Study On The Synthesis,pharmacology And Structure-activity Relationship Of Genotype HCV NS3/4A Protease Inhibitors

Hepatitis C is a disease caused by hepatitis C virus infection.Chronic HCV infection can lead to chronic inflammatory necrosis and fibrosis of the liver.Some patients can develop cirrhosis or even liver cancer.A total of 170-200 million people in the world are infected with HCV,of which 130-150 million are chronic HCV infections,accounting for about 3% of the global population,about 3.5 million new infections each year,and about 350,000-500,000 deaths from hepatitis C each year.The prevalence is different in different countries and regions.Africa and Asia are the most severely affected areas of hepatitis C epidemic,and China has been considered as a medium and high epidemic area of hepatitis C in the past.It is now generally accepted that the number of hepatitis C patients in China is about 10-40 million.This paper introduces the biological characteristics of hepatitis C virus(HCV),the replication cycle of HCV and the target of anti-HCV virus drugs.On this basis,an overview of the research progress in the treatment of hepatitis C virus drugs is described.Among them,the research on HCV NS3 / 4A enzyme inhibitors is relatively active.According to modern drug design theory,the existing NS3 / 4A protease crystal structure is used to MK-5172,TMC-435 and ABT-450 are positive control compounds.Using the principle of bioelectronics isosteria,a new biologically active macrocyclic non-covalent class NS3 / 4A inhibitor target molecule was designed and analyzed The synthetic route of each compound was designed.A total of 28 compounds with potential activity that have not been reported in the literature were synthesized and characterized by 1H NMR,MS and elemental analysis.By detecting the cell activity of the luciferase reporter gene,the compound's inhibitory effect on HCV replication was evaluated,and the experimental results were processed using Graph Pad Prism software to calculate the compound's EC50 for HCV replicon inhibition.Among them,there is a class of target compounds with activity equivalent to positive compounds.And hepatic microsome stability test was carried out on some compounds with better activity.This type of compound has better liver microsome stability and is not easily metabolized.Experimental data shows that this type of compound has better metabolic stability and better absorption than Paritaprevir.Therefore,when this type of compound is used in combination with other target drugs,Ritonavir may not be used,and the drug is more convenient and more economical.In addition,the activity of this class of compounds is outstanding,and it has good activity against genotype 1-6,and its activity against genotype 3 is better than that of the positive drug Grazoprevir(MK-5172);tissue distribution experiments show that the drugs are mainly distributed on the target Organ liver is more targeted.