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

Abstract

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 µM) and drug-resistant HBV (IC₅₀: 3.30 µM) than lamivudine (3TC, IC₅₀: 7.37 µM in wild-type HBV, IC₅₀: >440 µM 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 µg·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.

Keywords:

• anti-HBV activity
• APOBEC3G
• hepatitis B virus
• IMB-0523
• PK
• toxicity

Acknowledgments

This research was funded by the Drug Innovation Major Project (Nos. 2018ZX09711001-003-017 and 2018ZX09711001-003-003) and disciplines construction project of PUMC (201920101001).

Disclosure

Dr Si-Tu Xue and Professor Zhuo-Rong Li report a patent China National Intellectual Property Administration licensed to Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences. The authors report no other potential conflicts of interest in this work.