2'-脱氧-2'-氟-2'-甲基嘌呤核苷类似物的近端柔性类似物：合成及初步药代动力学和抗病毒评价。
Proximal fleximer analogues of 2'-deoxy-2'-fluoro-2'-methyl purine nucleos(t)ides: Synthesis and preliminary pharmacokinetic and antiviral evaluation.
机构信息
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD, USA.
Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD, USA.
出版信息
Bioorg Med Chem. 2024 Oct 1;112:117898. doi: 10.1016/j.bmc.2024.117898. Epub 2024 Aug 24.
Abstract
In this study, proximal fleximer nucleos(t)ide analogues of Bemnifosbuvir were synthesized and evaluated for their potential to serve as antiviral therapeutics. The final parent flex-nucleoside and ProTide modified flex-nucleoside analogues were tested against several viral families including flaviviruses, filoviruses, and coronaviruses. Modest activity against Zaire Ebola virus was observed at 30 μM for compound ProTide modified analogue. Neither compound exhibited activity for any of the other viruses tested. The parent flex-nucleoside analogue was screened for toxicity in CD-1 mice and showed no adverse effects up to 300 mg/kg, the maximum concentration tested.
摘要
在这项研究中，我们合成了贝那福布韦的近端柔性核苷酸类似物，并评估了它们作为抗病毒治疗药物的潜力。最后，我们对几种病毒家族进行了测试，包括黄病毒、丝状病毒和冠状病毒，对最终的母体柔性核苷和 ProTide 修饰的柔性核苷类似物进行了测试。在 30μM 时，我们观察到对扎伊尔埃博拉病毒有一定的活性，对化合物 ProTide 修饰的类似物有一定的活性。这两种化合物对测试的其他病毒均没有活性。我们对母体柔性核苷类似物在 CD-1 小鼠中的毒性进行了筛选，在 300mg/kg 的最大测试浓度下没有观察到不良反应。
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