为了克服核苷类抗乙肝病毒药物的毒性和耐药性而寻找一类非核苷类抗乙肝病毒活性新化合物。前期工作中，设计并合成结构为C6-C3骨架的肟类新衍生物，通过体外抗乙肝病毒活性实验证明了化合物具有显著的活性，且与乙型肝炎核心抗原表位特异结合的人白细胞抗原A(HLA-A，与抗原结合激活T细胞活性以抑制和清除病毒）的蛋白片段在理论上有很好的相互作用。研究内容是，在此基础上设计系列新的C6-C3类似骨架的肟类衍生物，利用上述模拟靶点对设计的化合物进行活性筛和优化，并合成。利用HepG2.2.15细胞株进行体外抗HBV活性试验并筛选出活性化合物。对活性化合物进行进一步结构优化并进行合成和活性试验，得到一系列显著抗乙肝病毒活性C6-C3骨架肟类化合物，并确定该类型化合物的构效关系。利用不同的动物体内活性试验方式初步研究活性化合物的作用机理。研究成果必将为非核苷类抗乙型肝炎病毒新化合物的设计和开发提供依据。

Hepatitis virus B is worldwide spread and threats health of human being. Therapies of HBV infection currently, which includes nucleosides or nucleotides analogues and interferons (interferon-α and pegylated interferon), are partially effective. Long-term therapy of HBV with nucleoside/nucleotide analogs lead resistance and decreased their effects dramatically. cccDNA of HBV is not eliminated even HBsAg and HBeAg are not detected in patients in therapies with nucleoside analogs, and it will lead HBVDNA duplication again. Finding new and more effective anti-HBV therapy agents are becoming necessary urgently. Our proposal project is about looking for new bioactive compounds to resist and inhibit hepatitis B virus. In our previous works, classes of compounds, which interacted theoretically with a piece of protein of human leukocyte antigen A2[HLA-A2, PDB code 3OX8, that binding to immunodominant hepatitis B core antigen 18–27 (HBcAg18–27) epitope], were designed, synthesized and screened for anti-HBV activities. Results showed these classes of compounds, which oxime derivatives possessed C6-C3 fragment, were obvious anti-HBV activities. Studies on this proposal project are focused to find new anti-HBV active compounds on the basis of previous works. A series of new C6-C3 oxime derivatives will be designed and then docked with HLA-A2. Compounds combined to targets strongly will be synthesized and then screened for anti-HBV activities in vitra with HepG2.2.15 cell line to give bioactive compounds. An initial relationship of structure-bioactivities of these compounds will be offered after analyzing the results. The anti-HBV active compounds will be redesigned and modified for more effective bioactivities on the basis of the relationship. These modifies molecules will be synthesized and assayed anti-HBV activities. These active compounds will be assayed for anti-HBV in vivo in different ways including test animals take agents before infected HBV, test animals take agents and infected HBV in same time, and test animals take agents after infected HBV. We hope in vivo tests in animals will give an elementary mechanism of interaction between the agents and anti-HBV. A more reasonable relationship between the structure of compounds and their anti-HBV activities will be obtained finally and it will be beneficial for design and development of new anti-HBV agents.