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 (11,?13,?14,?17,?20,?58,?60,?62, and?70) showed significantly improved anti-HAdV activities with nanomolar to submicromolar IC50?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?13,?62, and?70?exert their activities in the HAdV entry pathway, while compounds?14?and?60?likely target the HAdV DNA replication, and?11, 17, 20, and?58?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.