Synthesis and antienteroviral activity of a series of novel, oxime ether-containing pyridyl imidazolidinones

Article abstract of DOI:10.1016/j.bmcl.2004.07.084

A series of pyridyl imidazolidinones were synthesized and their antiviral activity was evaluated in a plaque reduction assay. It was found that the pyridyl imidazolidinone with an ethyl oxime ether functionality, 8b, exhibited extremely high activity against human enterovirus 71.

Full text of DOI:10.1016/j.bmcl.2004.07.084

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5051–5056
Synthesis and antienteroviral activity of a series of novel,
oxime ether-containing pyridyl imidazolidinones
a
a
a
Jyh-Haur Chern,a, Chung-Chi Lee, Chih-Shiang Chang, Yen-Chun Lee,
*
Chia-Liang Tai,a Ying-Ting Lin,a Kak-Shan Shia,a Ching-Yin Leeb and Shin-Ru Shihb,
*
aDivision of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 9F, 161, Sec.6, Min-Chiuan East Road,
Taipei 114, Taiwan, ROC
bSchool of Medical Technology, Chang Gung University, Taoyuan 333, Taiwan, ROC
Received 27 May 2004;accepted 31 July 2004
Available online 27 August 2004
Abstract—A series of novel, oxime ether-containing pyridyl imidazolidinones were synthesized and their antiviral activity was eval-
uated in a plaque reduction assay. It is very interesting that this class of compounds is specific for human enteroviruses, in particular,
enterovirus 71 (EV71). Some derivatives strongly inhibited enterovirus replication with activities higher or comparable to those of
the reference compounds such as A1 and A2. Preliminary SAR studies revealed that the chain length of the alkyl linker and the alkyl
substituent at the oxime ether group largely influenced the in vitro anti-EV71 activity of this new class of potent antiviral agents.
Among this series of compounds synthesized, the pyridyl imidazolidinone with an ethyl oxime ether group located at the para
position of the phenoxyl ring (8b) was identified as the most potent enterovirus 71 inhibitor (IC50 = 0.001lM) with no apparent
cytotoxic effect toward RD (rhabdomyosarcoma) cell lines (CC50 > 25lM). Furthermore, this compound has been shown broad-
spectrum activity against most of the serotypes of enteroviruses tested in the nanomolar range.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
can be lethal and life threatening, with high risk for mor-
bidity and mortality. Many epidemic outbreaks have
been reported from Asian countries.5 A major outbreak
of EV71 infection in Taiwan in 1998 caused many severe
cases and 78 deaths.6 This highlights the urgency and
significance for developing anti-EV71 agents.
Enterovirus 71 (EV71) was first recognized in 1969 in
California, USA, when it was isolated from the feces
of an infant suffering from encephalitis.1 EV71 belongs
to the human enterovirus A species of the Enterovirus
genus within the family of Picornaviridae.2 Virions con-
sist of a nonenveloped capsid surrounding a core of sin-
gle-stranded, positive-polarity RNA approximately
7.5kb in size. The viral capsid is icosahedral in symme-
try and is composed of 60 identical units each consisting
of the four structural proteins VP1–VP4. The complete
nucleotide sequence of the EV71 prototype strain BrCr
has been determined.3 Symptoms for EV71 infections
range from nonspecific upper respiratory infection
and mild fever to central nervous system infections par-
ticularly viral meningitis, encephalitis, and severe myo-
carditis.4 Children are considered to be relatively
immunodeficient, therefore EV71 infections of neonates
In 1966, a novel antienteroviral agent, pleconaril (Fig.
1), was made available for treatment of life threatening
enteroviral infections, such as meningitis, encephalitis,
myocarditis.7 It is under development by Viropharma,
Inc. for the treatment of severe enteroviral infection in
phase 2 clinical trials. Unfortunately, pleconaril has
been found to have limited activity against EV71 at con-
centrations tested in vitro.
