Design And Synthesis Of Furoxan Derivatives And Artemisinin-furoxan Analogues Targeted On Schistosoma TGR

Schistosomiasis is one of the most widely spread parasitic diseases in the world,and,is one of the main tropical disease endemic in Asia,Africa and South America.But it is also the most neglected tropical disease.In terms of morbidity and mortality,schistosomiasis is believed to be the most serious worm disease transmitted to the human population.It is estimated that more than 200 million people are infected worldwide and there are approximately 779 million individuals around the world bears the risk of schistosomiasis infection.Schistosomiasis is mainly caused by three species of the trematode flatworms,Schistosoma haematobium,Schistosoma mansoni and Schistosoma japoni-cum.Schistosomiasis is one of the major infectious diseases that seriously affect the health of Chinese people and the development of economic.In China,schistosomiasis is mainly caused by Schistosoma japonicum.Chinese schistosomiasis control began in the 1950s.At present,the prevention and control of schistosomiasis is mainly from transmission control to transmission blocking and elimination.Male and female schistosomes live in the mesenteric vein(Schistosoma mansoni,Schistosoma japonicum)or plexus(Schistosoma haematobium)of human hosts.Depending on the species,hundreds to thousands of fertilized eggs are laid each day.Numbers of the eggs remain in the host tissues,inducing inflammation,granulomatous tumors and fibrosis.Praziquantel(PZQ)appeared in 1972,is the first insect repellent to meet WHO's requirements,which can be used to treat all known schistosomiasis and against part of tapeworms and flukes.The single drug has been used to treat and control schistosomiasis for more than 40 years.Relying on a single drug to treat schistosomiasis with global public significance will promote the development and spread of drug resistance,in particular,PZQ-resistant isolates have already been identified.Thus,it's important to develop new type of anti-schistosomiasis drugs.Organisms are continuously attacked by endogenous or exogenous reactive oxygen species(ROS).There are two native mechanisms in the majority of eukaryotes,the glutathione(GSH)and the thioredoxin(Trx),which eliminate ROS for detoxification.Howere,it has been proved that instead of separate glutathione reductase(GR)and thioredoxin reductase(TrxR)of mammalian hosts,a single multifunctional selenocysteine-containing flavoenzyme designated thioredoxin glutathione reductase(TGR)in both Schistosoma mansoni and Schistosoma japonicum play critical role in maintaining proper redox balance for parasite survival.Therefore,schistosoma TGR provides a potential target for drug design of schistosomiasis.Through a quantitative high-throughput screen,researchers discovered that Furoxan had good inhibitory effect on Schistosoma mansoni TGR(SmTGR)and had the ability to kill the Schistosoma mansoni.Further studies have shown that the compound has a good effect on three major schistosomas(Schistosoma haematobium,Schistosoma mansoni,Schistosoma japonicum).Subsequently,a large number of Furoxan derivatives were synthesized,and most of them had good anti-schistosomiasis effect.Artemisinin and its derivatives are well known for their anti-malaria activity,but they are also reported to have anti-schistosomiasis activity.In general,this class of compounds,which contrary to praziquantel,has a higher antiparasitic activity against the immature form of the schistosome than adults.Structural conjugation is one of the important methods to design and develop new lead compounds,and the researchers obtained very optimistic results by combining artemisinin with praziquantel.This work is focused on the design and synthesize a class of derivatives based on the lead compound furoxan and our previous work.37 compounds containing different functional groups were obtained,and 4 hybrid compounds were synthesized by combining artemisinin and furoxan moieties in a single entity.The structures of these new compounds were confirmed by 1H-NMR,13C-NMR and HRMS.These compounds will be used to test their ability to inhibit the TGR and their ability to kill schistosoma.