新型苯丙酰胺衍生物作为非核苷乙型肝炎病毒抑制剂的设计

StephenW

Eur J Med Chem. 2017 Dec 16;144:424-434. doi: 10.1016/j.ejmech.2017.12.042. [Epub ahead of print]
Design, synthesis and evaluation of novel phenyl propionamide derivatives as non-nucleoside hepatitis B virus inhibitors.Qiu J1, Gong Q2, Gao J3, Chen W2, Zhang Y2, Gu X4, Tang D5.
Author information
1Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China; Department of Pharmaceutical Analysis, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China.2Department of Pharmaceutical Analysis, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China.3Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China.4Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China. Electronic address: [email protected].5Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China; Department of Pharmaceutical Analysis, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China. Electronic address: [email protected].

AbstractAs an ongoing search for potent non-nucleoside anti-HBV agents with novel structures, we described a series of phenyl propionamide derivatives (3a-b, 4a-e, 7a-g, 8a-h and 9a-b) by pharmacophore fusion strategy in the present work. All the compounds exhibited an anti-HBV activity to some extent. Among them, compounds 8d and 9b displayed most potent anti-HBV activity with IC50 values on HBV DNA replication of 0.46 and 0.14 μM, respectively. And the selective index values of 8d and 9b were more than 217.39 and 153.14, suggesting that 8d and 9b exhibited favorable safety profiles. Interestingly, 8d and 9b possessed significantly antiviral activities against lamivudine and entecavir resistant HBV mutants with IC50 values of 0.77 and 0.32 μM. Notably, preliminary anti-HBV action mechanism studies showed that 8d could inhibit intracellular HBV pgRNA and RT activity of the HBV polymerase. Molecular docking studies suggested that compound 8d could fit into the dimer-dimer interface of HBV core protein by hydrophobic interaction. In addition, in silico prediction of physicochemical properties showed that 8d conformed well to the Lipinski's rule of five, suggesting its potential for use as a drug like molecule. Taken together, 8d possessed significantly anti-HBV activity, low toxicity, diverse anti-HBV mechanism and favorable physicochemical properties, and warranted further investigation as a promising non-nucleoside anti-HBV candidate.


KEYWORDS: Anti-HBV agents; Non-nucleoside; Phenyl propionamide derivatives; Synthesis

PMID:29288943DOI:10.1016/j.ejmech.2017.12.042

StephenW

Eur J Med Chem。 2017年12月16日; 144：424-434。 doi：10.1016 / j.ejmech.2017.12.042。 [电子版提前打印]
新型苯丙酰胺衍生物作为非核苷乙型肝炎病毒抑制剂的设计合成与评价
邱1 1，龚二季，高3 3，陈炜2，张2 2，顾X4，唐铎5。
作者信息

1
    徐州医学院新药研究与临床药学江苏省重点实验室，中国徐州221004;徐州医学院药学院药物分析教研室，徐州221004
2
    徐州医学院药学院药物分析教研室，徐州221004
3
    徐州医学院药物新药研究与临床药学江苏省重点实验室，中国徐州221004
4
    徐州医学院药物新药研究与临床药学江苏省重点实验室，中国徐州221004电子地址：[email protected]。
五
    徐州医学院新药研究与临床药学江苏省重点实验室，中国徐州221004;徐州医学院药学院药物分析教研室，徐州221004电子地址：[email protected]。

抽象

作为正在进行的具有新颖结构的有效的非核苷抗HBV剂的研究，我们通过药效团融合策略描述了一系列苯丙酰胺衍生物（3a-b，4a-e，7a-g，8a-h和9a-b）在目前的工作中。所有化合物在一定程度上表现出抗HBV活性。其中化合物8d和9b表现出最强的抗HBV活性，IC50值分别为0.46和0.14μM。 8d和9b的选择性指数值分别大于217.39和153.14，说明8d和9b具有良好的安全性。有趣的是，8d和9b对拉米夫定和恩替卡韦耐药HBV突变体具有显着的抗病毒活性，IC50值分别为0.77和0.32μM。值得注意的是，初步的抗HBV作用机制研究表明8d能抑制HBV聚合酶的细胞内HBV pgRNA和RT活性。分子对接研究表明，化合物8d可以通过疏水相互作用进入HBV核心蛋白的二聚体 - 二聚体界面。此外，理化性质的硅片预测表明，8d与Lipinski的5条规则相符合，表明其可用作药物如分子。综上所述，8d具有明显的抗HBV活性，毒性低，抗HBV机制多样，理化性质良好，值得进一步研究作为有希望的非核苷类抗HBV候选药物。
关键词：

抗HBV药物;非核苷;苯基丙酰胺衍生物;合成

结论：
    29288943
DOI：
    10.1016 / j.ejmech.2017.12.042

windu

加油，赶快临床试验，不能进入临床的研究都是耍流氓

rxsm

小白兔看着老农手里的种子，眼里充满美美希望――明年有萝卜吃了。单纯的白兔，你能熬过这个冬天？
感谢楼主，新年更好！