Influence of 6- or 8-substitution on the antiviral activity of 3-arylalkylthiomethylimidazo[1,2-a]pyridine against human cytomegalovirus (CMV) and varicella-zoster virus (VZV): Part II

Article abstract of DOI:10.1016/j.bmc.2008.09.027

The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and diversely substituted on the 6 or 8 position, and their antiviral activities are reported. From the synthesized compounds, the imidazo[1,2-a]pyridines b

Full text of DOI:10.1016/j.bmc.2008.09.027

Bioorganic & Medicinal Chemistry 16 (2008) 9536–9545
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Influence of 6- or 8-substitution on the antiviral activity
of 3-arylalkylthiomethylimidazo[1,2-a]pyridine against human
cytomegalovirus (CMV) and varicella-zoster virus (VZV): Part II
Jean-Baptiste Véron a, Hassan Allouchi a, Cécile Enguehard-Gueiffier a, Robert Snoeck b, Graciela Andrei b,
Erik De Clercq b, Alain Gueiffier a,
*
a PCMB EA 4244, Faculté de Pharmacie, Université François Rabelais, 31 avenue Monge, 37200 Tours, France
b Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2008
Revised 4 September 2008
Accepted 10 September 2008
Available online 13 September 2008
The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and
diversely substituted on the 6 or 8 position, and their antiviral activities are reported. From the synthe-
sized compounds, the imidazo[1,2-a]pyridines bearing a 5 membered heterocycle (thiophene, furane or
pyrrole) in the 6 position or a phenylthio group in the 6 or 8 position (14, 16, 21, 28, 45) were the most
potent against human cytomegalovirus (CMV) and varicella-zoster virus (VZV), whereas several other
congeners (i.e., 22, 29 and 39), while less potent, were more selective in their inhibitory activity against
VZV and CMV. These compounds showed similar activity against thymidine kinase competent (TK+) and
deficient (TKꢀ) VZV strains, demonstrating a mechanism of action independent of the viral thymidine
kinase.
Keywords:
Antiviral drugs
Human cytomegalovirus (HCMV)
Varicella-zoster virus (VZV)
Imidazo[1,2-a]pyridine
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
thesis and biological evaluation of this new series of compounds is
subject of the present article. Indeed, as has already been docu-
In 1996, Alain Gueiffier and colleagues reported the antiviral
activity of 8-methyl-3-benzylthiomethylimidazo[1,2-a]pyridine
as potent inhibitor of human cytomegalovirus (HCMV) and vari-
cella-zoster virus (VZV).1 The antiviral activity optimization was
pursued in this series, with the investigation of the role of the thi-
oether side chain2 or the 2-substituent.3 It appeared that a phen-
ethylthiomethyl group enhances the activity and diminishes the
toxicity. Many functionalities were tolerated in position 2, but in
all cases, the unsubstituted compound remained the best inhibitor.
At this time, optimization of the pyridinic moiety substitution was
just initiated, as a lack of efficient methods of functionalization
made this investigation problematic. The development of new
metallo-catalyzed coupling reactions in our laboratory allowed
us to introduce new functionalities in the pyridinic part of the
scaffold. We lately reported on the antiviral activity of 6- or 8-
(hetero)aryl-3-phenethylthiomethylimidazo[1,2-a]pyridine deriv-
atives obtained via Suzuki-Miyaura coupling reactions.4 The
pharmacomodulation of positions 6 and 8 of the nucleus was pur-
sued using Buchwald metallo-catalyzed cross-coupling reactions,
for example, pallado-catalyzed aminations or copper-catalyzed
couplings of amines, lactam, azoles, nitrile or thiophenols. The syn-
mented in previous papers,1–4 development of new drugs against
herpes viruses with novel mechanisms of action, that are less toxic,
more effective, and orally bioavailable, is urgently needed.
2. Results and discussion
2.1. Chemistry
As shown in Scheme 1, the halogenated imidazo[1,2-a]pyri-
dines 4–9 were obtained through previously described proce-
dures.4 The suitably halogenated 2-aminopyridines 1a–d were
refluxed with chloroacetaldehyde in ethanol to yield around 85%
of the imidazo[1,2-a]pyridines 2a–d. Hydroxymethylation in posi-
tion 3 of this scaffold was performed using formaldehyde in acetic
media in the presence of sodium acetate at 40 °C. After 24 h of
heating, about 80% yield of the corresponding alcohols 3a–d were
obtained. The thioether side chain was introduced using phen-
ethylthiol in acetic media at 80 °C leading to 4–9 in moderate to
good yield (41–90%).
The pharmacomodulation of positions 6 and 8 of the nucleus
was performed using various metallo-catalyzed cross-coupling
reactions (Table 1), for example, Suzuki-Miyaura coupling reac-
tions, Buchwald pallado-catalyzed aminations or copper-catalyzed
couplings of amines, lactam, azoles or thiophenols. The previously
* Corresponding author. Tel.: +33 247 367 140; fax: +33 247 367 288.
