Experimental Studies On Effect Of Derivatives Of Praziquantel And Oxadiazoles Against Schistosoma Japonicum

Praziquantel as a high-efficiency, broad-spectrum oral antiparasite drug, is the firstchoice for the schistosomiasis etiology treatment, recommended by the world healthorganization. As widely applied, it played an important role in reduce and control theschistosomiasis in numerous countries. However, its preference against the adult worm,and being much less effective against the immature schistosomulum stage, so it has noeffective for prevention schistosomiasis. In addition, because of repeatedly and a largescale applied in epidemic area, this can lead to the rate of cure reduced and the wormsresistant to the drug. Studies confirm that schistosoma mansoni can produce drugresistance to praziquantel in laboratory. Then, in some African schistosoma mansonidisease severe epidemic region have report praziquantel efficacy dropped, recently,Schistosome isolated with diminished sensitivity to PZQ continues to be identified. Andschistosoma japonicum was reported can be induced to resistant to praziquantel in thelaboratory condition at present. Taken together, development of replacements for PZQis urgently needed. In recent, some researchers found that the antioxidant system ofschistosomiasis can be conducted as a treatment target, and then they found a kind ofcompounds of oxadiazoles have very good efficacy against the schistosoma mansoni invitro and in vivo tests for different stage of the worms. Because of the compound isreported offered by intraperitoneal injection, for five days, and this makes it far from aperfect drug. In this study we synthetized different derivatives of praziquantel andoxadiazoles compounds based on their basic structures, and evaluate effect against theS.japonicum through in vitro and in vivo experiments. 【Objective】To synthetize different derivatives of praziquantel and oxadiazolescompounds based on their basic structure, and evaluate effect against the s.japonicumthrough in vitro and in vivo experiments.【Methods】Derivatives of praziquantel and oxadiazoles were synthetized; kunmingmice were for in vitro studies and BALB/c mice were for in vivo studies. In vitrostudies, kunming mice were killed at6weeks after infected with cercarias under theaseptic conditions, to collect the adults in the janitrix of liver for in vitro culture. and theworms were divided into groups as follow: DMSO solvent control; PZQ and5kinds ofcompounds were set low doses groups (50μ mol/L), the middle dose groups (100μmol/L) and high dose groups (200μ mol/L) in respective. Observation the vitality score,tegumental damage and mortality of the worms, to evaluate the effect of the compoundsagainst the japonicum. In vivo tests, the6weeks old BALB/c mice were infected withcercarias, drug and compounds are all offered through the mouth for treatment, as adose of300mg/kg each mouse.2weeks after treatment, killed the mice, collected theworms in the portal vein and mesenteric vein, calculated the rate of worm reduce.【Results】In vitro studies showed that: except the compound ODZ2, other fourcompounds all have effect against Schistosomia japonicum in some degree. The mosteffective one is compound PZQ1. At the dose of50μ mol/L, cultured for72hours themortality of the worms was60%, while PZQ was55%, and the survival Worms werecompletely suppressed, their vitality score was0;100μ mol/L dose of72hours amortality rate of100%;200μ mol/L dose24hours that mortality100%, CompoundPZQ1demonstrated activity similar to PZQ. the difference was not statisticallysignificant (P﹥0.05); Compounds ODZ1at100μmol/L dose cultured for72hours themortality rate was90%, and200μmol/L dose for24hours that mortality was100%.compoundPZQ2、PZQ3and ODZ2100μmol/L dose for72hours the mortality rateswere75%,60%and30%respective;200μ mol/L dose for72hours the mortality rateswere100%,80%and45%respective, The in vivo studies showed that PZQ, PZQ1, PZQ2, PZQ3, ODZ1and ODZ2group of minus insect rates were98.2%,95.9%,31.8%,48.6%,45.5%and38.6%respective. Derivatives PZQ1showed effective effect againstSchistosomia japonicum. The worm reduction rate was95.9%, was similar to thepraziquantel group (P﹥0.05). The rest of the new synthetic compounds showed lowereffect to praziquantel (P <0.05).【Conclusion】Compound PZQ1in vitro and in vivo all demonstrated activity effectivesimilar to PZQ to against S. japonicum; compounds PZQ2and ODZ1have very goodeffective in vitro studies, but both of them showed less effective in vivo studies. PZQ3and ODZ2showed less effective both in vitro and in vivo studies.