The synthesis and antiviral activity of a series of novel polycyclic analogues of the orthopoxvirus egress inhibitor tecovirimat (ST‐246) is presented. Several of these compounds display sub‐micromolar activity against vaccinia virus, and were more potent than cidofovir (CDV). The more active compounds were about 10‐fold more active than CDV, with minimum cytotoxic concentrations above 100 μm. Chemical manipulations of the two carbon–carbon double bonds present in the compounds were carried out to further explore the structure–activity relationships of these new polycyclic imides. Hydrogenation of the two carbon–carbon double bonds decreases antiviral activity, whereas either cyclopropanation or epoxidation of the double bonds fully eliminates the antiviral activity.
Polycyclic N‐Benzamido Imides with Potent Activity against Vaccinia Virus