E-mail address: alain.gueiffier@univ-tours.fr (A. Gueiffier).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.09.027

J.-B. Véron et al. / Bioorg. Med. Chem. 16 (2008) 9536–9545
9537
R2
R2
R2
R2
N
iii
NH2
N
i
ii
N
N
N
N
N
R1
R1
R1
R1
S
CH2OH
n
2a-d
3a-d
1a-d
4-9
10-45
R2 = CH3, n = 2
5 R1 = Br, R2 = CH3, n = 2
6 R1 = I, R2 = CH3, n = 1
7 R1 = CH3, R2 = I, n = 2
8 R1 = CH3, R2 = Br, n = 2
9 R1 = CH3, R2 = I, n = 1
iv
(a) 6-I, 8-CH3
(b) 6-CH3,8-I
(c) 6-Br, 8-CH3
(d) 6-CH3, 8-Br
4 R1 = I,
Scheme 1. General scheme leading to compounds 4–45. Reagents and conditions: (i) ClCH2CHO, C2H5OH, reflux 24 h; (ii) HCHO, CH3COONa, CH3COOH, 40 °C for 24 h; (iii)
Ph(CH2)2SH or PhCH2SH, CH3COOH, 80 °C overnight; (iv) RB(OH)2, Pd(PPh3)4, NaOH, DME, H2O, 85 °C or amine, Pd2(dba)3, rac-BINAP, t-BuONa, toluene, 112 °C; or amine, CuI,
K3PO4, ethyleneglycol, isopropanol, 85 °C; or azole, CuI, K3PO4, N,N0-dimethylethylenediamine or ethyleneglycol, toluene, 112 °C; or NaCN, CuI, N,N0-dimethylethylenedi-
amine, toluene, 112 °C; or thiophenol, CuI, K2CO3, N,N0-dimethylethylenediamine or ethyleneglycol, isopropanol.
described Suzuki conditions were applied to the iodinated imi-
dazo[1,2-a]pyridine 4, 6, 7 or 9, using tetrakis(triphenylphos-
phine)palladium (0) as catalyst and NaOH as base in
1,2-dimethoxyethane. Two substituted phenyl (4-vinylphenyl or
4-formylphenyl) and various heterocycles (indol-5-yl, thien-2- or
-3-yl, and fur-2- or -3-yl) were thus introduced in positions 6
and 8 of the scaffold. After few hours of heating at 85 °C, the
attempted coupling products 10–16 and 30–32 were obtained in
31–91% yields (not optimized).
Two cyclic amines (morpholine and pyrrolidine) were then
introduced in the pyridine part of the scaffold using Buchwald pal-
ladium-catalyzed conditions.5 The reaction was performed in a
screw-capped tube in the presence of Pd2(dba)3 as catalyst, ter-
tio-BuONa as base and rac-BINAP as ligand, in 2 mL of toluene at
112 °C.
thien-2- or -3-yl substitution on positions 6 and 8 was also evalu-
ated and led to moderately active compounds as well (EC50 values
around 2 lg/mL).
In the present work, it appeared that the thienyl group can be
replaced by a furyl, the highest anti-CMV potency being observed
for the 6-(fur-3-yl) derivative 16 (EC50 > 0.8–0.27 lg/mL).
The presence of an oxygen atom in the 6 position is often no-
ticed in compounds with a moderate or good anti-CMV activity
(e.g., 16, 28). Nevertheless, some restrictions are associated with
the exact location of this atom. Thus, we previously reported that
a para- or ortho-hydroxyphenyl substituent in position 6 led to to-
tally inactive compounds (EC50 > 100
hydroxyphenyl analog was moderately active (EC50 = 2.2
In this work, the para-hydroxyphenylthio 28 presented an interest-
ing anti-CMV activity with an EC50 of 0.8 g/mL. This is also ob-
lg/mL), whereas the meta-
lg/mL).
l
Then, applying Buchwald copper-catalyzed coupling conditions
to the diversely halogenated imidazo[1,2-a]pyridines led to the
introduction of various substituents: an amine (4-methylpipera-
zine), a lactam (pyrrolidin-2-one), four azoles (pyrrole, imidazole,
indole, and pyrrolo[2,3-b]pyridine), a nitrile and three thiophenols
(4-chlorothiophenol, 4-hydroxythiophenol, and 4-aminothiophe-
nol).5–7 Depending on the nature of the coupling partner or the
substitution position, many different methods were applied using
CuI as catalyst, N,N0-dimethylethylenediamine or ethyleneglycol
as ligands, K3PO4 or K2CO3 as bases, and isopropanol or toluene
as solvents.
served when comparing the fur-3-yl and fur-2-yl derivatives 15
and 16, the latter being the more active. A hydrogen bonding be-
tween the oxygen in position 6 of our compounds and the active
site may be postulated. As an example, the chlorine analog 27 of
the hydroxyphenylthio 28 is inactive (EC50 > 4 lg/mL).
Nevertheless, a second polar atom or group in the 6 position
seems to be deleterious for the activity as seen with compounds
of which substitution is morpholine (17), N-methylpiperazine
(19), pyrrolidinone (20) or imidazole (23).
