Development of benzimidazole-based compounds as novel capsid assembly modulators for the treatment of HBV infection

Kaixin Du; Xianyang Wang; Yuxin Bai; Xue Zhang; Jie Xue; Shanshan Li; Youhua Xie; Zhipei Sang; Yu Tang; Xin Wang

doi:10.1016/j.ejmech.2024.116402

Development of benzimidazole-based compounds as novel capsid assembly modulators for the treatment of HBV infection

Eur J Med Chem. 2024 May 5:271:116402. doi: 10.1016/j.ejmech.2024.116402. Epub 2024 Apr 16.

Authors

Kaixin Du¹, Xianyang Wang², Yuxin Bai², Xue Zhang¹, Jie Xue², Shanshan Li², Youhua Xie³, Zhipei Sang⁴, Yu Tang⁵, Xin Wang⁶

Affiliations

¹ Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
² Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
³ Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Diseases and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: yhxie@fudan.edu.cn.
⁴ Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China. Electronic address: sangzhipei@126.com.
⁵ Key Laboratory of Marine Drugs, Chinese Ministry of Education, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266237, China; Marine Biomedical Research Institute of Qingdao, Qingdao, 266071, China. Electronic address: tangyu@ouc.edu.cn.
⁶ Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China. Electronic address: xinwangPharm@hainanu.edu.cn.

PMID: 38636128
DOI: 10.1016/j.ejmech.2024.116402

Abstract

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV infection. In this study, the hit compound CDI (IC₅₀ = 2.46 ± 0.33 μM) was identified by screening of an in-house compound library. And then novel potent benzimidazole derivatives were designed and synthesized as core assembly modulators, and their antiviral effects were evaluated in vitro and in vivo biological experiments. The results indicated that compound 26f displayed the most optimized modulator of HBV capsid assembly (IC₅₀ = 0.51 ± 0.20 μM, EC₅₀ = 2.24 ± 0.43 μM, CC₅₀ = 84.29 μM) and high selectivity index. Moreover, treatment with compound 26f for 14 days significantly decreased serum levels of HBV DNA levels in the Hydrodynamic-Injection (HDI) mouse model. Therefore, compound 26f could be considered as a promising candidate drug for further development of novel HBV CAMs with the desired potency and safety.

Keywords: Benzimidazole derivatives; Capsid assembly modulators; HDI mouse model; Hepatitis B virus infection.

MeSH terms

Animals
Antiviral Agents* / chemical synthesis
Antiviral Agents* / chemistry
Antiviral Agents* / pharmacology
Benzimidazoles* / chemical synthesis
Benzimidazoles* / chemistry
Benzimidazoles* / pharmacology
Capsid / drug effects
Capsid / metabolism
Dose-Response Relationship, Drug
Drug Development
Hep G2 Cells
Hepatitis B virus* / drug effects
Hepatitis B* / drug therapy
Humans
Mice
Microbial Sensitivity Tests
Molecular Structure
Structure-Activity Relationship

Substances

Benzimidazoles
Antiviral Agents
benzimidazole