Synthesis of acylguanidine zanamivir derivatives as neuraminidase inhibitors and the evaluation of their bio-activities

Article abstract of DOI:10.1039/c3ob40624e

A series of acylguanidine-modified zanamivir analogs were synthesized and their inhibitory activities against the NAs of avian influenza viruses (H1N1 and H3N2) were evaluated. In particular, zanamivir derivative 3j, with a hydrophobic naphthalene substituent, exhibits the best inhibitory activity against group-1 NA with an IC₅₀ of 20 nM. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40624e

Organic &
Biomolecular Chemistry
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Synthesis of acylguanidine zanamivir derivatives as
neuraminidase inhibitors and the evaluation of their
bio-activities†
Chien-Hung Lin,a Tsung-Che Chang,a Anindya Das,a Ming-Yu Fang,b
Hui-Chen Hung,b Kai-Cheng Hsu,c Jinn-Moon Yang,c Mark von Itzstein,d
Kwok Kong T. Mong,c Tsu-An Hsu*b and Chun-Cheng Lin*a
Cite this: Org. Biomol. Chem., 2013, 11,
3943
Received 28th March 2013,
Accepted 9th May 2013
DOI: 10.1039/c3ob40624e
www.rsc.org/obc
A series of acylguanidine-modified zanamivir analogs were syn- administered via nasal inhalation, have been developed and
thesized and their inhibitory activities against the NAs of avian are commercially available. However, the serious threat of
influenza viruses (H1N1 and H3N2) were evaluated. In particular, Tamiflu-resistant viruses5 increases the urgency of developing
zanamivir derivative 3j, with a hydrophobic naphthalene substitu- a new generation of anti-influenza NA inhibitors.6a–c
ent, exhibits the best inhibitory activity against group-1 NA with
an IC50 of 20 nM.
The analyses of the X-ray crystal structures of NAs have
revealed conformational differences among the subgroups
with respect to the 150-loop adjacent to the active site of NA:7
the group-1 NAs adopt an open 150-loop conformation with a
150-cavity near the active site, whereas the group-2 NAs show a
closed 150-loop. Moreover, molecular dynamics simulations
have suggested that the 150-loop and adjacent binding site
loops may be more flexible than observed in the crystal struc-
tures.8 In addition, recent evidence suggests that the 150-cavity
exists not only in group-1 NAs but also in group-2 NAs.9 These
findings clearly provide insights that may aid in the design of
new NA inhibitors that target the 150-cavity.
Previously, NA inhibitors were designed based on the tran-
sition state mimic of a hydrolyzed-sialic acid residue and the
structural information of the group-2 NAs.3,4 Since the discov-
ery of the 150-cavity near the active site of group-1 NAs,7 many
efforts have been made to target the newly found cavity by
extending the structures of the existing inhibitors by attaching
additional groups with a suitable shape, size, and hydrophobi-
city.10a–i In general, the amine or guanidine functional groups
of oseltamivir10a–d and zanamivir10e provide the chemical
foundation for the generation of compounds either by click
reaction or amide bond formation. Although several derivatives
have been proposed to access the 150-cavity based on compu-
tational methods,10a,c,d,i the synthetic derivatives seemed not
to maintain the same level of affinity for group-1 NAs as the
parent compounds did. For example, Mohan et al.10b employed
a click reaction to construct triazole derivatives at the C-3 posi-
tion of the similar structure of oseltamivir. However, the modi-
fication resulted in a decrease in the inhibition potency. In
addition, Wen et al.10e synthesized C-4 modified zanamivir
derivatives by employing N-alkylation, and the resulting deriva-
tives only showed inhibitory activities at the micromolar level.
