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 (K_D = 60.0 μM), which is equivalent to lead compound NZ-4 ((K_{D =} 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.

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（IC ₅₀ = 2.2±1.1μM）。还化合物IV-8eVII-5b和VII-5b分别显示出最佳的体外抗HBsAg分泌（IC ₅₀ = 3.8±0.7μM，CC ₅₀ > 100μM）和抗HBeAg分泌（IC ₅₀ = 9.7±2.8μM，CC ₅₀ > 100μM）。此外，II-8b可以以良好的亲和常数（K _D = 60.0μM）与HBV衣壳蛋白相互作用，这与先导化合物NZ-4（K _{D =} 50.6μM）相当。总结了新合成的化合物，这可能有助于研究人员发现更有效的抗HBV药物。