranate Ethanolic Extracts againstSchistosoma mansoni

“…Depending on the species, the schistosome worms persist in the liver and hepatic portal system or the urinary tract system of humans. Mature schistosomes lay eggs within their host, which often get trapped in the host's tissues, resulting in inflammatory and obstructive diseases of the affected organs [2, 3]. …”

Synthesis of Oxadiazole-2-Oxide Derivatives as Potential Drug Candidates for Schistosomiasis Targeted on SjTGR

“…Schistosomiasis is one of the most widely spread parasitic diseases in the world, as well as is one of the main tropical endemic disease in Asia, Africa and South America [1]. It is estimated that there are approximately 779 million individuals around the world bearing the risk of schistosomiasis infection [2].…”

“…In the previous study [1][2]7] D. L. William and co-workers have proved that some oxadiazole-2-oxide analogues were effective on inhibiting SmTGR and SjTGR, even had good antischistosomal activity in vive. Modi cations around oxadiazole-2-oxide skeleton have demonstrated to be the valuable strategy for discovering potential antischistosomal agents.…”

“…The application of bioisosteres is an effective strategy in drug design. The previous researchers mainly substituted on the benzene ring and changed in the CN moiety when designing the compound [1][2]7], but did not pay attention to modi cation of benzene ring and other moieties in the furoxan structure with corresponding bioisosteres. Therefore, in this work, the strategy of application of bioisosteres was exploited to design novel oxadiazole-2-oxide derivatives.…”

Structural insights into natural compounds as inhibitors of Fasciola gigantica thioredoxin glutathione reductase

“…have been found as Schistosoma TGR inhibitors . Oxadiazole‐2‐oxides (furoxans), as an efficient NO donor, has been found to have inhibitory activities against both juvenile and adult S. japonicum worms . In fact, several furoxans and thiadiazole have been found active against both trematode and cestode parasites …”