Structure-Activity Relationship Studies on Diversified Salicylamide Derivatives As Potent Inhibitors of Human Adenovirus Infection

The effective treatment of adenovirus (HAdV) infections in immunocompromised patients still poses great challenges. Herein, we reported our continued efforts to optimize a series of salicylamide derivatives as potent inhibitors of HAdV infection. Of these, nine compounds (, , , , , , , , and ) showed significantly improved anti-HAdV activities with nanomolar to submicromolar IC values and high selectivity indexes (SI > 100), indicating better safety windows, compared to those of the lead compound niclosamide. Our mechanistic assays suggest that compounds , , and exert their activities in the HAdV entry pathway, while compounds and likely target the HAdV DNA replication, and , and inhibit later steps after DNA replication. Given the broad anti-viral activity profile of niclosamide, these derivatives may also offer therapeutic potential for other viral infections.