School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt.
Rega Institute for Medical Research, KU Leuven, Herestraat 49 Box 1030, Leuven 3000, Belgium.
Bioorg Med Chem. 2019 Mar 15;27(6):1023-1033. doi: 10.1016/j.bmc.2019.02.005. Epub 2019 Feb 2.
A series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against herpes simplex virus 1 and 2 (HSV-1, HSV-2) and thymidine kinase deficient (ACV resistant) HSV-1. The tricyclic HBG derivatives were devoid of inhibitory activity however several of the tricyclic PCV derivatives showed promising antiviral activity, in particular 9g (R = 4-MeO-CH) displayed good inhibitory activity (HSV-1 EC 1.5 μM, HSV-2 EC 0.8 μM) and retained inhibitory activity in HSV-1 TK cells (EC 0.8 μM). Computational docking experiments supported the biological data observed and this preliminary study provides useful data for further development of tricyclic acyclic nucleoside derivatives with improved lipophilicity and retention of activity in HSV-1 TK deficient strains. Also, the new tricyclic derivatives were evaluated against a broad range of other DNA and RNA viruses, but were found to be inactive at subtoxic concentrations. In addition, weak to moderate cytostatic effect was observed for the new compounds.
已经通过一种有效的合成路线，制备了一系列具有增强亲脂性的三环型喷昔洛韦（PCV）和羟丁基鸟嘌呤（HBG）衍生物。所有新型三环衍生物均针对单纯疱疹病毒 1 和 2（HSV-1、HSV-2）和胸苷激酶缺失（ACV 耐药）HSV-1 的抑制活性进行了评估。三环 HBG 衍生物没有抑制活性，但是几种三环 PCV 衍生物表现出有希望的抗病毒活性，特别是 9g（R = 4-MeO-CH）显示出良好的抑制活性（HSV-1 EC 1.5 μM，HSV-2 EC 0.8 μM），并且在 HSV-1 TK 细胞中保留抑制活性（EC 0.8 μM）。计算对接实验支持了观察到的生物学数据，该初步研究为进一步开发具有改善的亲脂性和在 HSV-1 TK 缺陷株中保留活性的三环非环核苷衍生物提供了有用的数据。此外，新的三环衍生物还针对广泛的其他 DNA 和 RNA 病毒进行了评估，但在亚毒性浓度下发现它们没有活性。此外，还观察到新化合物具有弱至中度的细胞生长抑制作用。