In our laboratory, many structurally related pyridyl
imidazolidinones were recently found to have strong
activity against EV71.8 SAR studies demonstrated that
an aryl substituent at the para position of the phenoxyl
ring and a pyridine-containing imidazolidinone are key
structural requirements for anti-EV71 activity. Previ-
ously, we reported that the biphenyl analogues A1 and
A2 (Fig. 1) with either a phenyl or 4-chlorophenyl
Keyword: Enterovirus.
*
Corresponding authors. Tel.: +886 2 2653 4401x6573;fax: +886 2
2792 9703 (J.-H.C.);e-mail: jhchen@nhri.org.tw
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.07.084

5052
J.-H. Chern et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5051–5056
H C
3
X
CH
3
N
O
O
O
N
N
N
O
N
H C
3
CF
3
N
O
Pleconaril
A1: X = H
A2: X = Cl
R1
R1
O
R2
N
N
N
(CH2)n
O
OR3
N
B
Figure 1. Structures of pleconaril, pyridyl imidazolidinones A1, A2, and B.
moieties at the para position bestowed the best potency
to this class of compounds.8
intermediate in 80% yield. Subsequent intramolecular
cyclization of intermediate by treatment with sodium
hydride in the THF/DMF (1:1) cosolvent system at
room temperature resulted in the formation of cyclic
urea 1 in quantitative yield.
As part of our continuous efforts toward the identifica-
tion of more potent broad-spectrum antienteroviral
agents, a series of novel, oxime ether-containing pyridyl
imidazolidinones B (Fig. 1) were synthesized and as-
sayed for antiviral activity against EV71.9 Some deriva-
tives have shown significant improvement in potency
relative to the reference compounds A1 and A2 as well
as broad-spectrum activity against a variety of entero-
virus serotypes. Details of this investigation will be
described herein.
The oxime ether derivatives 8a–j were prepared by the
method summarized in Scheme 2. Mitsunobu reaction10
of the alcohol 2 with N-hydroxyphthalimide in the pres-
ence of diethyl azodicarboxylate and triphenylphos-
phine at room temperature gave N-alkoxyphthalimide
3. Subsequent Ing–Manske reaction11 of compound 3
with hydrazine followed by acidification with anhydrous
ethereal hydrogen chloride afforded the corresponding
alkoxyamine hydrochloride 4.12 Aldehyde (or ketone)
5 was condensed with the above key intermediate 4 in
aqueous solution with the aid of sodium acetate to give
compound 6 in moderate yields. Nucleophilic substitu-
tion of compound 6 with 1,5-dibromopentane using
potassium carbonate as a base in 1-methyl-2-pyrrolidi-
none (NMP) at refluxing temperature afforded
compound 7. Subsequent N-alkylation of 1-(4-pyridyl)-
2-imidazolidinone 1 with compound 7 in the presence
of sodium hydride in DMF gave the desired compounds
8a–j in excellent yields.
2. Results and discussion
In this paper, we describe the synthesis of the novel anti-
viral pyridyl imidazolidinones 8a–j and 11a–d via the
key nucleophilic substitution of 1-(4-pyridyl)-2-imidazol-
idinone 18 with various oxime ether-containing alkylat-
ing agents 7 and 10 (Schemes 1–3). All the resulting
compounds were then submitted for anti-EV71 testing
as well as cytotoxicity evaluation in the RD cell lines.
Preliminary structure–activity relationships against
EV71 are reported (Table 1). In all cases examined,
the ethyl oxime ether 8b was selected for further evalua-
tion against a variety of viruses since it appeared to dem-
onstrate excellent activity against EV71. The results of
this biological evaluation are illustrated in Table 2.
