Design And Synthesis Of Novel HCV NS3/NS4 Protease Inhibitors

Infection by the hepatitis C virus (HCV) accounts for a significant proportion of community acquired hepatitis cases worldwide. At present, no broadly effective therapies exist for this viral disease. The treatment of chronic diseases caused by the HCV is in unmet clinical need, since current therapeutic methods are only partially effective and limited with undesirable side effects. The viral NS3/NS4A serine protease is the well-investigated target for the development of novel therapeutic agents and set up screening assays for the identification of selective inhibitors. Considerable efforts have been made to the discovery of several classes of compounds with potential antiviral activity previously and two NS3/NS4A serine protease inhibitors are under preclinic trail.The derivative of benzimidazole is a kind of important heterocyclic compound and it has been reported to possess many biological activities and catalytic capabilities. Moreover, benzimidazole is the core active fragement of many pharmacological molecules. And due to the electron-rich system, these compounds can form complexes with metal ion containing empty orbits. Therefore, design and synthesis and application of new benzimidazole derivatives become an important field in recent years. The thiazoles existing in nature are of great significiance in the research and exploitation of drugs. There are thiazole rings in the structures of many clinic medicine molecules.Based on theories about drug design and the reported data of the NS3/NS4A serine protease crystal structure, the 3DQSAR investigation for the nonpeptidic protease inhibitors had been carried out and several compounds were synthesized in our laboratory. Some of these compounds showed satisfactory biological activity in the antiviral activity test carried out in Korea. Considering the previous research and the steric and electrostatic properties, we use bisbenzimidazolylmethanes as leading compounds and design three series of novel target compounds with potential bioactivity.In conclusion, eighteen novel substituted 1,3,4-oxadiazole derivatives have been synthesized by cyclization of N,N'-diacylhydrazines in presence of phosphorus oxychloride. N,N'-diacylhydrozines were obtained through different approaches. The structures were characterized by ¹H NMR, ¹³C NMR, IR, MS and elemental analysis.