Pertusati Fabrizio, Serafini Sara, Albadry Najmiyah, Snoeck Robert, Andrei Graciela
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, CF10 3NB, Cardiff, Wales, United Kingdom.
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, CF10 3NB, Cardiff, Wales, United Kingdom.
Antiviral Res. 2017 Jul;143:262-268. doi: 10.1016/j.antiviral.2017.04.013. Epub 2017 Apr 25.
Acyclic nucleoside phosphonates (ANPs) are nowadays one of the key drugs in the treatment of DNA virus and retrovirus infections. In this work, we report the synthesis and antiviral evaluation of phosphonoamidate and diamidates prodrugs of C5-pyrimidine acyclic nucleosides derivatives functionalized with but-2-enyl- chain. In the phosphonoamidate series, the most active compound 15, showed sub-micromolar activity against varicella zoster virus (VZV) (EC = 0.09-0.5 μM) and μM activity against human cytomegalovirus (HCMV) and herpes simplex virus (HSV). Separation of single diastereoisomers for compound 14, showed that 14b had better anti-herpesvirus activity and no cytotoxicity compared to the diastereoisomeric mixture 14. Very interestingly, phosphonodiamidate 21 showed anti-herpesvirus activity with excellent activity against wild type and thymidine kinase-deficient (TK) VZV strains (EC = 0.47 and 0.2 μM, respectively) and HCMV (EC = 3.5-7.2 μM) without any cytotoxicity (CC > 100).
无环核苷膦酸酯（ANPs）是目前治疗DNA病毒和逆转录病毒感染的关键药物之一。在本研究中，我们报道了用丁-2-烯基链官能化的C5-嘧啶无环核苷衍生物的膦酰氨基和二酰胺前药的合成及抗病毒评价。在膦酰氨基系列中，活性最高的化合物15对水痘带状疱疹病毒（VZV）表现出亚微摩尔活性（EC = 0.09 - 0.5 μM），对人巨细胞病毒（HCMV）和单纯疱疹病毒（HSV）表现出微摩尔活性。化合物14的单一非对映异构体的分离表明，与非对映异构体混合物14相比，14b具有更好的抗疱疹病毒活性且无细胞毒性。非常有趣的是，膦酰二酰胺21表现出抗疱疹病毒活性，对野生型和胸苷激酶缺陷型（TK）VZV毒株（EC分别为0.47和0.2 μM）以及HCMV（EC = 3.5 - 7.2 μM）具有优异活性，且无任何细胞毒性（CC > 100）。
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