Design, synthesis and structure-activity relationship of novel inhibitors against H5N1 hemagglutinin-mediated membrane fusion.
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 IC(50) 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 -CF(3) 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.
School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China.
Zhibo
Z
Zhu
Runming
R
Li
Gaokeng
G
Xiao
Zhipeng
Z
Chen
Jie
J
Yang
Qiuhua
Q
Zhu
Shuwen
S
Liu
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D017930:Genes, Reporter; D057809:HEK293 Cells; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D006801:Humans; D006859:Hydrogen / Q000737:chemistry; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D008156:Luciferases; D061985:Madin Darby Canine Kidney Cells; D008561:Membrane Fusion / Q000187:drug effects*; D010100:Oxygen / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014162:Transfection; D053586:Virus Internalization / Q000187:drug effects
C560737:3-fluoro-N-(2-(1-piperidinyl)ethyl)-5-(trifluoromethyl)benzamide; D000998:Antiviral Agents; D001549:Benzamides; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D010880:Piperidines; D006859:Hydrogen; D008156:Luciferases; D010100:Oxygen