Synthesis And Against Schistosoma Japonicum Of Nitric Oxide Releasing Derivatives Of Praziquantel-Nitrate And Furoxan

Schistosoma japonicum(S. japonicum) is a serious infectious disease which influences on human body, economic and social development in tropical and sub-tropical areas. At present, because of a lack of vaccines, the treatment for schistosomiasis depends almost exclusively on Praziquantel(PZQ). One problem associated with the extensive use of PZQ is the risk of the schistosomiasis developing resistance. Therefore, there is an urgent need to develop new chemical type of drug candidate molecules for S. japonicum control.Nitric Oxide(NO) is a physiological messenger which displays a variety of effects in the system, especially in S. japonicum treatment, however, it is yet difficulty to use as a drug for the control of S. japonicum directly just as its fast half-life, small diffusion radius and strong liposolubility. Therefore, the two types NO donor drug named PZQ-nitrate hybrid drugs and oxadiazole beared NO-releasing against S. japonicum were studied and tested for their ex vivo anti-schistosomal japonicum effect, whose possible action mechanisms were discussed. In this paper, the main research work was as follows:(1) A series of new hybrids of PZQ, bearing nitric oxide(NO)-releasing moieties with various lengths of the alkyl chains were designed and synthesized, and tested for their in vitro NO-releasing capacities in pH 7.4 buffered solution, as well as their ex vivo anti-schistosomal japonicum adult worms and cercaria. The results showed PZQ-nitrate hybrid drugs had a good ability of NO-releasing in vitro and obvious the activity against S. japonicum cercaria and adult worms. The length of the flexible chain(alkyl) had a significant influence on the activity of S. japonicum. It was interesting to learn that NO-releasing capacities of compounds had a certain relevance on activities of compounds against on adult worms and cercaria. In addition, the inhibition of PZQ-nitrate hybrid drugs on S. japonicum thioredoxin glutathione reductase was tested, and the compound 5 had a best inhibition. Furthermore, worm morphology treated by PZQ-nitrate hybrid drugs was monitored.(2) The oxadiazole 2-oxides were tested for their NO-releasing capacities and the inhibition on S. japonicum thioredoxin glutathione reductase in vitro, against S. japonicum adult worm activity, as well as the impact on S. japonicum worm morphology. The results showed that the NO-releasing capacities, whose compound contained a high NO-releasing capacities acted best on killing adult worms, was relative to against the adult worm. The compound 5 against adult worm activity is equivalent to PZQ. Therefore, the oxadiazole 2-oxides had a certain regulation function on Schistosoma japonicum adult worms form. Moreover, the oxadiazole had a strong inhibition on S. japonicum thioredoxin glutathione reductase. In addition, the activities of compounds against on cercaria were studied, and the compund 3 acted best.