posted on 2020-02-28, 14:35authored byJimin Xu, Judith Berastegui-Cabrera, Haiying Chen, Jerónimo Pachón, Jia Zhou, Javier Sánchez-Céspedes
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.