Design And Synthesis Of Novel Anti-HCV Compounds And The Study Of Their Structure-Activity Relationship

Hepatitis C Virus (HCV) is one of the main pathogens which cause lesion of liver. According to the World Health Organization (WHO), about 3% of the world’s population are chronically infected with HCV, and these individuals are at high risk to develop liver cirrhosis and hepatocellular carcinoma. At first, the therapies for the treatment of chronic HCV infection are various forms of interferon, in combination with Ribavirin, but these therapies are largely limited by both poor efficacy and severe adverse side effects.Last three years, four new direct-acting antiviral agents have been approved for the treatment of chronic HCV infection in combination with the IFNs and Ribavirin, while these current therapies achieve better efficacy compared with the former therapy, the side effects still remain. Undoubtfully, therapies consisting of DDAs with different mechanisms bearing better efficacy and fewer side effects provide future direction of the treatment of chronic HCV infection, so the development of novel classes of anti-HCV agents is of much importance.In our group, BM601(EC50=10.89μM, CC50>40μM, SI>3.67) was selected as the start point of this research. Comparing the structural components of BM601 with three reported compounds selected based on structural similarity led to the design of first round of modification in three groups, i.e. group A, B and C. After analyzing the initial SAR of the 32 compounds, we found two potential direction for further structural improvement, and 11 new compounds were synthesized with modified in two groups, i.e. group VCH-I and VCH-II. Compared with BM601, each of these two groups provided a compound with significantly improved potency: VCH-Ⅰ5(EC50=4.04μM, CC50>40μM, SI>10) for group VCH-Ⅰ and VCH-Ⅱ5(EC50=0.31μM, CC50>40μM, SI>129) for group VCH-Ⅱ. Particularly, VCH-Ⅱ5 had profiles similar to the reference compound AZD7295(EC50=0.29 μM, CC50>40μM, SI>137.9), and should be an attractive lead compound for further study.In summary, through two stages of improvement of BM601, we acquired two compounds with good anti-HCV activity and low cytotoxicity, representing a new starting point in our search for more potent molecules.