Variation in the length of the connecting chain was
accomplished according to Scheme 3. This procedure
was used for the preparation of the oxime ethers
11a–d. The key intermediate, 4-hydroxybenzaldehyde-
O-ethyloxime, was obtained in 90% yield by treating 4-
hydroxybenzaldehyde with ethoxyamine hydrochloride
and sodium acetate in aqueous solution. In the presence
of potassium carbonate, 4-hydroxybenzaldehyde-O-eth-
yloxime can undergo nucleophilic substitution with di-
bromo compound 9 to give compound 10. Subsequent
2.1. Chemistry
For the preparation of 1-(4-pyridyl)-2-imidazolidinone 1
(Scheme 1), 4-aminopyridine was first coupled with 2-
chloroethylisocyanate to give the corresponding urea
O
O
NaH
toluene
Cl
N
NH
NCO
N
N
NH2
N
H
N
H
N
+
Cl
DMF / THF
r.t., 4 h
r.t.,5 h
1
Scheme 1. Synthesis of 1-{4-pyridyl}-2-imidazolidinone 1.

J.-H. Chern et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5051–5056
5053
O
O
O
C
O
C
THF
+
+
(C H ) P
R OH
3
HO
+
N
6
5 3
R O
N
3
C H O
N N
OC H
2 5
2
5
r.t., 24 h
O
O
2
3
H NNH
anhydrous ethereal HCl
r.t., 1 h
2
2
R ONH Cl
3
3
ethanol, reflux, 1 h
4
OR
1
O
R
2
R
N
2
R
1
R ONH Cl
K CO , KI, Br(CH ) Br
R
N
1
3
2
3
2 5
2
Br
(CH2)5
O
NaOAc, H O
°
C
OR
3
NMP, 90 , 3 h
R
R
1
2
1
R
1
R
1
R
1
OH
80 ° , 2 h
C
OH
6
7
5
R
1
8a. R1 = H, R2 = H, R3 = CH3
8b. R1 = H, R2 = H, R3 = C2H5
8c. R1 = H, R2 = H, R3 = n-C3H7
8d. R1 = H, R2 = H, R3 = n-C4H9
8e. R1 = H, R2 = CH3, R3 = C2H5
8f. R1 = H, R2 = C2H5, R3 = C2H5
O
NaH, 1
DMF, r.t., overnight
R
2
N
N
N
(CH2)5
O
N
OR
3
R
1
8g. R1 = H, R2 = n-C3H7, R3 = C2H5
8h. R1 = CH3, R2 = H, R3 = CH3
8i. R1 = CH3, R2 = H, R3 = C2H5
8j. R1 = CH3, R2 = H, R3 = n-C3H7
Scheme 2. General synthetic route to oxime ethers 8a–j.
OC H
2
5
N
K CO , KI
2
3
Br(CH ) Br
2 n
(CH2)n
Br
O
+
°
C
, 3h
NMP, 90
N
OC H
2 5
10
OH
9
O
NaH,
DMF, r.t., overnight
1
N
N
N
(CH2)n
O
N
OC H
2 5
11a. n = 3
11b. n = 4
11c. n = 6
11d. n = 7
Scheme 3. General synthetic route to oxime ethers 11a–d.
N-alkylation of 1-(4-pyridyl)-2-imidazolidinone 1 with
compound 10 in the presence of sodium hydride in
DMF provided the desired compounds 11a–d in excel-
lent yields. All the new oxime ether derivatives were
anti-EV71 testing as well as cytotoxicity evaluation in
the RD cell lines. The results are shown in Table 1
and are compared to the reference compounds A1 and
bf A2. Replacement of the phenyl group at the para posi-
tion of the phenoxyl ring of A1 and A2 with a methyl
oxime ether (8a) resulted in a sixfold improvement in
activity against EV71. It is very interesting to note that
compound 8a exhibited excellent activity against EV71
(IC50 = 0.005lM) with no cytotoxicity up to the concen-
tration of 25lM. These significant results demonstrated
that the O-substituted oxime ether moiety of the pyridyl
imidazolidinones seem to play a very important role in
enhancing the anti-EV71 activity. This effect might be
due to their drastically conformational change and steric
requirement at the para position of the phenoxyl ring.
