N -Arylsulfonamide-based adenosine analogues to target RNA cap N 7-methyltransferase nsp14 of SARS-CoV-2.

RNA cap methylations have been shown to be crucial for the life cycle, replication, and infection of ssRNA viruses, as well as for evading the host's innate immune system. Viral methyltransferases (MTases) therefore represent an attractive target for the development of compounds as tools and inhibitors. In coronaviruses, N 7-methyltransferase function is localized in nsp14, which has become an increasingly important therapeutic target with the COVID-19 pandemic. In recent years, we have been developing SAH-derived bisubstrates with adenosine and an N -arylsulfonamide moiety targeting both SAM and RNA binding sites in nsp14. We report here the synthesis of 31 SAH analogues with the N -arylsulfonamide attached to the 5'-position of adenosine via different linkers such as N -ethylthioether, N -ethylsulfone, N -ethylamino or N -methyltriazole. The compounds were obtained efficiently by amine sulfonylation or click chemistry. Their ability to inhibit SARS-CoV-2 N 7-MTase was evaluated and the best inhibitors showed a submicromolar inhibitory activity against N 7-MTase nsp14.