Bioorganic & Medicinal Chemistry Letters
Caffeic acid derivatives: A new type of influenza neuraminidase
inhibitors
Yuanchao Xie a, Bing Huang b, Kexiang Yu b, Fangyuan Shi a, Tianqi Liu a, Wenfang Xu a,
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a Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, PR China
b Institute of Poultry Science, Shandong Academy of Agricultural Sciences, 1 Jiaoxiao Road, Jinan, Shandong 250023, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 January 2013
Revised 9 April 2013
Accepted 13 April 2013
Available online 22 April 2013
Recently, many natural products, especially some plant-derived polyphenols have been found to exert
antiviral effects against influenza virus and show inhibitory activities on neuraminidases (NAs). In our
research, we took caffeic acid which contained two phenolic hydroxyl groups as the basic fragment to
build a small compound library with various structures. The enzyme inhibition result indicated that some
compounds exhibited moderate activities against NA and compound 15d was the best with IC50 = 7.2
and 8.5 M against N2 and N1 NAs, respectively. The 3,4-dihydroxyphenyl group from caffeic acid was
important for the activity according to the docking analysis. Besides, compound 15d was found to be a
non-competitive inhibitor with Ki = 11.5 0.25 M by the kinetic study and also presented anti-influenza
lM
l
Keywords:
Influenza
Neuraminidase
Amino acid
Caffeic acid
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virus activity in chicken embryo fibroblast cells. It seemed promising to discover more potent NA inhib-
itors from caffeic acid derivatives to cope with influenza virus.
Ó 2013 Elsevier Ltd. All rights reserved.
Influenza virus, especially the highly pathogenic avian influenza
A (H5N1) virus is a great threat to human. In recent years, the
worldwide spread of H5N1 avian influenza virus in birds and the
increasing cases of bird-to-human transmission get heightened
concern. The viral surface protein, neuraminidase (NA) plays an
important role in the life cycle of influenza virus and has been dis-
covered as an important target for anti-influenza drugs design.
Oseltamivir, one kind of NA inhibitors is currently the first line de-
fense drug against influenza. However, more and more influenza
virus strains are resistant to oseltamivir, such as the seasonal
H1N1 viruses1 and avian H5N1 strains.2 In 2009, peramivir was ur-
gently authorized in America to cope with the novel swine-origin
H1N1 (A) influenza virus that was also resistant to oseltamivir.
At present, this drug has been approved in many countries, but it
is mainly administered intravenously, which is very inconvenient
for patients.
the NA activity by binding on some other sites of the enzyme,
rather than the catalytic center.
Caffeic acid, which is abundant in nature has a variety of poten-
tial pharmacological effects in vitro and in vivo, such as anti-
inflammatory, anti-cancer and antiviral activities.5 Some natural
products containing the fragment of caffeic acid, like chlorogenic
acid and its analogue also show inhibitory activities against influ-
enza NAs.6 A simple compound, caffeic acid phenethyl ester (CAPE,
Fig. 2) is found to have anti-mitogenic, anti-carcinogenic, anti-
inflammatory and especially anti-influenza virus properties
in vitro.7 In 2012, Liu et al. reported some novel dual-targeted
bifunctional zanamivir anti-influenza drugs formed by conjugation
of zanamivir with caffeic acid for simultaneous inhibition of influ-
enza virus NA and suppression of pro-inflammatory cytokine.
These conjugates provided remarkable protection of cells and mice
against influenza infections.8
According to recent studies, it seems hard to discover novel NA
inhibitors which would be better than oseltamivir simply based on
the NA active site. However, many natural products, especially
some small plant-derived polyphenols have been found to exert
antiviral effects against influenza virus and show inhibitory activ-
ities on NAs (Fig. 1).3,4 Unlike the classical ones, the structures of
these compounds are various and interestingly, most of them act
as noncompetitive NA inhibitors, indicating that they likely inhibit
Till now, except some natural products, there are no synthetic
compounds designed to target influenza NA based on caffeic acid.
Therefore, in our study, we took caffeic acid as the basic fragment
to design and synthesize a small compound library of caffeic acid
derivatives. Through determining the inhibitory effects on the N1
and N2 NAs of influenza virus, we discovered a new kind of NA
inhibitors with better activities than the natural products.
Compounds were synthesized using methods presented in
Schemes 1–3. Scheme 1 presented the synthesis of compounds
3a–3f. In order to increase the yields of target compounds, caffeic
acid was first acetylated to give (E)-3-(3,4-diacetoxyphenyl)acrylic
acid (compound 1) that had a relatively better solubility in
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0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.