Substituted N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues potently inhibit respiratory syncytial virus (RSV) replication and RSV infection-associated inflammatory responses.

[Display omitted] • A series of 5-chloro-2-hydroxybenzamides was discovered as potent RSV inhibitors. • Several molecules suppressed both RSV viral replication and associated cytokines. • Two selected compounds inhibited RSV-induced IRF3 and NF-κB activation. • These potential anti-inflammatory agents may alleviate RSV-associated symptoms. Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children, and specific treatment for RSV infections remains unavailable. We herein reported a series of substituted N -(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent RSV inhibitors. Among them, six low cytotoxic compounds (11 , 12 , 15 , 22 , 26, and 28) have been identified and selected to study associated inhibitory mechanisms. All these compounds suppressed not only the viral replication but also RSV-induced IRF3 and NF-κB activation and associated production of cytokines/chemokines. The two most potent compounds (15 and 22) were selected for further molecular mechanism studies associated with their suppression effect on RSV-activated IRF3 and NF-κB. These two compounds decreased RSV-induced IRF3 phosphorylation at serine 396 and p65 phosphorylation at serine 536 at both early and late infection phases. In addition, compound 22 also inhibited RSV-induced p65 phosphorylation at serine 276 at the late phase of RSV infection. [ABSTRACT FROM AUTHOR]