Synthesis And Antischistosomal Activity Of Curcumin Analogues For Schistosoma Japonicum

Schistosomiasis japonicum is one of the major diseases that seriously affect the health of Chinese people.The treatment of schistosomiasis japonicum is only dependent on praziquantel,which has the risk of drug resistance,and praziquantel has no obvious protective and recovery effect on the host liver fibrosis damage.Therefore,the search for other or alternative anti-schistosomiasis drugs has become a public health priority.Bioantioxidants are an important source of ideal anti-schistosomiasis drugs for the development of a new generation of treatment and protection.Curcumin(Cur)is a typical representative of biological antioxidants,which has certain anti-schistosomiasis activity and the ability to reduce schistosomiasis liver fibrosis.Therefore,in this paper,three series of Schistosoma japonicum analotes were synthesized based on the chemical structure characteristics of the Cur,and their in vitro anti-insect activity and safety(normal cytotoxicity and acute toxicity in mice)were evaluated.The anti-insect activity,anti-fibrosis ability and normal physiological function of liver(antioxidant capacity and metabolic function of liver)of low-toxic compounds were carried out in positive model animals(mice),and the preliminary mechanism of anti-schistosomiasis action of typical compounds in vitro was explored.(1)To a Cur matrix structure,the synthesis of different substituent Cur analogues,detailed evaluation on their in vitro activity of insect-resistant,found α,β-unsaturated Michael receptor unit is the key part of Cur play a role of insect-resistant,substituent on the benzene ring to improve activity,Among them,the Cur analogue(A7)of 3,4-dissubstituted methoxy had the best activity against schistosomiasis in vitro.At the same time,A7 has high cytocompatibility and low toxicity to mice.Positive mice were intragastric with 500 mg/kg A7 for 5 days,the insect load decreased by78.7%,and the egg reduction rates in liver and small intestine were 79.6% and 78.9%,respectively.In addition,A7 can significantly reduce liver fibrosis in positive mice,restore liver antioxidant capacity and liver function,and has an obvious protective effect on the host.(2)By eliminating methylene,acetone curcumin analogue was synthesized.It was found that4-hydroxyl(B3),3,4-dimethyl(B5),3,4,5-trimethoxy(B6),4-fluoride(B8)and 3,4-difluoride(B13)had high anti-insect activity in vitro,and B5,B6 and B8 had low cytotoxicity and low toxicity to mice.In particular,when B5 was given 500 mg/kg for 5 consecutive days in vivo,the insect load was reduced by 50.3%,the ovulation reduction rate in liver was 42.8%,and the ovulation reduction rate in small intestine was 84.6%.At the same time,B5 can protect the liver of positive mice to a certain extent,reduce liver fibrosis,repair liver antioxidant capacity and liver function,and has a certain protective effect on the host.(3)By introducing the structure of cyclohexanone,several analogs of curcumin were synthesized,which further improved the anti-schistosomiasis activity.Among them,the number and location of methoxy group and strong electron absorbing group significantly affected the activity,among which dimethoxy(C4,C7)and 4-cyanogroup(C13)had the best activity.At the same time,C4 and C13 had little cytotoxicity and low toxicity to mice,especially C13 had outstanding insecticidal effect in vivo,and could achieve 86.7% insect reduction rate,90.1% liver egg reduction rate and 95.3% small intestine egg reduction rate when administered 500 mg/kg adult for 5consecutive days,and 40% of mice were completely cured.In particular,C13 can significantly protect the mouse liver,reverse liver fibrosis,up-regulate the antioxidant capacity of the liver,avoid the occurrence of liver lipid peroxidation,maintain the normal liver function,and has a prominent protective effect on the host.(4)The stability of curcumin and three representative analogues with high in vitro and in vivo anti-insect activity with different structural characteristics were studied,and the effects on the ultrastructure of the curcumin and the main REDOX indexes in the curcumin were found to induce the production of ROS such as superoxide anion radicals by destroying the membrane structure of the curcumin.Regulate and inhibit the antioxidant defense system of the insect body,resulting in a large amount of lipid peroxidation damage in the insect body,further damage the integrity of the membrane structure,and promote the inactivation or death of the insect body.At the same time,because of their different structure and stability,each Cur analog has different ability to control the enzymatic and non-enzymatic antioxidant activity in schistosoma,and has different ability to kill schistosoma.In conclusion,in this paper,the in vivo and in vitro efficacy of Cur and its analogues against Schistosoma japonicum,the effects of anti-liver fibrosis and liver function repair were studied in detail,and the structural-activity relationship and mechanism of action were initially discussed,which provided better information for the discovery of more effective and highly active antischistosoma molecules with anti-liver fibrosis based on Cur structure modification and modification.