Synthesis and Bioactivity of N -(4-Chlorophenyl)-4-Methoxy-3-(Methylamino) Benzamide as a Potential Anti-HBV Agent.

Introduction: Hepatitis B virus (HBV) is a global health concern that can cause acute and chronic liver diseases. Thus, there is an urgent need to research novel anti-HBV agents. Our previous reports show that N-phenylbenzamide derivatives exert broad-spectrum antiviral effects against HIV-1, HCV, and EV71 by increasing intracellular levels of APOBEC3G (A3G). As A3G is capable of inhibiting the replication of HBV, we screened the N-phenylbenzamide derivatives against HBV. Methods: In this study, a new derivative, N-(4-chlorophenyl)-4-methoxy-3-(methylamino) benzamide (IMB-0523), was synthesized and its anti-HBV activity was evaluated in vitro and in vivo. The acute toxicity and pharmacokinetic profiles of IMB-0523 were also investigated. Results: Our results show that IMB-0523 has higher anti-HBV activity in both wild-type HBV (IC50 : 1.99 mu M) and drug-resistant HBV (IC50 : 3.30 uM) than lamivudine (3TC, IC50 : 7.37 mu M in wild-type HBV, IC50 : >440 mu M in drug-resistant HBV). The antiviral effect of IMB-0523 against HBV may be due to an increased level of intracellular A3G. IMB-0523 also showed low acute toxicity (LD50 : 448 mg/kg) in mice and promising PK properties (AUC(0)(-t): 7535.10 +/- 2226.73 mu g.h/L) in rats. Further, IMB-0523 showed potent anti-HBV activity in DHBV-infected ducks. Conclusion: Thus, IMB-0523 may be a potential anti-HBV agent with different mechanisms than current anti-HBV treatment options.