title: Oxadiazole-2-oxides may have other functional targets, in addition to SjTGR, through which they cause mortality in Schistosoma japonicum.
abstract: BACKGROUND
  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. Oxadiazole-2-oxides have been identified as potential antischistosomal reagents, with thioredoxin glutathione reductase (TGR) being one of their molecular targets.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  Most 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Key Laboratory on Technology for Disease Prevention and Control, Ministry of Health, Jiangsu Provincial Key laboratory of Parasite Molecular Biology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, 214064, China. songlijun1025@163.com.|Public Health Research Center, Jiangnan University, Wuxi, 214122, China. songlijun1025@163.com.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Song
authors.affiliation: School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China. 1464371728@qq.com.
authors.forename: Huan
authors.initials: H
authors.lastname: Luo
authors.affiliation: School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China. fanwenhua1987@163.com.
authors.forename: Wen-Hua
authors.initials: WH
authors.lastname: Fan
authors.affiliation: School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China. p85615822@yeah.net.
authors.forename: Gu-Ping
authors.initials: GP
authors.lastname: Wang
authors.affiliation: Key Laboratory on Technology for Disease Prevention and Control, Ministry of Health, Jiangsu Provincial Key laboratory of Parasite Molecular Biology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, 214064, China. yinxuren@sohu.com.|Public Health Research Center, Jiangnan University, Wuxi, 214122, China. yinxuren@sohu.com.
authors.forename: Xu-Ren
authors.initials: XR
authors.lastname: Yin
authors.affiliation: Key Laboratory on Technology for Disease Prevention and Control, Ministry of Health, Jiangsu Provincial Key laboratory of Parasite Molecular Biology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, 214064, China. 2496049650@163.com.|Public Health Research Center, Jiangnan University, Wuxi, 214122, China. 2496049650@163.com.
authors.forename: Shuang
authors.initials: S
authors.lastname: Shen
authors.affiliation: Key Laboratory on Technology for Disease Prevention and Control, Ministry of Health, Jiangsu Provincial Key laboratory of Parasite Molecular Biology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, 214064, China. sunflower1230@163.com.|Public Health Research Center, Jiangnan University, Wuxi, 214122, China. sunflower1230@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory on Technology for Disease Prevention and Control, Ministry of Health, Jiangsu Provincial Key laboratory of Parasite Molecular Biology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, 214064, China. 502240773@qq.com.|Public Health Research Center, Jiangnan University, Wuxi, 214122, China. 502240773@qq.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Key Laboratory on Technology for Disease Prevention and Control, Ministry of Health, Jiangsu Provincial Key laboratory of Parasite Molecular Biology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, 214064, China. 543608268@qq.com.|Public Health Research Center, Jiangnan University, Wuxi, 214122, China. 543608268@qq.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Key Laboratory on Technology for Disease Prevention and Control, Ministry of Health, Jiangsu Provincial Key laboratory of Parasite Molecular Biology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, 214064, China. 648010057@qq.com.|Public Health Research Center, Jiangnan University, Wuxi, 214122, China. 648010057@qq.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Gao
authors.affiliation: Key Laboratory on Technology for Disease Prevention and Control, Ministry of Health, Jiangsu Provincial Key laboratory of Parasite Molecular Biology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, 214064, China. 284661103@qq.com.|Public Health Research Center, Jiangnan University, Wuxi, 214122, China. 284661103@qq.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China. wwenlong2011@163.com.
authors.forename: Wen-Long
authors.initials: WL
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China. fengbainian@jiangnan.edu.cn.
authors.forename: Bainian
authors.initials: B
authors.lastname: Feng
authors.affiliation: Key Laboratory on Technology for Disease Prevention and Control, Ministry of Health, Jiangsu Provincial Key laboratory of Parasite Molecular Biology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, 214064, China. chxnyu@163.com.|Public Health Research Center, Jiangnan University, Wuxi, 214122, China. chxnyu@163.com.|Medical College, Jiangnan University, Wuxi, 214122, China. chxnyu@163.com.
authors.forename: Chuan-Xin
authors.initials: CX
authors.lastname: Yu
mesh_terms: D000818:Animals; D005260:Female; D006367:HeLa Cells; D015801:Helminth Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D010087:Oxides / Q000138:chemical synthesis / Q000494:pharmacology*; D011223:Praziquantel / Q000494:pharmacology*; D012549:Schistosoma japonicum / Q000502:physiology*; D012554:Schistosomiasis japonica / Q000188:drug therapy* / Q000469:parasitology; D012556:Schistosomicides / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D015801:Helminth Proteins; D009097:Multienzyme Complexes; D010069:Oxadiazoles; D010087:Oxides; D012556:Schistosomicides; D009569:Nitric Oxide; D011223:Praziquantel; D009247:NADH, NADPH Oxidoreductases; C466433:thioredoxin glutathione reductase