Concerning the functionalization of the 8 position, a
action with the active site may be postulated, as all the aliphatic
derivatives tested (33–35, 37) appeared inactive (EC50 > 4–20 g/
mL), whereas the aromatic compounds 30–32, 38–40, 42 present
a moderate anti-CMV activity (EC50 = 1.3–4 g/mL). The nature of
p–p inter-
l
2.2. Anti-CMV activity
l
As seen in Tables 2 and 3, the tested compounds can be classi-
fied in three groups depending on their range of anti-CMV activi-
ties: a group of inactive compounds (11–13, 17, 19–20, 23, 26–
the heteroaromatic ring in position 8 influenced the activity to a
lesser extent than in position 6. The best activity was displayed
by the phenylthio derivative 45.
27, 33–35, 37, and 41) with an EC50 > 4
ately active compounds (10, 18, 21, 22, 24–25, 29–32, 38–40,
42–43) with an EC50 between 1 and 4 g/mL depending on the
strain, and a group of four active compounds (14, 16, 28, 45) with
an EC50 < 1 g/mL. It should be noted that many of the tested com-
l
g/mL, a group of moder-
As previously observed, the compounds showing the highest
anti-CMV potency (14, 16, 28) (EC50 < 1 lg/mL) were also the most
cytotoxic (MCC values of the same order as EC50 values). Only the
4-hydroxyphenylthio derivative 45 exhibited an interesting value
l
l
of MCC > 100
viz. 22, 24–25, 29, 30–32, 38–39, and 42–43, wich showed an
EC50 of 1–4 g/mL and no alteration of cell morphology at the ac-
lg/mL. On the other hand, a wealth of compounds,
pounds inhibited mostly the Davis strain and, to a lesser extent, the
AD-169 strain, as seen with 24 and 42.
l
In previous work,4 we reported on the influence of 6- or 8-
substituted phenyl on the anti-CMV activity of the 3-phenethylth-
iomethylimidazo[1,2-a]pyridine series. From the anti-CMV results,
we noticed that the 6-iodo or 6-bromo starting materials and the
tive concentrations, had selectivity indexes (ratio of CC50 to EC50
)
superior to 10.
2.3. Anti-VZV activity
6-phenyl analog showed the highest activities (EC50 < 1
However, most of the tested compounds were at least moderately
active with EC50 values close to 2 g/mL. The influence of the
lg/mL).
As previously observed, contrarily to acyclovir and brivudin
wich require phosphorylation to exert their antiviral activity, our
l

9538
J.-B. Véron et al. / Bioorg. Med. Chem. 16 (2008) 9536–9545
Table 1
morphology, and had selectivity indexes (ratio of CC50 to EC50
equal to or higher than 8.
)
Synthesis methods and yields for the obtention of compounds 10 to 45
Cpd R1
4-Vinylphenyl
R2
n
Meth. Yield (%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
2
1
2
2
1
2
2
2
2
2
2
2
1
2
2
2
2
2
2
2
1
2
2
2
2
1
2
2
2
1
2
2
2
2
2
2
A
A
A
A
A
A
A
B
B
C
D
E
E
E
D
E
F
31
73
81
83
91
71
83
87
84
62
90
96
93
20
62
93
94
96
60
47
37
80
65
30
80
60
35
54
94
87
42
37
48
94
84
21
3. Conclusion
4-Vinylphenyl
4-Formylphenyl
Indol-5-yl
Thien-3-yl
Fur-2-yl
In the present work, the impact of the substituent at the 6 or 8
position on the antiviral activity of the 3-phenethylthiomethylimi-
dazo[1,2-a]pyridine was confirmed. From the synthesized com-
pounds, eight (14, 16, 21–22, 28–29, 39, 45) were the most potent
against CMV and/or VZV. They present either a small heteroaro-
matic ring or a phenylthio group in position 6, or a phenylsulfanyl
in position 8. On the other hand, 22, 29, 39 and 45 were the most
selective in their inhibitory activity against both VZV and CMV.
All compounds showed similar or even greater activity against
the TKꢀ VZV strain compared to the TK+ strain, confirming a mech-
anism of action that is independent of the viral thymidine kinase.
Based on its potency and/or selectivity, the 4-hydroxyphenyl-
thio derivative 45 deserves to be pursued in follow-up studies for
its potential in the treatment of VZV and HCMV infections.