1
characterized by H NMR and ES mass spectra.13
According to previous literature report, we have as-
signed this series of compounds as the trans or E stereo-
1
isomer forms of the oxime ether by H NMR spectra.14
3. Bioactivity
The oxime ether derivatives described herein were tested
in a plaque reduction assay9 under a standard proce-
dure. Compounds 8a–j and 11a–d were submitted for

5054
J.-H. Chern et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5051–5056
Table 1. Anti-EV71 activity and cytotoxicity for compounds 8a–j and 11a–d
R1
N
O
R2
N
R3
N
N
(CH2)n
O
O
R1
Compound
n
R1
R2
R3
IC50 (lM)a EV71c
CC50 (lM)b RDd
8a
8b
8c
5
H
H
H
H
H
CH3
0.005 0.001
0.001 0.001
0.021 0.003
0.079 0.019
16.85 0.65
1.08 0.17
0.65 0.03
0.80 0.11
0.36 0.08
>25
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>12.5
>6.25
>12.5
>12.5
>12.5
>6.25
>12.5
>12.5
5
H
C2H5
n-C3H7
n-C4H9
C2H5
C2H5
C2H5
CH3
5
H
8d
8e
5
H
5
H
CH3
C2H5
8f
5
H
8g
8h
8i
5
H
n-C3H7
H
5
CH3
CH3
CH3
H
5
H
C2H5
n-C3H7
C2H5
C2H5
C2H5
C2H5
––
8j
5
H
11a
11b
11c
11d
A1
A2
3
H
21.35 1.57
0.24 0.01
0.010 0.004
0.025 0.001
0.028 0.005
0.032 0.004
4
H
H
6
H
H
7
H
H
––
––
––
––
––
––
––
a Mean of triplicate well values. All experiments were performed at least twice. Plaque reduction assay was employed.
b Mean of triplicate well values. All experiments were performed at least twice.
c EV71: human enterovirus 71 strain 4643.
d RD: human rhabdomyosarcoma cells.
Table 2. Comparative evaluation of compound 8b and A2 against various viruses
IC50 (lM)a
A2
8b
Enterovirus 71 (2231) genotype C
Enterovirus 71 (4643) genotype C
Enterovirus 71 (2086) genotype C
Enterovirus 71 (BrCr) genotype A
Enterovirus 71 (1743) genotype B
Enterovirus 68
0.087 0.009
0.032 0.004
0.071 0.003
0.054 0.011
0.097 0.020
>25
0.019 0.004
0.001 0.001
0.004 0.001
0.005 0.001
0.009 0.001
6.73 1.30
0.025 0.004
0.64 0.06
0.36 0.03
0.031 0.011
1.20 0.38
>25
Coxsackievirus A9
Coxsackievirus A10
0.049 0.006
8.61 1.22
>25
Coxsackievirus A16
Coxsackievirus A24
0.14 0.01
>25
>25
Coxsackievirus B1
Coxsackievirus B2
Coxsackievirus B3
Coxsackievirus B4
>25
>25
3.14 0.43
4.18 0.33
>25
1.18 0.16
4.74 1.09
>25
Coxsackievirus B5
Coxsackievirus B6
Echovirus 9
Echovirus 29
0.30 0.01
0.038 0.004
0.26 0.01
0.021 0.003
a Mean of triplicate well values. All experiments were performed at least twice. Plaque reduction assay was employed.
These encouraging results prompt us to further investi-
gate this class of novel, oxime ether-containing pyridyl
imidazolidinones.
n-propyl (8c) and n-butyl (8d) was detrimental to activity.
This effect might be due to their distinct differences of
hydrophobic properties. On the other hand, when an al-
kyl substituent (Me, Et, n-Pr) was introduced at the
oxime carbon (R2), compounds 8e, 8f, and 8g showed a
dramatic decrease in activity against EV71 as compared
with the corresponding ethyl oxime ether 8b. However, it
is also very interesting to note that the 3,5-dimethylphen-
oxyl derivatives (R1 = Me), such as compounds 8h, 8i,
and 8j, were considerably less active than their corre-
sponding 3,5-unsubstituted phenoxyl derivatives 8a, 8b,
Increasing the length of the O-substituent (R3) of the
oxime ether group from methyl to n-butyl, in the case
of the five-carbon homologues 8a–d, resulted in an inter-
esting pattern in activity against EV71. Chain extension
from methyl (8a) to ethyl (8b) at this position in this ser-
ies of compounds resulted in a fivefold increase in activ-
ity (IC50 = 0.001lM), and a further chain extension to

J.-H. Chern et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5051–5056
5055
and 8c. This unexpected biological result is not fully
understood and is worthy of further study.
