Proximal fleximer analogues of 2′-deoxy-2′-fluoro-2′-methyl purine nucleos(t)ides: Synthesis and preliminary pharmacokinetic and antiviral evaluation

IF 3.3 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic & Medicinal Chemistry Pub Date : 2024-08-24 DOI:10.1016/j.bmc.2024.117898
Charles D. Waters III , Evan Carlyle , Viviana Smart , Apurv Rege , Charles J. Bieberich , Katherine L. Seley-Radtke
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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.

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2′-脱氧-2′-氟-2′-甲基嘌呤核苷(t)ides 的近端柔性类似物:合成及初步药代动力学和抗病毒评估
在这项研究中,合成了苯尼夫布韦的近端柔性核苷(t)ide 类似物,并评估了它们作为抗病毒疗法的潜力。对最终的母体柔核苷和 ProTide 修饰的柔核苷类似物进行了针对多个病毒家族(包括黄病毒、丝状病毒和冠状病毒)的测试。在 30 μM 的浓度下,ProTide 改性类似物对扎伊尔埃博拉病毒具有微弱的活性。这两种化合物对测试的其他病毒都没有表现出活性。母体柔性核苷类似物在 CD-1 小鼠体内进行了毒性筛选,在 300 毫克/千克(测试的最大浓度)的浓度下没有显示出不良反应。
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来源期刊
Bioorganic & Medicinal Chemistry
Bioorganic & Medicinal Chemistry 医学-生化与分子生物学
CiteScore
6.80
自引率
2.90%
发文量
413
审稿时长
17 days
期刊介绍: Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.
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