Recently, von Itzstein et al.10f modified the well-known
Due to its rapid global spread, influenza is one of the most
widespread pandemic human diseases. Despite advances in
the understanding of the molecular and cellular aspects of
influenza, this disease affects millions of people, causing
serious public health and economic problems. The influenza
virus is an RNA virus of the Orthomyxoviridae family, and the
subtypes of influenza virus are classified based on the distinct
antigenic properties of two viral surface membrane glyco-
proteins, hemagglutinin (HA) and neuraminidase (NA). Both
glycoproteins are essential for virus infection, and there are
currently 17 HA (H1–H17) and 9 NA (N1–N9) serotypes of influ-
enza A virus circulating in the avian population.1a,b The NAs
are phylogenetically categorized into two groups: group 1 con-
tains the N1, N4, N5, and N8 subtypes, whereas group 2 con-
tains N2, N3, N6, N7, and N9.2 Furthermore, NA has been
targeted in the development of structure-based drug design
programs. As a result, two drugs, oseltamivir (1, Tamiflu),3 an
orally active NA inhibitor, and zanamivir (2, Relenza),4
aDepartment of Chemistry, National Tsing Hua University, 101, Section 2,
Kuang-Fu Road, Hsinchu 30013, Taiwan
bDivision of Biotechnology and Pharmaceutical Research, National Health Research
Institutes, 35, Keyan Road, Zhunan 35053, Taiwan
cDepartment of Biological Science and Technology and Applied Chemistry
Department, National Chiao Tung University, University Road, Hsinchu 30010,
Taiwan
dInstitute for Glycomics, Griffith University (Gold Coast Campus), Southport,
Queensland 4222, Australia. E-mail: cclin66@mx.nthu.edu.tw;
Fax: +886 3-571-1082
†Electronic supplementary information (ESI) available: Experimental details,
characterization data and NMR spectra for new compounds. See DOI:
10.1039/c3ob40624e
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neuraminidase inhibitor 5-acetamido-2,6-anhydro-3,5-dideoxy- such as EDC with HOBt or HBTU, HBTU with HOBt, and
D-glycero-D-galacto-non-2-enonic acid (Neu5Ac2en) at its C-3 ByBop, resulted in low yields. To circumvent this problem, as
position with a (p-tolyl)allyl group and demonstrated by X-ray illustrated in Scheme 1, the synthetic route was modified by
crystallography that the inhibitor locks the flexible 150-loop of first forming the acylguanidine derivative 5, followed by react-
group-1 NAs. Furthermore, these two synthesized derivatives ing this derivative with the corresponding amine 612 to give
exhibited the selective inhibition of group-1 NAs, including the N-acylated guanidine 7. Initially, the N-terminal region
the NAs of A/Hong Kong/156/97 (H5N1), A/California/07/2009 of 1H-pyrazole-1-carboximidamide (4),13
a guanidinylation
(H1N1), and A/Paris/0497/2007 (H1N1), over the group-2 NA reagent, was protected with Boc2O,14 followed by deprotona-
A/Paris/908/97 (H3N2). However, due to the lack of a guanidine tion using NaH and then acylation with N-hydroxysuccinimide-
group at the C-4 position of Neu5Ac2en, the activities of the activated acid to give 5 as a mixture of two stereoisomers.
synthesized compounds are far lower (Ki = 15.3 × 10−5 M) than Notably, the yields of the amide bond formation reaction were
that of zanamivir (Ki = 0.13 × 10−9 M) against the pandemic moderate (40–60%) due to the decomposition of the activated
2009 A/H1N1 influenza virus.
acid by NaH. In addition, the direct coupling of 4 with acid
However, a close examination of the crystal structure of the failed. The guanidinylation of 6 with 5 under slightly basic
zanamivir-bound group-1 NA revealed that the C-4 guanidino conditions in THF gave acylguanidine 7 (75–87%), which was
group of zanamivir is also located near the 150-cavity and can deprotected under acidic conditions (TFA in DCM) to afford
serve as a potential modification site in the design of group-1 compound 8 as a single isomer with an excellent yield. Finally,
NA-specific inhibitors. Inspired by these findings and the the hydrolysis of 8 with K2CO3 gave the zanamivir derivatives
identification of viruses less resistant to zanamivir, we modi- 3a–3ac (Table 1). However, when the acid was protected as the
fied the C-4 guanidino group of zanamivir and evaluated the methyl ester, in some cases (such as 3r), the hydrolysis of
activities of the derivatives against NAs. In contrast to the pre- the methyl ester resulted in a low yield due to the instability of
vious findings for zanamivir with an N-alkylated guanidino the acylguanidine group under strong basic conditions, and
group, the N-acylated zanamivir analogs (3 in Fig. 1) main- further attempts to improve the yield were unsuccessful (see
tained potent inhibitory effects.
Table S1†). Considering the potential instability of the acyl-
To synthesize the C-4 guanidino-modified zanamivir deriva- guanidine group,15 the methyl ester-protecting group in 6 was
tives 3, zanamivir 2 (Scheme 1) was prepared from sialic acid replaced with an ethyl ester, which has been demonstrated to
by following the reported procedures.11 The initial attempt to be much more labile than the former under basic deprotection
synthesize acylguanidines by the direct coupling of the guani- conditions.16 In addition, the release of ethanol is less toxic
dino group in zanamivir with acids using coupling reagents, in vivo, benefiting future prodrug development.17 Thus, full
deprotection was achieved by using molar equivalents of
K2CO3 in H2O–methanol (v/v = 1/4) at 0 °C (Table S1, entry 7†)
to afford the final products in 70–90% yields.
