Human cytomegalovirus (HCMV) is a major human pathogen and is associated with severe pathology, such as life-threatening courses of infection in immunocompromised individuals and neonates. Currently, antiviral therapy is still hampered by a considerable toxicity of the available drugs and induction of viral resistance. Recently, we and others reported the very potent antiviral activity of the broad antiinfective drug artesunate in vitro and in vivo. Here, we investigated further optimized analogs including monomeric, dimeric and trimeric derivatives belonging to this highly interesting chemical group of experimental drugs (sesquiterpenes/trioxanes) and compared these to the previously identified trimeric artesunate compound TF27. We could demonstrate that (i) seven of the eight investigated monomeric, dimeric and trimeric artesunate derivatives, i.e. TF79, TF85, TF87, TF93.2.4, TF111, TF57a and TF57ab, exerted a strong anti-HCMV activity in primary human fibroblasts, (ii) the EC₅₀ values ranged in the low to sub-micromolar concentrations and indicated a higher antiviral potency than the recently described artesunate analogs, (iii) one trimeric compound, TF79, showed a very promising EC₅₀ of 0.03 ± 0.00 μM, which even exceled the antiviral potency of TF27 (EC₅₀ 0.04 ± 0.01 μM), (iv) levels of cytotoxicity (quantitative measurement of lactate dehydrogenase release) were low in a range between 100 and 30 μM and thus different from antiviral concentrations, (v) an analysis of protein expression levels indicated a potent block of viral protein expression, and (vi) data from a NF-κB reporter cell system strongly suggested that these compounds share the same antiviral mechanism. Taken together, our data on these novel compounds strongly encourages our earlier concept on the oligomerization and hybridization of artesunate analogs, providing an excellent platform for the generation of antiherpesviral drugs.

人巨细胞病毒（HCMV）是主要的人类病原体，并与严重的病理学相关，例如免疫功能低下的个体和新生儿感染威胁生命的病程。当前，可用药物的相当大的毒性和病毒抗性的诱导仍然阻碍了抗病毒治疗。最近，我们和其他人报告了广泛的抗感染药药物青蒿琥酯的非常有效的抗病毒活性体外和体内。在这里，我们研究了进一步优化的类似物，包括属于该实验药物这一高度有趣的化学组（倍半萜烯/三恶烷）的单体，二聚体和三聚体衍生物，并将其与先前鉴定的三聚青蒿琥酯化合物TF27进行了比较。我们可以证明（i）八种被研究的单体，二聚体和三聚体青蒿琥酯衍生物中的七种，即TF79，TF85，TF87，TF93.2.4，TF111，TF57a和TF57ab在原代人成纤维细胞中发挥了强大的抗HCMV活性，（ ii）EC ₅₀值在低至亚微摩尔浓度范围内，表明比最近描述的青蒿琥酯类似物具有更高的抗病毒效力，（iii）一种三聚体化合物TF79显示出非常有前途的EC ₅₀0.03±0.00μM，甚至优于TF27的抗病毒效力（EC ₅₀ 0.04±0.01μM），（iv）细胞毒性水平（乳酸脱氢酶释放的定量测量）在100至30μM范围内较低，因此有所不同（v）对蛋白表达水平的分析表明病毒蛋白表达有很强的阻断作用，并且（vi）来自NF-κB报告细胞系统的数据强烈表明这些化合物具有相同的抗病毒机制。综上所述，我们关于这些新型化合物的数据强烈鼓励了我们关于青蒿琥酯类似物的低聚和杂交的较早概念，为抗疱疹病毒药物的产生提供了极好的平台。