设计，面向多样性的合成和作为非核苷HBV衣壳蛋白抑制剂的

StephenW

Design, diversity-oriented synthesis and biological evaluation of novel heterocycle derivatives as non-nucleoside HBV capsid protein inhibitors
Haiyong Jia  1 , Ji Yu  2 , Xianhong Du  3 , Srinivasulu Cherukupalli  2 , Peng Zhan  4 , Xinyong Liu  5
Affiliations
Affiliations

    1
    Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; School of Pharmacy, Weifang Medical University, 261053, Weifang, Shandong, PR China.
    2
    Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
    3
    School of Pharmacy, Weifang Medical University, 261053, Weifang, Shandong, PR China; Department of Immunology, Key Laboratory for Experimental, Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection and Immunology, Shandong University School of Medicine, Jinan, 250012, Shandong Province, China.
    4
    Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: [email protected].
    5
    Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: [email protected].

    PMID: 32712535 DOI: 10.1016/j.ejmech.2020.112495

Abstract

The capsid assembly is a significant phase for the hepatitis B virus (HBV) lifespan and is an essential target for anti-HBV drug discovery and development. Herein, we used scaffold hopping, bioisosterism, and pharmacophore hybrid-based strategies to design and synthesize six series of various heterocycle derivatives (pyrazole, thiazole, pyrazine, pyrimidine, and pyridine) and screened for in vitro anti-HBV non-nucleoside activity. Drug candidate NZ-4 and AT-130 were used as lead compounds. Several compounds exhibited prominent anti-HBV activity compared to lead compound NZ-4 and positive drug Lamivudine, especially compound II-8b, showed the most prominent anti-HBV DNA replication activity (IC50 = 2.2 ± 1.1 μM). Also compounds IV-8e and VII-5b showed the best in vitro anti-HBsAg secretion (IC50 = 3.8 ± 0.7 μM, CC50 > 100 μM) and anti-HBeAg secretion (IC50 = 9.7 ± 2.8 μM, CC50 > 100 μM) respectively. Besides, II-8b can interact HBV capsid protein with good affinity constants (KD = 60.0 μM), which is equivalent to lead compound NZ-4 ((KD = 50.6 μM). The preliminary structure-activity relationships (SARs) of the newly synthesized compounds were summarized, which may help researchers to discover more potent anti-HBV agents.

Keywords: Capsid protein; Diversity-oriented synthesis; HBV; Heterocycle derivatives.

Copyright © 2020 Elsevier Masson SAS. All rights reserved.

StephenW

设计，面向多样性的合成和作为非核苷HBV衣壳蛋白抑制剂的新型杂环衍生物的生物学评估
海用家1，季育2，鲜红度3，Srinivasulu Cherukupalli 2，彭占4，刘新勇5
隶属关系
隶属关系

    1个
    山东大学药学院药物化学系，化学生物学教育部重点实验室（教育部），山东济南西文化路44号250012；潍坊医科大学药学院，山东潍坊261053。
    2
    山东大学药学院药物化学系，化学生物学教育部重点实验室（教育部），山东济南西文化路44号250012
    3
    潍坊医科大学药学院，山东潍坊261053；山东大学医学院免疫学教研室，实验性教育部重点实验室，山东省感染与免疫学重点实验室，山东济南250012
    4
    山东大学药学院药物化学系，化学生物学重点实验室（教育部），山东济南西文化路44号250012电子地址：[email protected]。
    5
    山东大学药学院药物化学系，化学生物学重点实验室（教育部），山东济南西文化路44号250012电子地址：[email protected]。

    PMID：32712535 DOI：10.1016 / j.ejmech.2020.112495

抽象

衣壳装配是乙肝病毒（HBV）寿命的重要阶段，也是抗HBV药物发现和开发的重要目标。在本文中，我们使用基于支架跳跃，生物等位基因和药效团杂交的策略设计和合成了六个系列的各种杂环衍生物（吡唑，噻唑，吡嗪，嘧啶和吡啶），并筛选了体外抗HBV非核苷活性。候选药物NZ-4和AT-130被用作先导化合物。与先导化合物NZ-4相比，几种化合物具有突出的抗-HBV活性，阳性药物拉米夫定，尤其是化合物II-8b，具有最突出的抗-HBV DNA复制活性（IC50 = 2.2±1.1μM）。化合物IV-8e和VII-5b分别显示出最佳的体外抗HBsAg分泌（IC50 = 3.8±0.7μM，CC50> 100μM）和抗HBeAg分泌（IC50 = 9.7±2.8μM，CC50> 100μM） 。此外，II-8b可以以良好的亲和常数（KD = 60.0μM）与HBV衣壳蛋白相互作用，这与先导化合物NZ-4（KD = 50.6μM）等效。总结了合成的化合物，这可能有助于研究人员发现更有效的抗HBV药物。

关键词：衣壳蛋白；面向多样性的综合；乙肝病毒杂环衍生物。

版权所有©2020 Elsevier Masson SAS。版权所有。