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New pseudodimeric aurones as palm pocket inhibitors of Hepatitis C virus RNA-dependent RNA polymerase.

Abstract：

:The NS5B RNA-dependent RNA polymerase (RdRp) is a key enzyme for Hepatitis C Virus (HCV) replication. In addition to the catalytic site, this enzyme is characterized by the presence of at least four allosteric pockets making it an interesting target for development of inhibitors as potential anti-HCV drugs. Based on a previous study showing the potential of the naturally occurring aurones as inhibitors of NS5B, we pursued our efforts to focus on pseudodimeric aurones that have never been investigated so far. Hence, 14 original compounds characterized by the presence of a spacer between the benzofuranone moieties were synthesized and investigated as HCV RdRp inhibitors by means of an in vitro assay. The most active inhibitor, pseudodimeric aurone 4, induced high inhibition activity (IC50 = 1.3 μM). Mutagenic and molecular modeling studies reveal that the binding site for the most active derivatives probably is the palm pocket I instead of the thumb pocket I as for the monomeric derivatives.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Meguellati A,Ahmed-Belkacem A,Nurisso A,Yi W,Brillet R,Berqouch N,Chavoutier L,Fortuné A,Pawlotsky JM,Boumendjel A,Peuchmaur M

doi

10.1016/j.ejmech.2016.03.005

subject

Has Abstract

pub_date

2016-06-10 00:00:00

pages

217-29

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(16)30179-9

journal_volume

115

pub_type

杂志文章

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