PDF(Pubmed)
Abstract：
1,2,4-Triazole derivatives have a wide range of biological activities. The most well-known drug that contains 1,2,4-triazole as part of its structure is the nucleoside analogue ribavirin, an antiviral drug. Finding new nucleosides based on 1,2,4-triazole is a topical task. The aim of this study was to synthesize ribosides and deoxyribosides of 1,2,4-triazole-3-thione derivatives and test their antiviral activity against herpes simplex viruses. Three compounds from a series of synthesized mono- and disubstituted 1,2,4-triazole-3-thione derivatives were found to be substrates for E. coli purine nucleoside phosphorylase. Of six prepared nucleosides, the riboside and deoxyriboside of 3-phenacylthio-1,2,4-triazole were obtained at good yields. The yields of the disubstituted 1,2,4-triazol-3-thiones were low due to the effect of bulky substituents at the C3 and C5 positions on the selectivity of enzymatic glycosylation for one particular nitrogen atom in the triazole ring. The results of cytotoxic and antiviral studies on acyclovir-sensitive wild-type strain HSV-1/L2(TK+) and acyclovir-resistant strain (HSV-1/L2/RACV) in Vero E6 cell culture showed that the incorporation of a thiobutyl substituent into the C5 position of 3-phenyl-1,2,4-triazole results in a significant increase in the cytotoxicity of the base and antiviral activity. The highest antiviral activity was observed in the 3-phenacylthio-1-(β-D-ribofuranosyl)-1,2,4-triazole and 5-butylthio-1-(2-deoxy-β-D-ribofuranosyl)-3-phenyl-1,2,4-triazole nucleosides, with their selectivity indexes being significantly higher than that of ribavirin. It was also found that with the increasing lipophilicity of the nucleosides, the activity and toxicity of the tested compounds increased.
摘要：
1,2,4-三唑衍生物具有广泛的生物活性。最著名的含有1,2,4-三唑作为其结构一部分的药物是核苷类似物利巴韦林，一种抗病毒药物.寻找基于1,2,4-三唑的新核苷是一项局部任务。这项研究的目的是合成1,2,4-三唑-3-硫酮衍生物的核苷和脱氧核苷，并测试其对单纯疱疹病毒的抗病毒活性。发现来自一系列合成的单-和二取代的1,2,4-三唑-3-硫酮衍生物的三种化合物是大肠杆菌嘌呤核苷磷酸化酶的底物。在六种准备好的核苷中，3-苯甲酰硫代-1,2,4-三唑的核苷和脱氧核苷以良好的收率获得。二取代的1,2,4-三唑-3-硫酮的产率较低，这是由于C3和C5位置的大取代基对三唑环中一个特定氮原子的酶促糖基化选择性的影响。在VeroE6细胞培养物中对阿昔洛韦敏感的野生型菌株HSV-1/L2（TK）和阿昔洛韦耐药菌株（HSV-1/L2/RACV）的细胞毒性和抗病毒研究结果表明，在3-苯基-1,2,4-三唑的C5位置掺入一个硫代丁基取代基，导致碱基的细胞毒性和抗病毒活性显着增加。在3-苯甲酰硫基-1-（β-D-呋喃核糖基）-1,2,4-三唑和5-丁硫基-1-（2-脱氧-β-D-呋喃核糖基）-3-苯基-1,2,4-三唑核苷中观察到最高的抗病毒活性，其选择性指数明显高于利巴韦林。还发现，随着核苷的亲脂性增加，测试化合物的活性和毒性增加。
