Study on the structure optimization and anti-hepatitis B virus activity of novel human La protein inhibitor HBSC11

In our previous study, Methyl pyrazolo[1,5-a] pyridine-2-carboxylate (HBSC11) was shown to combine with La protein, which conferred anti-hepatitis B virus (HBV) effects. The purpose of this study was to optimize, synthesize, and evaluate the anti-HBV activity of HBSC11. The methyl group of HBSC11 was substituted with hydrophobic, hydrophilic, and tricyclic groups to generate novel HBV inhibitors with desirable potency. On in vitro evaluation, several derivatives exhibited good anti-HBV activity compared with control. In particular, compound 5a reduced the level of HBV antigen by approximately 50%, which was similar to the activity of entecavir. In a mouse model, 5a showed 98.9% inhibition rate for HBV DNA, 57.4% for HBsAg, and 46.4% for HBeAg; the corresponding rates in the control group were 90.8, 3.8, and 9.8%, respectively. In addition, prediction of binding modes and physicochemical properties showed that 5a formed hydrogen bonds with La protein and conformed well to the Lipinski's rule of five. Our results suggest that 5a is a potential new anti-HBV drug.