However, the amide bond formed at the guanidino group
may affect the ability of the guanidine to form hydrogen bonds
with the interacting amino acid residues of NA due to the elec-
tron-withdrawing property of the amide group. Thus, the
N-alkylated guanidino groups of zanamivir derivatives 14ad–14af
were synthesized to investigate the electronic effect of the gua-
Fig. 1 NA inhibitors of transition state and zanamivir derivatives.
nidine on H-bonding interactions. As shown in Scheme 2, the
synthesis of 14 was similar to that described in Scheme 1
except that Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-
sulfonyl)-protected thiourea (11) was used as a guanidine
precursor. Compound 11 was obtained by reacting
tetrabutylammonium thiocyanate [(n-Bu)4NSCN] with PbfCl,
followed by the addition of an amine.18 Finally, the guanidine
was formed by coupling thiourea 11 with 6 in the presence of
EDC and DIEPA19 to afford 12. The removal of the Pbf group
under acidic conditions (TFA–DCM) was followed by the hydro-
lysis of the ethyl ester under basic conditions (K2CO3–EtOH) to
yield the N-alkylated guanidino group on zanamivir, derivative
14, in 73–88% yield.
The inhibitory activities of synthetic compounds 3a–3ac
and 14ad–14af against the H1N1 and H3N2 NAs were evalu-
ated, and the results are shown in Table 1. In our assay, zana-
Scheme 1 Synthesis of acylated zanamivir derivatives by modifying the guani-
dino group of zanamivir. Reagents and conditions: (a) Boc2O, DIPEA, DCM, DMF,
mivir, with an IC50 of 0.74 0.03 nM, was used as a positive
control. The results indicate that the amide derivatives
rt, 95%; (b) NaH, RCOOSuc, DCM, rt, 40–60%; (c) 6, Et3N, THF, rt, 75%–87%;
(d) TFA, DCM, rt, 95%; (e) K2CO3, EtOH, H2O, rt, 70–90%.
3944 | Org. Biomol. Chem., 2013, 11, 3943–3948
This journal is © The Royal Society of Chemistry 2013

Table 1 Inhibitory activities of novel zanamivir derivatives against group-1 (H1N1) and group-2 (H3N2) neuraminidases
H1N1
IC50 (nM)
H3N2
IC50 (nM)
H1N1
IC50 (nM)
H3N2
IC50 (nM)
H1N1
IC50 (nM)
H3N2
IC50 (nM)
Compd
Relenza
R
Compd
R
Compd
R
0.74 0.03
3k
275
1
334 63
3v
421
9
399
1
3a
3b
>1000
>1000
>1000
>1000
3l
203 10
189
234
211
7
6
3w
3x
180
397
9
1
173
472
2
4
3m
5
3c
152
3
147
9
3n
3o
462 60
606 17
205 27
3y
3z
260 21
293 23
421 72
3d
>4000
>4000
196
2
360
3
3e
3f
46.1 0.4
54.9 0.5
44.9 2.7
58.3 0.6
3p
3q
134 17
332 22
134 16
472 31
3aa
3ab
775 16
541 24
868 38
615 20
3g
3h
3i
98.3 2.9
209 18
74.9 0.8
84.4 8.9
243 13
66.9 0.5
3r
3s
3t
176 10
1200 10
160 13
209
8
3ac
203
1
196
1
1400 14
14ad
14ae
39 400 1400
34 644 2786
29 600 1100
38 303 859
182
1
3j
20.1 0.7
25.5 1.0
3u
239 16
337 20
14af
>40 000 (43%)
>40 000 (35%)

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Fig. 2 Structures and inhibition activities of zanamivir and its derivatives.
Scheme 2 Synthesis of N-alkylated zanamivir derivatives by modifying the
guanidino group of zanamivir. Reagents and conditions: (a) (n-Bu)4NSCN, DCM,
rt, 60%; (b) R-NH2, DCM, rt 78%; (c) 6, EDC, DIPEA, DCM, rt, 65%–83%; (d) TFA,
DCM, rt, 70%–83%; (e) K2CO3, EtOH, H2O, rt, 73–88%.
participate in an interaction that contributes to the observed
inhibitory activities against the neuraminidase of group-2
influenza viruses. Although the 150-loop of the N2 neuramini-
dase has the closed form, the inhibitor may induce a confor-
mational change in the 150-loop, yielding the open form,
when it interacts with NA.7
In addition, the N-alkylated zanamivir analogs, such as
14ad, 14ae, and 14af, show very low inhibitory activities for N1
(IC50 > 30 μM), similar to a previous observation.10e Interest-
ingly, the N-alkylated zanamivir analog 14ad exhibits more
than 200-fold lower potency relative to acyl zanamivir analogs,
such as 3m (Fig. 2). These results clearly indicate that the
change in the electronic properties of the guanidium moiety
affects the binding affinity and that the carbonyl function of
the acylguanidino group has a prominent role in the NA
inhibitory activity.