Fur-3-yl
Morpholin-1-yl
Pyrrolidin-1-yl
N-Methylpiperazin-1-yl
2-Oxopyrrolidin-1-yl
Pyrrol-1-yl
Pyrrol-1-yl
Imidazol-1-yl
Indol-1-yl
Pyrrolo[2,3-b]pyridin-1-yl CH3
Cyano
4-Chlorophenylthio
4-Hydroxyphenylthio
CH3
CH3
CH3
CH3
Thien-3-yl
Fur-2-yl
Fur-3-yl
Morpholin-1-yl
Pyrrolidin-1-yl
Pyrrolidin-1-yl
N-Methylpiperazin-1-yl
2-Oxopyrrolidin-1-yl
Pyrrol-1-yl
Pyrrol-1-yl
Imidazol-1-yl
Indol-1-yl
Pyrrolo[2,3-b]pyridin-1-yl
Cyano
4-Chlorophenylthio
4-Hydroxyphenylthio
G
G
H
A
A
A
B
B
B
C
C
E
E
I
4-Aminophenylthio
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4. Experimental
4.1. General details
The melting points were determined in a capillary apparatus
and are uncorrected. NMR experiments were performed at
200 MHz (1H) and 50 MHz (13C) in CDCl3 or DMSO-d6 on Bruker
DPX 200 instruments. Signals are described as singlet (s), broad
singlet (br s), doublet (d), triplet (t), quartet (q) and multiplet
(m). Possible inversion of two values in the NMR spectra is ex-
pressed by an asterisk. Elemental analyses (C, H, N) were within
0.4% of theory. Tetrakis(triphenylphosphine)palladium(0) was
prepared as described in the literature.8 The starting halogenated
aminopyridine derivatives 1a–d were prepared by iodination9 or
bromination10 of commercially available aminopyridines.
The 6-iodo-8-methyl-3-phenethylthiomethylimidazo[1,2-a]pyr-
idine 4, 8-iodo-6-methyl-3-phenethylthiomethylimidazo[1,2-a]pyri-
dine 7, 6-bromo-8-methyl-3-phenethylthiomethyl-imidazo[1,2-a]-
pyridine 5, 8-bromo-6-methyl-3-phenethylthiomethylimidazo-
[1,2-a]pyridine 8 were prepared by a multistep synthesis previously
reported in the literature.4
C
E
F
J
J
Method A: R(B(OH)2 (1.2 mmol), Pd(PPh3)4 (0.05 mmol), NaOH (2 mmol), DME
(8 mL) and H2O (4 mL) at 85 °C.
Method B: Amine (1.5 mmol), Pd2(dba)3 (0.01 mmol), t-BuONa (1.4 mmol), rac-
BINAP (0.03 mmol) and toluene (2 mL) at 112 °C.
Method C: Amine (1.2 mmol) or azole or lactam (1.5 mmol), CuI (0.15 mmol), K3PO4
(2.1 mmol), ethylene glycol (2 mmol) and isopropanol (1 mL) at 85 °C.
Method D: Azole or lactam (1.5 mmol), CuI (0.15 mmol), K3PO4 (2.1 mmol), N,N0-
dimethylethylenediamine (0.15 mmol) and toluene (2 mL) at 112 °C.
Method E: Azole (1.2 mmol), CuI (0.05 mmol), K3PO4 (2.1 mmol), N,N0-dimethyl-
ethylenediamine (0.15 mmol) and toluene (2 mL) at 112 °C.
Method F: CuI (0.1 mmol), NaCN (1.2 mmol), N,N0-dimethylethylenediamine
(1 mmol) and toluene (2 mL) at 112 °C.
4.2. Chemistry
Method G: Thiophenol (1.2 or 1.5 mmol), CuI (0.05 mmol), K2CO3 (2 mmol), N,N0-
dimethylethylenediamine (0.15 mmol) and isopropanol (1 mL) at 85 °C.
Method H: Thiophenol (1.5 mmol), CuI (0.20 mmol), K2CO3 (2 mmol), N,N0-dimeth-
ylethylenediamine (0.20 mmol) and isopropanol (1 mL) at 85 °C.
Method I: Azole (1.5 mmol), CuI (0.15 mmol), K3PO4, (2.1 mmol), N,N0-dimethyl-
ethylenediamine (0.30 mmol) and toluene (2 mL) at 112 °C.
4.2.1. 3-Benzylthiomethyl-6-iodo-8-methylimidazo[1,2-
a]pyridine (6)
To a solution of 3a4 (2.66 g, 9.2 mmol) in 12 mL of acetic
acid was added benzylmercaptan (1 mL, 8.3 mmol). The mixture
was heated at 80 °C overnight. After cooling, the solution was
diluted with water, made basic with sodium carbonate, and ex-
tracted with dichloromethane. The organic layers were dried
and evaporated to dryness. The residue was chromatographed
on neutral alumina eluting with CH2Cl2/petroleum ether
(30:70). 84% yield. Mp 124–125 °C. 1H NMR (CDCl3) d: 8.11
(m, 1H, H5), 7.39 (s, 1H, H2), 7.35–7.23 (m, 5H, Ph), 7.17 (d,
1H, J = 1.3 Hz, H7), 3.82 (s, 2H, CH2), 3.55 (s, 2H, CH2), 2.56 (s,
3H, CH3). 13C NMR (CDCl3) d: 145.62 (C8a), 137.70 (Ph-1),
133.36 (C2), 131.20 (C7), 129.29 (C8, Ph-2,6*), 128.96 (Ph-3,5*),
127.60 (Ph-4*), 127.43 (C5*), 119.64 (C3), 76.15 (C6), 35.78
(CH2), 24.39 (CH2), 17.11 (CH3).
