Design,Synthesis And Anti-HCV Activity Studies Of Heterocyclic HCV NS5B Polymerase Inhibitors

Hepatitis C is caused by hepatitis C virus,it is a serious threatens to the health of human liver,according to the World Health Organization,about 180 million people worldwide are infected with HCV,and there are 35 thousand new cases each year.In theory,interfere with or inhibit HCV replication cycle of any link can inhibit the replication of HCV,which provides an effective target for anti-HCV drugs.At present,the specificity targeted agents mainly include NS3/NS4 serine protease inhibitors,NS5A protease inhibitors and NS5B polymerase inhibitors.Among them,as a result of human cells do not express similar function with NS5B polymerase enzyme,NS5B polymerase inhibitors with good selectivity,can block the replication of HCV,become a hotspot research in the specificity targeted agents.We has been engaged in the study of benzimidazole derivatives and pyrimidone derivatives HCV NS5B polymerase inhibitors.Based on the related literature review and previous works,with N-(4-methoxyphenyl)-2-((1-tosyl-lH-benzo[d]imidazol-2-yl)thio)acetamide(compound A)and 6-(cyclohexylmethyl)-5-ethyl-2-((2-hydroxy-2-phe-nylethyl)thio)pyrimidin-4(3H)-one(compound B)as the lead compound respectively,design a series of novel 1-alkyl/replace phenyl-lH-benzimidazole-2-((2-(replace phenyl)amino-2-oxoethyl)thio)-5-replace and 5,6-replace-2-replace phenyl hudroxyl methyl thiol-pyrimidine-4(3H)-one.Starting from 3,4-diaminobenzoic acid,the benzimidazole derivatives were prepared via 5 steps including cycloaddition,esterification,amination and hydrolyzation,in benzimidazole rings’s N-1,C-2 and C-5 introduction of different types substituents,obtain target compounds;Pyrimidone derivatives were starting from replace malonic acid diethyl ester,were prepared via 5 steps including Pedersen or Clay reaction,condensation,alkylation and reduction,in pyrimidone rings’s C-2,C-5 and C-6 introduction of different types substituents,obtain target compounds.95 intermediates and target compounds were synthesized in this paper,with 38 compounds as the new target compounds.At the same time,all target compounds structure were confirmed by 1H NMR and 13C NMR,some compounds were characterized by IR and ESI-MS,and with 10b、11d、14b and 23u as an example for structural analysis.All the pyrimidone compounds synthesized by our group had anti-HCV activity,and 9 compounds showed good inhibitory activity,with EC50 range from 0.13～7.53μM,which are better than Ribavirin(EC50=10.35μM).Among them,6-(cyclohexyl-methyl)-5-ethyl-2-((2-hydroxy-2-phenylethyl)thio)pyrimidin-4(3H)-one turned out to be the most potent inhibitor,with an EC50 of 0.13μM,against HCV.Its anti-HCV activity was about 77-fold higher than that of Ribavirin.Notably,this compound also exhibited a higher selectivity index than Ribavirin.In addition,4 compounds also showed higher anti-HCV activity(EC50=2.02,0.27,2.17,1.64 μM,respectively)and better selectivity index(SI=97,22,52,56,respectively)than Ribavirin(SI=9).The benzimidazole derivatives of biological activity screening work is still in progress.