Hepatitis C Virus Ns3/ns4a Protease Inhibitors Design And Synthesis

The treatment of chronic diseases caused by the hepatitis C virus (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.Bisbenzimidazolylmethanes have high potation for inhibition of the hepatitis C virus (HCV) NS3/NS4A serine protease. The main active ion is the Zn²⁺ in the protease. Displaying highly potent inhibition against NS3/NS4A serine protease and being nonpeptidic, this class of compounds will be the most hopeful anti-HCV agents. A variety of new potential inhibitors of this type have been designed and synthesized, and the steric and electrostatic properties of the reported compounds are analyzed by both the basic and the computer-aided drug-design theories. The 3DQSAR investigation for the reported compounds was also carried out with SYBYL 7.0 software. Replacement of one benzimidazole fragment with benzothiazole or benzoxazole and optimization of the structure to create the new frame of the compounds were also carried out with the exception to find more potent compounds. The purpose of design and synthesis of these compounds is to investigate the QSAR of this class of compounds with the inhibition of HCV NS3/NS4A protease and eventually to develop more potent inhibitors.Total 48 target compounds have been synthesized by the newly-developed synthetic routes, among which 41 are new compounds. The structure of all the compounds were characterized by ¹H NMR spectroscopy, FT-IR spectroscopy, ESI-Mass spectrometry, and elemental analyses, and the results were in agreement with the proposed structures.The 48 compounds include 24 diheteroarylmethanes with asymmetric and symmetric structures; 6 (Benzothiazol-2-yl)(heteroaryl-2-yl)methanes; 1...