Synthesis And Antischistosomal Activity Of Praziquanamine-Nitrates And Furoxans

Reactive oxygen species(ROS),as a dual stimuli-responsive reactor,not only play important roles in the biochemisty of every living organism,but have the potential to cause oxidative stress,leading to various cytotoxic effects on body tissues and subsequent functional decline of organ systems.Compared to host,Schistosomasis more vulnerable to further ROS insults.Therefore,the difference in counteract ROS stress in host and Schistosomasis would provide a biological cue for selective killing of Schistosomasis using an exogenous ROS-generating agent.Nitric oxide(NO)a ‘Star of ROS' molecule,which displays a variety of effects in aerobic organism,especially causes oxidative stress and death in Schistosomasis.Therefore,in my dissertation,two series NO-releasing analogs of praziquanamine-nitrates and furoxans were designed and synthesized,and their NO releasing ability,ex vivo antischistosmal adult and cercaria activities were investigated.Further,the antischistosmal adult mechanism of furoxans was studied by fluorescent probe technology.The main research works and results are as follows:(1)Praziquantel is the only commercially available drug for Schistosoma japonicum(S.japonicum)disease.Praziquanamine was confirmed to be crucial pharmacophore and skeleton for praziquantel antischistosmal activity.We synthesized a series of praziquanamine-nitrates which had different length of amido linkage,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 praziquanamine-nitrates hybrid drugs had a good ability of NO-releasing in vitro and limited the activity against S.japonicum cercaria and adult worms.The length of the amido linkage had a significant influence on the activity of S.japonicum.It was interesting to learn NO-releasing capacities of compounds had a certain relevance on activities of compounds against on adult worms and cercaria,and the compound 4a had a best activity.Furthermore,worm morphology treated by praziquanamine-nitrates hybrid drugs was monitored.(2)We synthesized a series of furoxans NO donor,and tested for their NO-releasing capacities,against S.japonicum adult worm activity.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 8 and 9 had obvious the activity of against S.japonicum.Furthermore,the compound 6 which had aldehyde substituents also had higher activity of against S.japonicum,which might be concerned with its high electrophilic ability.Moreover,worm morphology treated by furoxans had different between praziquantel was monitored.(3)Based on the high activity of against S.japonicum.of the furoxans,We synthesized a furoxan fluorescent probe and studied its fluorescence imaging in the adult worms.The results showed that the fluorescent probe of furoxan retained the activity of against S.japonicum.and its fluorescence signal in the adult worms was mainly concentrated in the membrane of the schistosome body,which explained that the medicine was majorly absorbed by the cuticular layer and was difficult to enter into the internal body of the adult worms.In conclusion,the furoxans was against S.japonicum mainly on the surface of the worms.