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Phenyl substituted 3-hydroxypyridin-2(1H)-ones: inhibitors of influenza A endonuclease.

Abstract：

:Inhibition of the endonuclease activity of influenza RNA-dependent RNA polymerase is recognized as an attractive target for the development of new agents for the treatment of influenza infection. Our earlier study employing small molecule fragment screening using a high-resolution crystal form of pandemic 2009 H1N1 influenza A endonuclease domain (PAN) resulted in the identification of 5-chloro-3-hydroxypyridin-2(1H)-one as a bimetal chelating ligand at the active site of the enzyme. In the present study, several phenyl substituted 3-hydroxypyridin-2(1H)-one compounds were synthesized and evaluated for their ability to inhibit the endonuclease activity as measured by a high-throughput fluorescence assay. Two of the more potent compounds in this series, 16 and 18, had IC50 values of 11 and 23nM in the enzymatic assay, respectively. Crystal structures revealed that these compounds had distinct binding modes that chelate the two active site metal ions (M1 and M2) using only two chelating groups. The SAR and the binding mode of these 3-hydroxypyridin-2-ones provide a basis for developing a new class of anti-influenza drugs.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Parhi AK,Xiang A,Bauman JD,Patel D,Vijayan RS,Das K,Arnold E,Lavoie EJ

doi

10.1016/j.bmc.2013.08.053

subject

Has Abstract

pub_date

2013-11-01 00:00:00

pages

6435-46

issue

21

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(13)00756-6

journal_volume

21

pub_type

杂志文章

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