An Isomer of Galidesivir That Potently Inhibits Influenza Viruses and Members of the <i>Bunyavirales</i> Order.
Sparrow KJ, Shrestha R, Wood JM, Clinch K, Hurst BL, Wang H, Gowen BB, Julander JG, Tarbet EB, McSweeney AM, Ward VK, Evans GB, Harris LD.
We report for the first time the antiviral activities of two <i>iminovirs</i> (antiviral imino-<i>C</i>-nucleosides) <b>1</b> and <b>2</b>, structurally related to galidesivir (Immucillin A, BCX4430). An <i>iminovir</i> containing the 4-aminopyrrolo[2,1-<i>f</i>][1,2,4-triazine] nucleobase found in remdesivir exhibited submicromolar inhibition of multiple strains of influenza A and B viruses, as well as members of the <i>Bunyavirales</i> order. We also report the first syntheses of ProTide prodrugs of <i>iminovir</i> monophosphates, which unexpectedly displayed poorer viral inhibition than their parent nucleosides <i>in vitro</i>. An efficient synthesis of the 4-aminopyrrolo[2,1-<i>f</i>][1,2,4-triazine]-containing <i>iminovir</i> <b>2</b> was developed to enable preliminary <i>in vivo</i> studies, wherein it displayed significant toxicity in BALB/c mice and limited protection against influenza. Further modification of this anti-influenza <i>iminovir</i> will therefore be required to improve its therapeutic value.