Method J: Thiophenol (1.2 mmol), CuI (0.05 mmol), K2CO3 (2 mmol), ethylene glycol
(2 mmol) and isopropanol (1 mL).
compounds showed the same range of activity or a higher activity
against TKꢀ than TK+ VZV strains, demonstrating a mechanism of
action independent of the virus-encoded thymidine kinase (Tables
2 and 3).
The compounds that were moderately active against CMV (16,
22, 29, 39, 45) were also efficient against VZV with EC50 values
around 2 l
g/mL for the TKꢀ strain, that represent much higher
potencies than the two references. Thus, small heteroaromatic
rings such as fur-3-yl and pyrrol-1-yl are well tolerated in position
6. A phenylthio group introduced in position 6 or 8 led also to ac-
tive compounds.
Moreover, compounds 22, 29, 39, and 45, inhibited VZV plaque
formation at concentrations that resulted in no alteration of cell
4.2.2. 3-Benzylthiomethyl-8-iodo-6-methylimidazo[1,2-
a]pyridine (9)
To a solution of 3b4 (1.96 g, 6.8 mmol) in 10 mL of acetic acid
was added benzylmercaptan (0.75 mL, 6.12 mmol). The mixture

J.-B. Véron et al. / Bioorg. Med. Chem. 16 (2008) 9536–9545
9539
Table 2
Anti-CMV and -VZV activities and cytotoxic properties in human embryonic lung (HEL) cells of compounds 10–29 substituted at position 6
a
Compound
R1
R2
n
Antiviral activity EC50
VZV
(lg/mL)
Cytotoxicity (lg/mL)
c
CMV
Cell morphology (MCC)b
Cell growth (CC50)
OKA strain TK+
07/1 strain TKꢀ
AD-169 strain
Davis strain
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4-Vinylphenyl
4-Vinylphenyl
4-Formylphenyl
Indol-5-yl
Thien-3-yl
Fur-2-yl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
2
1
2
2
1
2
2
2
2
2
2
2
1
2
2
2
2
2
2
2
>4
2.9
30
6.0
>4
0.8
>0.8
0.27
>20
2.0
20
14
59
9.4
26
9.4
40
>100
12.6
>20
>0.8
>0.8
>0.8
>20
4.0
>20
>20
>0.8
1.6
P100
100
P20
4
>4
>4
100
20
20
>100
P4
20
100
>20
20
20
20
4
20
>400
400
100
P100
>0.8
>4
2.4
>20
>4
>4
>100
>4
>4
10.7
>20
>4
>0.8
>0.8
>0.8
>20
>4
Fur-3-yl
12
45
12
32
89
11
17
23
18
16
14
14
100
23
137
122
146
47
Morpholin-1-yl
Pyrrolidin-1-yl
N-Methylpiperazin-1-yl
2-Oxopyrrolidin-1-yl
Pyrrol-1-yl
Pyrrol-1-yl
Imidazol-1-yl
Indol-1-yl
Pyrrolo[2,3-b]pyridin-1-yl
Cyano
4-Chlorophenylthio
4-Hydroxyphenylthio
4-Aminophenylthio
>4
4
>20
>0.8
2.1
11.4
>4
>4
>4
>4
>0.8
2.2
>20
1.3
1.3
6.8
1.8
1.4
8.9
>4
8.9
>4
2.0
8.9
>4
>0.8
1.8
26
27
28
29
>4
>4
>0.8
>4
0.24
0.0037
N.D.d
N.D.d
0.8
1.8
N.D.d
N.D.d
0.80
0.12
Aciclovir
Brivudin
Ganciclovir
Cidofovir
13
N.D.d
N.D.d
0.51
0.10
>50
N.D.d
N.D.d
a
Effective concentration required to reduce virus plaque formation by 50%. Virus input was 100 plaque forming units (PFU) for HCMV. Virus input was 20 plaque forming
units (PFU) for VZV.
b
Minimum cytotoxic concentration that causes a microscopically detectable alteration of cell morphology.
Cytotoxic concentration required to reduce cell growth by 50%.
Not Determined.
