Design, synthesis and structure–activity relationship of novel inhibitors against H5N1 hemagglutinin-mediated membrane fusion

Abstract

We reported previously that a small molecule named CL-385319 could inhibit H5N1 influenza virus infection by targeting hemagglutinin, the envelope protein mediating virus entry. In the present study, a novel series of derivatives focused on the structural variation of CL-385319 were synthesized as specific inhibitors against the H5 subtype of influenza A viruses. These small molecules inhibited the low pH-induced conformational change of hemagglutinin, thereby blocking viral entry into host cells. Compound 1l was the most active inhibitor in this series with an IC50 of 0.22 μM. The structure–activity relationships analysis of these compounds showed that the 3-fluoro-5-(trifluoromethyl)benzamide moiety was very important for activity, and the –F group was a better substituent group than –CF3 group in the phenyl ring. The inhibitory activity was sensitive to the benzamide because the oxygen and hydrogen of the amide served as H-bond acceptor and donor, respectively.