新型喹唑啉酮衍生物的设计与合成作为具有 TLR8 激动剂作用

StephenW

新型喹唑啉酮衍生物的设计与合成作为具有 TLR8 激动剂作用的抗 HBV 药物
邱晶莹 1 , 周青青 2 , 邹月亭 2 , 李淑琼 2 , 杨丽华 2 , 王晨 2 , 高建 3 , 顾小可 4
隶属关系
隶属关系

    1
    徐州医科大学江苏省新药研究与临床药学重点实验室, 徐州, 221004;徐州医科大学药学院药物分析系, 徐州, 221004
    2
    徐州医科大学药学院药物分析系, 徐州, 221004
    3
    徐州医科大学江苏省新药研究与临床药学重点实验室, 徐州, 221004电子地址：[email protected]。
    4
    徐州医科大学江苏省新药研究与临床药学重点实验室, 徐州, 221004电子地址：[email protected]。

    PMID：35123297 DOI：10.1016/j.ejmech.2022.114159

抽象的

乙型肝炎病毒 (HBV) 感染是对公众健康的全球威胁。在这项工作中，合成了一系列新型喹唑啉酮衍生物 (5a-q)，并作为新型抗 HBV 药物进行了评估。其中，化合物 5l 对野生型和耐药（拉米夫定和恩替卡韦）HBV 株的 HBV DNA 复制表现出有效的抑制作用，IC50 值分别为 0.15 和 0.10 μM。值得注意的是，5l 的选择性指数值高于 66.67，表明安全性良好。分子对接研究表明，化合物5l很好地适应了TLR8蛋白-蛋白界面的结合口袋。双荧光素酶报告基因检测进一步证实化合物5l可以剂量依赖性地激活TLR8，从而有效诱导TLR8依赖性NF-κB的活性。总的来说，化合物 5l 在体外显示出有效的抗 HBV 活性和 TLR8 激动剂作用，可能是一种潜在的免疫调节抗 HBV 药物，值得进一步研究。

关键词：抗HBV药物；喹唑啉酮衍生物；合成; TLR8激动剂。

版权所有 © 2022 Elsevier Masson SAS。版权所有。

StephenW

Design and synthesis of novel quinazolinone derivatives as anti-HBV agents with TLR8 agonist effect
Jingying Qiu  1 , Qingqing Zhou  2 , Yueting Zou  2 , Shuqiong Li  2 , Lihua Yang  2 , Wang Chen  2 , Jian Gao  3 , Xiaoke Gu  4
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
    Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, People's Republic of China. Electronic address: [email protected].
    4
    Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, People's Republic of China. Electronic address: [email protected].

    PMID: 35123297 DOI: 10.1016/j.ejmech.2022.114159

Abstract

Hepatitis B virus (HBV) infection is a worldwide threat to public health. In this work, a series of novel quinazolinone derivatives (5a-q) were synthesized and evaluated as novel anti-HBV agents. Among them, compound 5l exhibited potent inhibitory effect on HBV DNA replication in both wild type and drug resistant (lamivudine and entecavir) HBV strains with IC50 values of 0.15 and 0.10 μM, respectively. Notably, the selective index value of 5l was high above 66.67, indicating the favorable safety profile. Molecular docking study indicated that compound 5l well fitted into the binding pocket of TLR8 protein-protein interface. Dual-luciferase reporter gene assay further confirmed that compound 5l could dose-dependently activate TLR8, thus effectively inducing the activity of TLR8-dependent NF-κB. Collectively, compound 5l displayed potent anti-HBV activities and TLR8 agonist effect in vitro, and might be a potential immunomodulatory anti-HBV agent to warrant further investigation.

Keywords: Anti-HBV agents; Quinazolinone derivatives; Synthesis; TLR8 agonist.

Copyright © 2022 Elsevier Masson SAS. All rights reserved.