c
d
Table 3
Anti-CMV and -VZV activities and cytotoxic properties in human embryonic lung (HEL) cells of compounds 30–45 substituted at position 8
a
Compound
R1
R2
n
Antiviral activity EC50
VZV
(lg/mL)
Cytotoxicity (lg/mL)
c
CMV
Cell morphology (MCC)b
Cell growth (CC50)
OKA strain TK+
07/1 strain TKꢀ
AD-169 strain
Davis strain
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Thien-3-yl
Fur-2-yl
Fur-3-yl
1
2
2
2
2
1
2
2
2
1
2
2
2
2
2
2
7.3
6.6
20
6.5
7.9
4
2.1
2.7
1.3
8.2
100
100
100
>100
>100
P20
N.D.d
20
100
100
20
100
100
P20
4
100
41
64
2.5
1.8
>4
>20
36.6
>20
>4
Morpholin-1-yl
Pyrrolidin-1-yl
Pyrrolidin-1-yl
N-Methylpiperazin-1-yl
2-Oxopyrrolidin-1-yl
Pyrrol-1-yl
Pyrrol-1-yl
Imidazol-1-yl
Indol-1-yl
Pyrrolo[2,3-b]pyridin-1-yl
Cyano
4-Chlorophenylthio
4-Hydroxyphenylthio
53.6
35.7
17.7
N.D.d
>4
>20
2.2
>4
>20
6.6
16.4
>0.8
58
0.24
0.0037
N.D.d
N.D.d
49
>20
10
20
>100
52
5.2
N.D.d
>4
N.D.d
>4
N.D.d
>4
N.D.d
25
>20
1.8
>4
>20
14
>4
>0.8
2.9
13
>50
N.D.d
N.D.d
1.8
6.3
3.1
20
1.8
2.9
2.3
10.5
1.8
2.0
>0.8
0.8
26
15
10
>100
>100
>100
100
79
137
122
146
47
4
2.2
>0.8
>0.8
N.D.d
N.D.d
0.51
0.10
>100
>400
400
100
P100
Aciclovir
Brivudin
Ganciclovir
Cidofovir
N.D.d
N.D.d
0.80
0.12
a
Effective concentration required to reduce virus plaque formation by 50%. Virus input was 100 plaque forming units (PFU) for HCMV. Virus input was 20 plaque forming
units (PFU) for VZV.
b
Minimum cytotoxic concentration that causes a microscopically detectable alteration of cell morphology.
Cytotoxic concentration required to reduce cell growth by 50%.
Not determined.
c
d
was heated at 80 °C overnight. After cooling, the solution was
worked up as for 6. The residue was chromatographed on neu-
tral alumina eluting with a CH2Cl2/petroleum ether (50:50) then
with CH2Cl2. 81% yield. Mp 110–111 °C. 1H NMR (CDCl3) d: 7.77
(s, 1H, H5), 7.61 (s, 1H, H7), 7.51 (s, 1H, H2), 7.41–7.24 (m, 5H,
Ph), 3.86 (s, 2H, CH2), 3.61 (s, 2H, CH2), 2.34 (s, 3H, CH3). 13C
NMR (CDCl3) d: 145.25 (C8a), 137.96 (Ph-1), 137.13 (C7),
134.16 (C2), 129.56 (Ph-2,6*), 129.14 (Ph-3,5*), 127.82 (Ph-4),

9540
J.-B. Véron et al. / Bioorg. Med. Chem. 16 (2008) 9536–9545
123.37 (C6), 122.78 (C5), 121.14 (C3), 84.56 (C8), 35.88 (CH2),
24.86 (CH2), 18.54 (CH3).
4.2.3.4. 6-(Indol-5-yl)-8-methyl-3-phenethylthiomethylimidazo-
[1,2-a]pyridine (13). The compound was obtained following the
general procedure using 4 (226 mg, 0.55 mmol), indol-5-ylboronic
acid (107 mg, 0.66 mmol). After 3 h at 75 °C and usual treatment, pure
product was obtained by column chromatography on neutral alumina
eluted with CH2Cl2. 83% yield. Mp 173–174 °C. 1H NMR (CDCl3) d: 8.73
(br s, 1H, NH), 8.21 (m, 1H, H5), 7.89 (m, 1H, indole), 7.55 (s, 1H, H2),
7.54 (d, 1H, J = 6.7 Hz, indole), 7.45 (m, 2H, H7, indole), 7.35–7.15 (m,
6H, Ph, indole), 6.68 (m, 1H, indole), 4.05 (s, 2H, CH2), 2.85 (m, 2H,
CH2), 2.74 (s, 3H, CH3), 2.68 (m, 2H, CH2). 13C NMR (CDCl3) d: 145.41
(C8a), 140.18 (Ph-1), 135.72 (indole), 131.72 (C2), 129.47 (indole),
128.68 (Ph-2,6*), 128.60 (Ph-3,5*), 126.88 (C8), 126.57 (indole), 125.93
(Ph-4*), 125.48 (C7*), 121.64 (indole), 119.85 (C3), 119.46 (indole),
119.29 (C5), 111.79 (indole), 103.02 (indole), 36.09 (CH2), 32.73 (CH2),
25.48 (CH2), 17.28 (CH3), C6 not found. Anal. Calcd for C25H23N3S: C,
75.53; H, 5.83; N, 10.57. Found: C, 75.51; H, 5.82; N, 10.55.
4.2.3. General procedure for Suzuki cross-coupling reactions
Into a three necked round bottom flask was introduced under
argon, iodinated imidazo[1,2-a]pyridines 4, 6, 7, or 9 (1 mmol), tet-
rakis(triphenylphosphine)palladium (58 mg, 0.05 mmol), the boro-
nic acid (1.1 or 1.2 mmol), 8 mL of 1,2-dimethoxyethane, and
NaOH (80 mg, 2 mmol) solubilized in 4 mL of water. The reaction
mixture was heated at 85 °C and followed by TLC. The mixture
was diluted with water and extracted with CH2Cl2. The combined
organic layers were dried on CaCl2, filtered and evaporated to dry-
ness. The residue was purified by column chromatography.
