Preparation Of Gossypol And Its Derivatives And Biological Evaluation Against Schistosomiasis

Schistosomiasis is one of the major diseases that threaten human health.The only effective treatment is praziquantel.Due to single-use drugs,the emergence of drug-resistant schistosomiasis in large-scale makes the development of new anti-schistosomiasis drugs very urgent.The new drug strategy can improve the speed of the development of anti-schistosomiasis drug.Gossypol,with a wide range of bioactivities,has the activity of inhibiting the restructuring of lactate dehydrogenase of the Schistosoma japonicum.Therefore,gossypol is likely to be the same as artemisinin,and has insecticidal activity against Schistosoma japonicum.The basic idea of this study is to obtain the raw material of synthetic gossypol derivatives by extracting gossypol from cottonseed,and obtain the variety of gossypol derivative compound library by chemical synthesis.It is expected to obtain the new structure,active superior anti-japanese schistosoma japonicum drug leads.The specific process was divided into two parts: 1)To improve the yield and quality of gossypol and obtain the new gossypol extraction process,the yield of gossypol and the purity of gossypol were evaluated by using acetone extraction-aniline precipitation method and lye extraction-aniline precipitation method.2)Based on the structural skeleton of gossypol and the aldehyde group in the molecule,a series of gossypol derivatives were synthesized.The obtained gossypol and gossypol derivatives were tested for in vitro resistance to schistosomiasis then the structure-activity relationship information was obtained.Selected representative gossypol derivatives and made a study on the activity of Schistosoma japonicum in vivo,then we get preliminary data on the activity of Schistosoma japonicum in vivo.The results of gossypol extraction showed that the extraction effect of acetone extraction and aniline precipitation method was higher than that of alkali extraction and aniline precipitation method,and 400 mg of gossypol acetate could be extracted from 20 g of cotton with total 2.0% yield.The purity of gossypo reached 98%.The results of activity of Schistosoma japonicum in vivo showed that the insecticidal activity of gossypol was better than that of the drug praziquantel,and the insecticidal effect on the female was better than that of the male.Further,the substitution of 9 gossypol derivatives had different insecticidal activity to schistosomiasis.The results showed that when R was a substituted benzene ring,the substitution of chlorine atoms on the benzene ring was not conducive to the improvement of insecticidal activity.When R was a benzene ring,the insecticidal activity of gossypol derivative 26 is superior to that of gossypol and other substituted benzene ring derivatives.When R is benzyl or cyclohexylmethyl,the insecticidal activity is obviously lower than that of pHenyl derivative 26,When the pHenylalanine methyl ester was condensed with gossypol to produce the derivative 29,the insecticidal activity was the highest in vitro,and the insecticidal rate reached 100% after 48 hours at the concentration of 10 μM,and the effect of insects of males is better than females.Further anti-schistosomiasis lad experiments showed that the gossypol derivative 29 showed 71.7%,75.0%,and 81.7% insecticidal rates respectively for 24 hours,48 hours and 72 hours at a concentration of only 2 μM.Insecticidal activity is much higher than the positive control of artemisinin and gossypol.Finally,the in vivo activity of the mice showed that through the abdominal cavity to medicine,the reduction rate of adult worms was 72.3%,and the reduction rate of females was 76.8%,and the egg loss rate of the eggs was 43.3%,and the insecticidal activity and the oviposition rate of the gossypol derivative 29 were significantly higher than that of the gossypol.In contrast to it,through the lavage to medicine,the gossypol derivatives 29 The rate of reduction was 57.4%,the female reduction rate was 53.5%,the ovulation rate was 22.2%,and the insecticidal effect was higher than that of gossypol.This study found a new anti-Japanese schistosomiasis drug and made a new attempt to find a new type of anti-schistosomiasis drugs to provide new research ideas.