To better understand the effect of a carbonyl group at the
acylguanidino group on activity, computer docking studies of
the inhibitors with NA were performed (Fig. 3). GEMDOCK20
was employed to predict the docked conformations of the
inhibitors in the binding cavity of H1N1 neuraminidase based
on calculated binding energies. The 3D structures of the
inhibitors were generated using ACD/ChemSketch, and the
open-form crystal structure of H1N1 neuraminidase (PDB code
3BEQ) was selected for the docking procedure. The binding
site of NA was defined to include the residues within a 10 Å
radius sphere centered around the 150-loop (residues 147–152)
of the H1N1 neuraminidase. The simulation for compound 3j
clearly shows that the hydrophobic substituent of the guani-
dine interacts with the 150-cavity, as shown in Fig. 3A. In
addition, to avoid the steric hindrance involving the Asp151
residue of NA generated by the modification of the guanidine,
the docking conformation of compound 3j is slightly different
from the docking mode of zanamivir, as shown in Fig. 3B and
3D. The carboxylic acid of zanamivir forms an H-bond with
residue Arg118 of NA, but in 3j, Arg118 interacts with the car-
bonyl group of the amide of the guanidine moiety. In addition,
the guanidine of zanamivir forms six hydrogen bonds with the
residues Glu119 and Asp151, and the carboxylic acid of zana-
mivir forms five hydrogen bonds with the residues Arg118,
Arg292, and Arg371. However, the total number of hydrogen
bonds generated by the same groups as above is reduced to
seven in the interaction between 3j with NA. The acylguanidine
of 3j forms three hydrogen bonds with the Arg118 and Asp151
(3a–3ac) are, in general, more potent inhibitors than the N-
alkylated derivatives (14ad–14af) but are slightly less active
than the parent compound, zanamivir. Although the inhibitory
activity gradually decreased with increasing alkyl chain length
in the arylguanidine groups (3e, 3l, 3y, and 3z), compound
3ac, with the longest alkyl chain tested, still maintained inhibi-
tory activity, with an IC50 of 203 nM. This result may be due to
the increased flexibility of the benzene ring, allowing it to fit
into the 150-cavity, when the linker is longer. Notably, the
activity seems to be reduced in the absence of a linker between
the aromatic ring and the acylguanidine (3a, 3b, and 3d).
However, the presence of a strong electron-withdrawing group
(NO2) on the aromatic ring of 3c shows an intricate effect on
the enhancement of the inhibitory activity (3c vs. 3a and 3d).
Moreover, the inhibitory activity is significantly enhanced to
46.1 nM by introducing a methylene unit between the acyl-
guanidine and aromatic ring (3e vs. 3a). Although the potency of
inhibition decreases slightly to 54.9 nM with the incorporation
of a more hydrophobic naphthalene group (3f), compound 3j,
with an internal S atom, is the most potent NA inhibitor (IC50
= 20.1 nM) among those tested in this study. The results show
that the heteroatom, S, in the internal chain and the hydro-
phobic naphthalene group are important factors to increase
the inhibitory activity (3i vs. 3j, 3l vs. 3m, and 3i vs. 3l).
Although the heteroatom located at the ortho position of an
aromatic ring can increase the inhibitory activity (3p), the
steric hindrance imposed would likely decrease the inhibitory
activity, as for 3e vs. 3h and 3l vs. 3n–3q. Substituents at the
other positions (3t and 3u) of the benzene ring or the replace-
ment of benzene with acyclic substituents (3aa–3ab) or other
carbocyclic analogs (3s and 3x) only produce moderate inhibi-
tory activities. In addition, the replacement of the benzene
ring (3y) with cyclohexane (3x) results in a decrease in the inhi-
bition potency.
To further investigate whether the synthesized inhibitors
exhibit selectivity among the different NA subgroups, the
activities of the inhibitors against the H3N2 NA were evaluated.
The results indicate that the zanamivir analogs show inhibi-
tory activities against N2 that are similar to those against N1
(Table 1), although the activity against N2 is lower. Therefore,
the acylguanidium moiety of the zanamivir analogs may also
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may provide an overall advantage of a better oral bioavailability
due to the improved hydrophobicity of zanamivir resulting
from the addition of hydrophobic groups at its guanidine site.
Finally, we anticipate that these findings may provide new
insight that will aid in the development of a new generation of
anti-influenza drugs.
The research was supported by the National Tsing Hua Uni-
versity, the National Health Research Institutes, the National
Chiao Tung University and the National Science Council in
Taiwan.
Notes and references
Fig. 3 Computational conformations of the compounds in the open-form of
H1N1 neuraminidase. Molecular surface of N1 neuraminidase with bound
compound 3j (A) and the docking results of compounds 3j (B), 14ad (C), and
zanamivir (D) with neuraminidase in the open form with carbon atoms of inhibitor
in cyancolor and protein carbons in light blue color. Oxygen and nitrogen atoms
are red and blue, respectively. Hydrogen bonds between the compounds and
the protein are represented by green dotted lines.
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