Design,Synthesis And HQSAR Studies Of 2-Thio-Benzimidazole Analogues As HCV NS5B Polymerase Inhibitors

Hepatitis C virus(HCV)infection is a common risk factor for the development of liver cancer which causes chronic liver diseases and is a major global health problem.The hepatitis C virus NS5B RNA-dependent RNA polymerase(RdRp)is a key enzyme involved in viral replication.NS5B has no functional equiv in human cells,which has good selectivity that doesn’t impact the cells in a negative manner when the cells replication,as an important target for anti-HCV drug development.Benzimidazole derivatives are one of the important hepatitis C virus NS5B RNA-dependent RNA polymerase(HCV NS5B RdRp).A series of 2-thio-benzimidazole compounds were designed and synthesized by our group as HCV NS5B polymeraseinhibitors.The bioactivity test showed that these compounds had a significant inhibitory effect on HCV replication,but they were higher toxicity and lower activity than the existing benzimidazole HCV NS5B polymerase inhibitors.Based on the previous compounds which was synthesized by our group,structural modification of the N-1 and C-2 side chain.Synthesis routes of target compounds are introduced in this article.(Ⅰ)Using bromoacetyl bromide and various aniline as raw material,the bromo group was replaced with various anilinethe react to give us reactants.Treatment of various anilinethe with 2-mercaptobenzimidazol in the presence of K2CO3 in DMF to yield the required chemical intermediate.Treatment of these chemical intermediate with alkane or arene to yield the target compounds.(Ⅱ)Using 2-fluoronitrobenzene and various amine as raw material to yield the N-ortho-nitroaniline,after the reduction reaction,the chemical intermediate was obtained successfully.Treatment of 2’-bromoacetanilide with the chemical intermediate in the presence of K2CO3 in DMF under 80 degree to got target compounds.118 intermediates and final products were synthesized in this paper,and among them 30 compounds were the target molecules which have not been reported in literature.These compounds were confirmed by 1H NMR,1C NMR,MS and IR analysis.The anti-HCV activity of these compounds are in progress.After that we try to find out its structure activity relationship which can provide additional tool in HCV NS5B polymerase inhibitor designing and optimizing.Using hologram quantitative structure-activity relationship(HQSAR)techniques,the 129 benzimidazole 5-carboxylic derivatives of hepatitis C virus NS5B polymerase inhibitors were investigated between their structure and activity.The influences of molecular fragment parameter,fragment distinction parameter and molecular holographic length on the HQSAR models were considered.Using 99 compounds composed of the training set to establish the optimal model,which was obtained by the partial least square(PLS)technique,the cross-validated q2=0.820,convention r2=0.963 and standard deviation SEE=0.213.The model was then externally validated using a test set of 30 compounds and the predicted values were in good agreement with the experimental results(r2pred = 0.98).It’s shown that the model has well ability for prediction and fitting.The contributions of different atoms to activity were explored with color coding figures.According to the best HQSAR model,a series of 9 benzimidazole 5-carboxylic derivatives with excellent anti-HCV inhibition properties were designed,and it can be a reference to design and optimize a new series of HCV NS5B polymerase inhibitors.