4.2.3.1. 8-Methyl-3-(phenethylthiomethyl)-6-(4-vinylphenyl)-
imidazo[1,2-a]pyridine (10). The compound was obtained fol-
lowing the general procedure using 4 (320 mg, 0.78 mmol), 4-
vinylphenylboronic acid (139 mg, 0.94 mmol). After 3 h at 85 °C
and usual treatment, pure product was obtained by column
chromatography on neutral alumina eluted with CH2Cl2/petroleum
ether (70:30). 31% yield. Mp 119–120 °C. 1H NMR (CDCl3) d: 8.21
(m, 1H, H5), 7.62–7.53 (m, 5H, H2, Phvinyl-2,3,5,6), 7.36–7.15 (m,
6H, Ph, H7), 6.81 (dd, 1H, J = 17.6–10.9 Hz, vinyl), 5.85 (dd, 1H, J =
17.6–0.8 Hz, vinyl), 5.35 (dd, 1H, J = 10.9–0.8 Hz, vinyl), 4.05 (s, 2H,
CH2), 2.84 (m, 2H, CH2), 2.73 (s, 3H, CH3), 2.66 (m, 2H, CH2). 13C
NMR (CDCl3) d: 146.62 (C8a), 139.56 (Ph-1*), 138.04 (Phvinyl-1,4*),
136.97 (vinyl-CH), 134.11 (C2), 129.74 (Ph-2,6). 129.32 (Ph-3,5),
128.15 (C8), 127.86 (Phvinyl-2,6*), 127.63 (Phvinyl-3,5*), 127.44
(Ph-4), 126.92 (C6), 124.32 (C7), 120.29 (C3), 119.97 (C5), 115.06
(vinyl-CH2), 36.26 (CH2), 33.02 (CH2), 25.69 (CH2), 17.53 (CH3).
Anal. Calcd for C25H24N2S: C, 78.09; H, 6.29; N, 7.28. Found: C,
78.21; H, 6.19; N, 7.34.
4.2.3.5. 3-Benzylthiomethyl-8-methyl-6-(thien-3-yl)imidazo[1,2-
a]pyridine (14). The compound was obtained following the
general procedure using 6 (394 mg, 1 mmol), thien-3-ylboronic
acid (154 mg, 1.2 mmol). After 3 h at 85 °C and usual treatment,
pure product was obtained by column chromatography on neutral
alumina eluted with CH2Cl2. 91% yield. Mp 113–114 °C. 1H NMR
(CDCl3) d: 8.13 (m, 1H, H5), 7.50 (s, 1H, H2), 7.48–7.46 (m, 2H,
Thio-2,4), 7.37 (dd, 1H, J = 4.3–2.1 Hz, Thio-5), 7.35–7.27 (m, 6H,
Ph, H7), 3.95 (s, 2H, CH2), 3.61 (s, 2H, CH2), 2.69 (s, 3H, CH3). 13C
NMR (CDCl3 ) d: 146.34 (C8a), 139.00 (Ph-1), 137.98 (Thio-3),
133.67 (C2), 129.37 (Ph-2,6*), 128.98 (Ph-3,5*), 127.84 (C8), 127.59
(Thio-2), 127.24 (Ph-4), 126.44 (Thio-5), 123.86 (C7), 122.05 (C6),
121.13 (Thio-4), 119.94 (C3), 119.18 (C5), 35.73 (CH2), 24.69 (CH2),
17.50 (CH3). Anal. Calcd for C20H18N2S2: C, 68.53; H, 5.18; N, 7.99.
Found: C, 68.77; H, 5.25; N, 8.02.