chain length of the alkyl linker. On the basis of these
biological results, the ethyl oxime ether 8b was found
to exhibit the most potent antiviral activity against
EV71 (IC50 = 0.001lM) with no apparent cytotoxic ef-
fect toward RD (rhabdomyosarcoma) cell lines
(CC50 > 25lM). Additionally, we observed that this
compound has been shown to have a broad-spectrum
activity against most of the serotypes of enteroviruses
tested in the nanomolar range. Further SAR studies
and mechanistic studies on this new class of antiviral
compounds are currently under active investigation
and will be reported in due course.
Several ethyl oxime ethers with various tether lengths
(11a–d) were synthesized in order to determine the opti-
mal spacing between the imidazolidinone and the phen-
oxyl ring. Interestingly, the chain length of the alkyl
linker was found to be of considerable importance for
the activity of the compounds. The results are shown
in Table 1 and are compared to the corresponding
five-carbon homologue 8b. However, the six- and se-
ven-carbon homologues, 11c and 11d, respectively,
showed a 10- and 25-fold loss in activity against EV71,
and the three- and four-carbon homologues, 11a and
11b, respectively, drastically reduced activity. These sig-
nificant results demonstrated that the five-carbon homo-
logues in this series were routinely more active against
EV71 than their corresponding longer or shorter
compounds. These observations provide remarkable
evidence that the hydrophobic interaction and conform-
ational flexibility of the alkyl linker largely influence
anti-EV71 activity of these novel oxime ether-containing
pyridyl imidazolidinones.
Acknowledgements
We are grateful to the National Health Research Insti-
tutes of the Republic of China for Financial support.
References and notes
1. (a) Schmidt, N. J.;Lennette, E. H.;Ho, H. H. J.Infect.
Dis. 1974, 129, 304–309;(b) Melnick, J. L. Rev.Infect.Dis.
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Eds.;Academic: New York, 2000;pp 657–673.
In this study, the ethyl oxime ether 8b was selected for
further evaluation since it appeared to demonstrate
excellent activity against EV71 (IC50 = 0.001lM). A
comparison of the activity of 8b and A2 against 14 sero-
types is illustrated in Table 2. The compounds were indi-
vidually subjected to evaluation against a variety of
human enteroviruses, including coxsackieviruses (10 sero-
types), echoviruses (2 serotypes), human enteroviruses
68 and 71. As shown, the ethyl oxime ether 8b was
found, in addition to strongly inhibiting all of the geno-
types (A, B, and C) of EV71, to possess antiviral activity
against coxsackieviruses A9, A10, A16, A24, B1, B4,
and B5, echovirus 9, echovirus 29, and enterovirus 68.
However, this compound showed no activity against
coxsackieviruses B2, B3, and B6 up to the concentra-
tion tested (25lM). On the basis of these extensive bio-
logical evaluation, we observed that compound 8b is
more potent against most of the serotypes of human
enteroviruses tested, in particular, enterovirus 71
(IC50 = 0.001–0.019lM) and also possess a very low
cytotoxic effect on the uninfected rhabdomyosarcoma
(RD) host cells (IC50 > 25lM). Therefore, for our pur-
pose, the ethyl oxime ether 8b is well qualified to serve
as a lead compound for the further development of
anti-EV71 agent.
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In summary, we have developed an efficient synthesis of
this series of novel, oxime ether-containing pyridyl imid-
azolidinones in an attempt to evaluate their anti-EV71
activity in a plaque reduction assay. According to our
SAR investigation, the alkyl substituent at the oxime
ether group and the phenoxyl ring largely influenced
the in vitro anti-EV71 activity of this new class of potent
antiviral agents. On the other hand, it is also very inter-
esting to note that the activities of this series of com-
pounds were very sensitive to the variation in the
L.;Tai, C. L.;Shih, S. R.
