2-芳硫基-5-碘嘧啶衍生物作为新型抗乙型肝炎病毒DNA复制非核苷抑制剂的研究
Study on 2-arylthio-5-iodo pyrimidine derivatives as novel nonnucleoside inhibitors against hepatitis B virus DNA replication.
作者信息
Zhao Jianxiong, Tu Jing, Fan Ningning, Chen Xiangmei, Lu Fengmin, Zhang Yu, Zhang Liang, Tian Chao, Zhang Zhili, Liu Junyi, Wang Xiaowei
机构信息
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Department of Microbiology & Infectious Disease Center, School of Basic Medical Science, Peking University, Beijing 100191, China.
出版信息
Future Med Chem. 2016 May;8(7):751-63. doi: 10.4155/fmc.16.13. Epub 2016 May 13.
BACKGROUND
Novel nonnucleoside hepatitis B virus inhibitors have been recently developed for the reason of drug-resistant mutations and adverse effects of nucleoside analogs. In this study, two series of 2-arylthio-5-iodo pyrimidine analogs were firstly reported as potential anti-HBV agents.
METHODOLOGY
Target compounds were prepared according to two high-yielded synthetic routes, and their anti-HBV activities were evaluated on Hep2.2.15 and HepAD38 cell lines, respectively. To probe the mechanism of active agents, a cell-based (Huh-7) study of biochemical markers (e.g., HBeAg, HBsAg, intracellular HBV DNA and pgRNA) was performed. Furthermore, the pharmacophore models were constructed for future optimization of lead compounds.
CONCLUSION
2-Arylthio-5-iodo pyrimidine derivatives firstly proved to be effective against HBV, which paves the way for future development of nonnucleoside anti-HBV agents.
背景
由于核苷类似物的耐药性突变和不良反应，新型非核苷类乙型肝炎病毒抑制剂最近被开发出来。在本研究中，首次报道了两个系列的2-芳硫基-5-碘嘧啶类似物作为潜在的抗乙肝病毒药物。
方法
根据两条高产合成路线制备目标化合物，并分别在Hep2.2.15和HepAD38细胞系上评估其抗乙肝病毒活性。为了探究活性剂的作用机制，在基于细胞（Huh-7）的研究中检测了生化标志物（如HBeAg、HBsAg、细胞内乙肝病毒DNA和pgRNA）。此外，构建了药效团模型，以便将来对先导化合物进行优化。
结论
2-芳硫基-5-碘嘧啶衍生物首次被证明对乙肝病毒有效，这为非核苷类抗乙肝病毒药物的未来发展铺平了道路。
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