tetano
Editor, Senior Moderator
Eur J Med Chem. 2020 Jan 11;189:112048. doi: 10.1016/j.ejmech.2020.112048. [Epub ahead of print] [h=1]Synthesis and SARs of dopamine derivatives as potential inhibitors of influenza virus PA[SUB]N[/SUB] endonuclease.[/h]
Liao Y[SUP]1[/SUP], Ye Y[SUP]2[/SUP], Li S[SUP]3[/SUP], Zhuang Y[SUP]4[/SUP], Chen L[SUP]4[/SUP], Chen J[SUP]5[/SUP], Cui Z[SUP]6[/SUP], Huo L[SUP]4[/SUP], Liu S[SUP]7[/SUP], Song G[SUP]8[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Currently, influenza PA[SUB]N[/SUB] endonuclease has become an attractive target for development of new drugs to treat influenza infections. Herein we report the discovery of new PA[SUB]N[/SUB] endonuclease inhibitors derived from a chelating agent dopamine moiety. A series of dopamine amide derivatives and their conformationally constrained 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based analogs were elaborated and assayed against influenza virus A/WSN/33 (H1N1). Most compounds exhibited moderate to excellent antiviral activities, generating a preliminary SARs. Among them, compounds 14 and 19 showed stronger anti-IAV activity compared with the reference Peramivir. Moreover, 14 and 19 demonstrated a concentration-dependent inhibition of PA[SUB]N[/SUB] endonuclease based on both FRET assay and SPR assay. Docking studies were also performed to elucidate the binding mode of 14 and 19 with the PA[SUB]N[/SUB] protein and to identify amino acids involved in their mechanism of action, which were well consistent with the biological data. This finding was beneficial to laying the foundation for the rational development of more effective PA[SUB]N[/SUB] endonuclease inhibitors.
Copyright ? 2020 Elsevier Masson SAS. All rights reserved.
[h=4]KEYWORDS:[/h] Influenza a virus; PA(N) endonuclease inhibitors; Polyphenols; SARs
PMID: 31954881 DOI: 10.1016/j.ejmech.2020.112048
Liao Y[SUP]1[/SUP], Ye Y[SUP]2[/SUP], Li S[SUP]3[/SUP], Zhuang Y[SUP]4[/SUP], Chen L[SUP]4[/SUP], Chen J[SUP]5[/SUP], Cui Z[SUP]6[/SUP], Huo L[SUP]4[/SUP], Liu S[SUP]7[/SUP], Song G[SUP]8[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Currently, influenza PA[SUB]N[/SUB] endonuclease has become an attractive target for development of new drugs to treat influenza infections. Herein we report the discovery of new PA[SUB]N[/SUB] endonuclease inhibitors derived from a chelating agent dopamine moiety. A series of dopamine amide derivatives and their conformationally constrained 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based analogs were elaborated and assayed against influenza virus A/WSN/33 (H1N1). Most compounds exhibited moderate to excellent antiviral activities, generating a preliminary SARs. Among them, compounds 14 and 19 showed stronger anti-IAV activity compared with the reference Peramivir. Moreover, 14 and 19 demonstrated a concentration-dependent inhibition of PA[SUB]N[/SUB] endonuclease based on both FRET assay and SPR assay. Docking studies were also performed to elucidate the binding mode of 14 and 19 with the PA[SUB]N[/SUB] protein and to identify amino acids involved in their mechanism of action, which were well consistent with the biological data. This finding was beneficial to laying the foundation for the rational development of more effective PA[SUB]N[/SUB] endonuclease inhibitors.
Copyright ? 2020 Elsevier Masson SAS. All rights reserved.
[h=4]KEYWORDS:[/h] Influenza a virus; PA(N) endonuclease inhibitors; Polyphenols; SARs
PMID: 31954881 DOI: 10.1016/j.ejmech.2020.112048