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J.-H. Chern et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5051–5056
11. Ing, H. R.;Manske, R. H. F. J.Chem.Soc. 1926, 2349.
12. Grochowski, E.;Jurczak, J. Synthesis 1976, 682–684.
13. All the new compounds gave satisfactory spectral data
consistent with their proposed structures. Selected spectral
data for compounds 8a, 8b, 11a, and 11b. Compound 8a:
2H), 1.87–1.78 (m, 2H), 1.67–1.48 (m, 4H), 1.30 (t,
J = 7.2Hz, 3H);ESMS 397.2 (M + 1). Compound 11a:
mp 97–99°C;IR (CHCl 3) mmax 1710, 1594, 1509, 1479,
1424, 1248, 1052cmÀ1; 1H NMR (300MHz, CDCl3) d 8.42
(d, J = 5.7Hz, 2H), 7.99 (s, 1H), 7.49–7.43 (m, 4H), 6.85
(d, J = 8.7Hz, 2H), 4.18 (q, J = 7.2Hz, 2H), 4.05 (t,
J = 6.0Hz, 2H), 3.80 (dd, J = 10.5Hz, J = 7.2Hz, 2H),
3.59–3.48 (m, 4H), 2.12–2.04 (m, 2H), 1.30 (t, J = 7.2Hz,
3H);ESMS 369.1 (M + 1). Compound 11b: mp 144–
146°C;IR (CHCl 3) mmax 1701, 1603, 1508, 1489, 1420,
mp 116–118°C;IR (CHCl ) mmax 1714, 1592, 1506, 1481,
3
1428, 1257, 1060cmÀ1; 1H NMR (300MHz, CDCl3) d 8.43
(d, J = 6.3Hz, 2H), 7.99 (s, 1H), 7.49–7.45 (m, 4H), 6.85
(d, J = 8.7Hz, 2H), 3.98 (t, J = 6.3Hz, 2H), 3.94 (s, 3H),
3.81 (dd, J = 10.5Hz, J = 6.9Hz, 2H), 3.54 (dd, J = 8.7Hz,
J = 6.0Hz, 2H), 3.34 (t, J = 6.9Hz, 2H), 1.86–1.79 (m,
2H), 1.65–1.49 (m, 4H);ESMS 383.2 (M + 1). Compound
8b: mp 109–111°C;IR (CHCl 3) mmax 1711, 1594, 1511,
1480, 1425, 1250, 1052cmÀ1; 1H NMR (300MHz, CDCl3)
d 8.42 (d, J = 6.0Hz, 2H), 7.99 (s, 1H), 7.49–7.44 (m, 4H),
6.84 (d, J = 8.7Hz, 2H), 4.18 (q, J = 7.2Hz, 2H), 3.96 (t,
J = 6.3Hz, 2H), 3.79 (dd, J = 10.2Hz, J = 6.9Hz, 2H),
3.52 (dd, J = 9.0Hz, J = 6.0Hz, 2H), 3.33 (t, J = 6.9Hz,
1
1243, 1052cmÀ1; H NMR (300MHz, CDCl3) d 8.42 (d,
J = 5.1Hz, 2H), 7.98 (s, 1H), 7.48–7.43 (m, 4H), 6.84 (d,
J = 8.7Hz, 2H), 4.18 (q, J = 7.2Hz, 2H), 4.01 (t, J =
5.7Hz, 2H), 3.77 (dd, J = 9.9Hz, J = 6.6Hz, 2H), 3.53 (dd,
J = 9.0Hz, J = 5.7Hz, 2H), 3.38 (t, J = 6.9Hz, 2H), 1.83–
1.76 (m, 4H), 1.30 (t, J = 7.2Hz, 3H);ESMS 383.3
(M + 1).
14. Karabatsos, G. J.;Hsi, N. Tetrahedron 1967, 23, 1079.