Novel tricycle expanded purine nucleosides with pan-viral activity

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 EC₅₀ 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.