Study Of Benzimidazole Derivatives As Novel Inhibitors Of Hepatitis B Virus

Hepatitis B virus (HBV) is a cause of chronic liver disease worldwide, affecting more than 5% of the world’s population. HBV can cause both acute and chronic infections. Chronic HBV infection leads to liver damage, cirrhosis, andliver cancer with high mortality. There are approximately 350-400 million who are chronically infected, resulting in 0.5-1.2 million deaths annually. HBV infection represents serious global medical, social and economic burden. The drugs available for the clinical treatment of hepatitis B could be categorized as interferons and nucleotides analogues. However, they have limited efficacy in a significant proportion of patients and often have severe adverse effects (such as exacerbations of hepatitis, limited efficacy and high relapse rate). Therefore, drugs with novel structures and mechanisms of action are urgently needed for the treatment of HBV infection.Benzimidazole derivatives attract wide interest because of their diverse biological activity and clinical applications. Our previous study involving benzimidazole derivative BM601 was screened which exhibited potent anti-HBV activity, but its cytotoxicity was very strong. In view of its novel scaffold, compound BM601 was chosen as the new template for further optimization. Three new series of benzimidazole derivatives based on compound BM601 were designed. More than 20 benzimidazole analogues were synthesized. Their in vitro anti-HBV activities and cytotoxicity were investoigated. The majority of the derivatives showed more potent inhibition of HBV-DNA replication than BM601, However, all of the compounds exhibited weaker inhibitory effect on the secretion of HBsAg than BM601. Then, additional two new series of compounds were designed and synthesized, Among them, compound 16e demonstrated most potent inhibition of HBV-DNA replication.In summary, several series benzimidazole derivatives based on BM601 were synthesized and evaluated for their in vitro anti-HBV activity and cytotoxicity. Inhibition assay data reported in this study showed that the substituents at 5-position of the pyridine ring might play an important role in activities. The preliminary SAR study provides valuable reference for our ongoing anti-HBV studies on benzimidazole compounds.