2. Academic Validation
  3. Discovery of benzimidazole substituted 1, 2, 4-oxadiazole compounds as novel anti-HBV agents with TLR8-agonistic activities

Discovery of benzimidazole substituted 1, 2, 4-oxadiazole compounds as novel anti-HBV agents with TLR8-agonistic activities

  • Eur J Med Chem. 2022 Dec 15:244:114833. doi: 10.1016/j.ejmech.2022.114833.
Jingying Qiu 1,  Yueting Zou 2,  Shuqiong Li 2,  Lihua Yang 2,  Zibin Qiu 3,  Fanyun Kong 4,  Xiaoke Gu 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, People's Republic of China; Department of Pharmaceutical Analysis, School of Pharmacy, Xuzhou Medical University, Xuzhou, 221004, People's Republic of China.
  • 2 Department of Pharmaceutical Analysis, School of Pharmacy, Xuzhou Medical University, Xuzhou, 221004, People's Republic of China.
  • 3 College of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
  • 4 Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, People's Republic of China. Electronic address: kong.fanyun@163.com.
  • 5 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, People's Republic of China. Electronic address: gu_xk@xzhmu.edu.cn.
PMID: 36228413 DOI: 10.1016/j.ejmech.2022.114833
Abstract

Hepatitis B virus (HBV) Infection is a public health threat worldwide and characterized by a dysfunctional immune response. In the present work, a new series of benzimidazole substituted 1, 2, 4-oxadiazole compounds were designed as immunomodulatory anti-HBV agents. Data showed compound 11o displayed significant in vitro anti-HBV activities against wild-type and nucleos(t)ide analogues-resistant HBV with IC50 values of 0.53 and 0.44 μM, respectively. In contrast, nucleos(t)ide analogue lamivudine is only effective for wild-type HBV (IC50 < 0.1 μM) but not effective for resistant HBV (IC50 > 100 μM). Dual-luciferase reporter gene and ELISA assay revealed that 11o exhibited a dose-dependent effect on inducing TLR8-regulated NF-κB activity, and could promote the secretion of cytokines TNF-α and IL-12 in supernatant from human PBMC cells. Molecular docking studies found that 11o formed tight interactions with binding pocket residues located at the dimer interface of TLR8. Considering the potent in vitro anti-HBV activity, effective TLR8-agonistic potency, and relatively safe profile with a selectivity index (SI) value high above 37, compound 11o deserves further investigation as a potential immunomodulatory anti-HBV agent.

Keywords

1,2,4-Oxadiazole; Anti-HBV; Benzimidazole; Inflammatory cytokines; TLR8 agonist.

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