Martin-Ghoteimi Céline, Davis Kyle A, Ghoteimi Rayane, Amare Meareg, Diefenbacher Meghan V, Kutz Christianna, Smith Jessica L, Stevens Laura J, Tchesnokov Egor, Walker Simon M, Denison Mark, Götte Matthias, Halfmann Peter, Hirsch Alec J, Sheahan Timothy P, Seley-Radtke Katherine L
Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA.
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711, USA.
Bioorg Med Chem. 2025 Dec 1;130:118384. doi: 10.1016/j.bmc.2025.118384. Epub 2025 Sep 8.
A series of thiophene-expanded tricyclic nucleosides featuring modifications not previously investigated, including sugar and nucleobase modifications, were synthesized as potential antiviral therapeutics. In addition, their corresponding prodrugs were also pursued to probe their potential antiviral activity, as typically prodrugs increase solubility and delivery. Initial interest was focused on ribose analogues as we had previously only synthesized a few compounds, and none had been tested against new viruses, particularly those of pandemic concern. In that regard, CEM-007, showed promising antiviral activity against several viral families. Given this promising lead, the 2'-α-fluoro-2'-β-methyl-modified analogues of CEM-007 were also synthesized for comparison. While 2'-modified analogue CEM-024 showed little to no antiviral activity, several of its prodrugs including CEM-042, CEM-052, CEM-053, CEM-054 and CEM-055, exhibited potent, broad-spectrum antiviral activity across several viral families including flaviviruses, filoviruses, and coronaviruses, with EC values in the single digit low micromolar range, with minimal toxicity. Additional studies are underway to elucidate the mechanism of action of these analogues. The design, synthesis, and biological testing of these structurally novel analogues are reported herein.
合成了一系列具有先前未研究过的修饰的噻吩扩展三环核苷，包括糖基和碱基修饰，作为潜在的抗病毒治疗药物。此外，还研究了它们相应的前药，以探究其潜在的抗病毒活性，因为通常前药可提高溶解度和递送效果。最初的兴趣集中在核糖类似物上，因为我们之前只合成了少数化合物，且没有针对新病毒进行测试，特别是那些引起大流行关注的病毒。在这方面，CEM-007对几个病毒家族显示出有前景的抗病毒活性。鉴于这一有前景的先导化合物，还合成了CEM-007的2'-α-氟-2'-β-甲基修饰类似物用于比较。虽然2'-修饰类似物CEM-024几乎没有抗病毒活性，但其几种前药，包括CEM-042、CEM-052、CEM-053、CEM-054和CEM-055，在包括黄病毒、丝状病毒和冠状病毒在内的几个病毒家族中表现出强效、广谱的抗病毒活性，其半数有效浓度（EC）值在个位数低微摩尔范围内，且毒性极小。正在进行进一步的研究以阐明这些类似物的作用机制。本文报道了这些结构新颖的类似物的设计、合成及生物学测试。
