Design, diversity-oriented synthesis and biological evaluation of novel heterocycle derivatives as non-nucleoside HBV capsid protein inhibitors
Design, diversity-oriented synthesis and biological evaluation of novel heterocycle derivatives as non-nucleoside HBV capsid protein inhibitors
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作为非核苷HBV衣壳蛋白抑制剂的新型杂环衍生物的设计、多样性合成和生物学评价
DOI：
10.1016/j.ejmech.2020.112495
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发表时间：
2020-09-15
影响因子：
6.7
通讯作者：
Liu, Xinyong
中科院分区：
文献类型：
--
作者：
Jia, Haiyong;Yu, Ji;Liu, Xinyong
衣壳组装是B型肝炎病毒（HBV）生命周期的重要阶段，也是抗HBV药物发现和开发的重要靶点。在此，我们使用基于骨架跳跃、生物电子等排和药效团杂交的策略来设计和合成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和阳性药物拉米夫定相比，几种化合物显示出显著的抗HBV活性，尤其是化合物II-8b，显示出最显著的抗HBV DNA复制活性（IC 50 = 2.2 +/- 1.1 μ M）。化合物IV-8 e和VII-5 b也分别显示出最好的体外抗HBsAg分泌（IC 50 = 3.8 +/-0.7 μ M，CC 50> 100 μ M）和抗HBeAg分泌（IC 50 = 9.7 +/-2.8 μ M，CC 50> 100 μ M）。此外，II-8b与HBV衣壳蛋白的结合亲和力常数（K-D = 60.0 μ M）与先导化合物NZ-4相当（K-D = 50.6 μ M）。对新合成的化合物进行了初步的构效关系分析，为开发更有效的抗HBV药物提供参考。(C)2020 Elsevier Masson SAS。All rights reserved.
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 mu M). Also compounds IV-8e and VII-5b showed the best in vitro anti-HBsAg secretion (IC50 = 3.8 +/- 0.7 mu M, CC50 > 100 mu M) and anti-HBeAg secretion (IC50 = 9.7 +/- 2.8 mu M, CC50 > 100 mu M) respectively. Besides, II-8b can interact HBV capsid protein with good affinity constants (K-D = 60.0 mu M), which is equivalent to lead compound NZ-4 ((K-D = 50.6 mu M). The preliminary structure-activity relationships (SARs) of the newly synthesized compounds were summarized, which may help researchers to discover more potent anti-HBV agents. (C) 2020 Elsevier Masson SAS. All rights reserved.