Organic Chemistry Chair I and Interdisciplinary Center for, Molecular Materials (ICMM), Friedrich-Alexander University of, Erlangen-Nürnberg, Nikolaus Fiebiger-Straße 10, 91058, Erlangen, Germany.
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2, 37077, Göttingen, Germany.
Chemistry. 2020 Sep 16;26(52):12019-12026. doi: 10.1002/chem.202001803. Epub 2020 Aug 18.
Viral infections cause life-threatening diseases in millions of people worldwide every year and there is an urgent need for new, effective antiviral drugs. Hybridization of two chemically diverse compounds into a new bioactive effector product is a successful concept to improve the properties of a hybrid drug relative to the parent compounds. In this study, (iso)quinoline-artemisinin hybrids, obtained through copper-catalyzed azide-alkyne cycloaddition or metal-free click reactions (in organic solvents or in the presence of water), were analyzed in vitro, for the first time, for their inhibitory activity against human cytomegalovirus (HCMV), relative to their parent compounds and the reference drug ganciclovir. EC (HCMV) values were obtained in a range 0.22-1.20 μm, which indicated highly potent antiviral properties in the absence of cytotoxic effects on normal cells (CC >100 μm). The most active hybrid, 1 (EC =0.22 μm), is 25 times more potent than its parent compound artesunic acid (EC =5.41 μm) and 12 times more efficient than the standard drug ganciclovir (EC =2.6 μm). Interestingly, hybrid 1 also shows inhibitory activity against hepatitis B virus in vitro (EC (HBeAg)=2.57 μm).
病毒感染每年在全球范围内导致数百万人患上危及生命的疾病，因此迫切需要新的、有效的抗病毒药物。将两种化学性质截然不同的化合物杂交成新的生物活性效应产物是一个成功的概念，可以提高杂种药物相对于母体化合物的性质。在这项研究中，（异）喹啉-青蒿素杂种通过铜催化的叠氮-炔环加成或无金属点击反应（在有机溶剂中或在水存在下）获得，首次在体外分析了它们对人巨细胞病毒（HCMV）的抑制活性，与母体化合物和参考药物更昔洛韦相比。在不存在对正常细胞的细胞毒性作用的情况下（CC >100 μm），获得了 EC（HCMV）值在 0.22-1.20 μm 的范围内，这表明具有高度有效的抗病毒特性。最活跃的杂种 1（EC =0.22 μm）比其母体化合物青蒿琥酯（EC =5.41 μm）有效 25 倍，比标准药物更昔洛韦（EC =2.6 μm）有效 12 倍。有趣的是，杂种 1 还显示出体外抑制乙型肝炎病毒的活性（EC（HBeAg）=2.57 μm）。