4.2.3.2. 3-(Benzylthiomethyl)-8-methyl-6-(4-vinylphenyl)imidazo-
[1,2-a]pyridine (11). The compound was obtained following the
general procedure using 6 (394 mg, 1 mmol), 4-vinylphenylboronic
acid (178 mg, 1.2 mmol). After 3 h at 85 °C and usual treatment, pure
product was obtained by column chromatography on neutral alumina
eluted with CH2Cl2/petroleum ether (80:20). 73% yield. Mp 123–
125 °C. 1H NMR (CDCl3) d: 8.11 (m, 1H, H5), 7.55 (m, 4H, Phvinyl-
2,3,5,6), 7.52 (s, 1H, H2), 7.34–7.26 (m, 6H, Ph, H7), 6.80 (dd, 1H, J =
17.6–10.9 Hz, vinyl), 5.86 (dd, 1H, J = 17.6–0.8 Hz, vinyl), 5.35 (dd,
1H, J = 10.9–0.8 Hz, vinyl), 3.95 (s, 2H, CH2), 3.61 (s, 2H, CH2), 2.71 (s,
4.2.3.6. 6-(Furan-2-yl)-8-methyl-3-(phenethylthiomethyl)imi-
dazo[1,2-a]pyridine (15). The compound was obtained following
the general procedure using 4 (408 mg, 1 mmol), fur-2-ylboronic
acid (123 mg, 1.1 mmol). After 1 h at 85 °C, boronic acid was
again added (56 mg, 0.5 mmol). After 2 h more at 85 °C and
usual treatment, pure product was obtained by column chroma-
tography on neutral alumina eluted with CH2Cl2. 71% yield. Mp
112–113 °C. 1H NMR (CDCl3) d: 8.36 (m, 1H, H5), 7.53 (dd, 1H,
J = 1.8–0.7 Hz, Furan-5), 7.51 (s, 1H, H2), 7.35–7.46 (m, 6H, Ph,
H7), 6.68 (d, 1H, J = 3.4 Hz, Furan-3), 6.54 (dd, 1H, J = 3.4–1.8 Hz,
Furan-4), 4.03 (s, 2H, CH2), 2.85 (m, 2H, CH2), 2.69 (s, 3H, CH3),
2.66 (m, 2H, CH2). 13C NMR (CDCl3) d: 151.42 (Furan-2), 146.26
(C8a), 142.72 (Furan-5), 140.51 (Ph-1), 133.35 (C2), 128.96 (Ph-
2,6*), 128.89 (Ph-3,5*), 128.03 (C8), 126.86 (Ph-4), 121.06 (C7),
120.54 (C3), 117.61 (C6), 117.51 (C5), 112.17 (Furan-4), 106.20
(Furan-3), 36.42 (CH2), 32.97 (CH2), 25.62 (CH2), 17.45 (CH3).
Anal. Calcd for C21H20N2OS: C, 72.38; H, 5.79; N, 8.04. Found:
C, 72.32; H, 5.83; N, 8.12.
13
3H, CH3). C NMR (CDCl3) d: 146.55 (C8a), 138.16 (Ph-1*), 137.62
(Phvinyl-1,4*), 136.79 (vinyl-CH), 133.93 (C2), 129.52 (Ph-2,6),
129.12 (Ph-3,5), 127.96 (C8), 127.71 (Phvinyl-2,6*), 127.44 (Phvinyl-
3,5*, Ph-4), 126.70 (C6), 124.21 (C7), 120.16 (C3), 119.83 (C5), 114. 95
(vinyl-CH2), 35.93 (CH2), 24.89 (CH2), 17.73 (CH3). Anal. Calcd for
C24H22N2S: C, 77.80; H, 5.98; N, 7.56. Found: C, 77.83; H, 5.98; N, 7.54.
4.2.3.3. 4-(8-Methyl-3-(phenethylthiomethyl)imidazo[1,2-a]pyri-
din-6-yl)benzaldehyde (12). The compound was obtained following
the general procedure using 4 (408 mg, 1 mmol), 4-formylphenylbo-
ronic acid (180 mg, 1.2 mmol). After 5 h at 85 °C and usual treatment,
pure product was obtained by column chromatography on neutral
alumina eluted with ethyl acetate/petroleum ether (30:70). 81% yield.
Mp 88–90 °C. 1H NMR (CDCl3) d: 10.12 (s, 1H, CHO), 8.29 (m, 1H, H5),
8.03 (d, 2H, J = 8.4 Hz, PhCHO-3,5), 7.79 (d, 2H, J = 8.4 Hz, PhCHO-2,6),
7.58 (s, 1H, H2), 7.37 (m,1H, H7), 7.33–7.14 (m, 5H, Ph), 4.06 (s,2H, CH2),
2.84 (m,2H, CH2), 2.75 (s,3H, CH3), 2.67 (m,2H, CH2). 13CNMR(CDCl3)d:
192.10 (CHO), 146.49 (C8a), 144.12 (PhCHO-1), 140.38 (Ph-1), 135.93
(PhCHO-4), 133.71 (C2), 130.89 (PhCHO-3,5), 128.94 (Ph-2,3,5,6),
128.36 (C8), 128.00 (PhCHO-2,6), 126.89 (Ph-4), 125.79 (C6), 123.81
(C7), 120.71 (C5), 120.49 (C3), 36.30 (CH2), 32.94 (CH2), 25.69 (CH2),
17.57 (CH3).Anal. Calcd for C24H22N2OS: C, 74.58; H, 5.74; N, 7.25. Found
C, 74.79; H, 5.69; N, 7.33.
4.2.3.7. 6-(Furan-3-yl)-8-methyl-3-(phenethylthiomethyl)imi-
dazo[1,2-a]pyridine (16). The compound was obtained follow-
ing the general procedure using 4 (408 mg, 1 mmol), fur-3-
ylboronic acid (123 mg, 1.1 mmol). After 1 h at 85 °C, boronic
acid was again added (56 mg, 0.5 mmol). After 2 h more at 85 °C
and usual treatment, pure product was obtained by column
chromatography on neutral alumina eluted with CH2Cl2. 83%
yield. Mp 80–81 °C. 1H NMR (CDCl3) d: 8.12 (m, 1H, H5), 7.78 (m,
1H, Furan-5), 7.56 (t, 1H, J = 1.8 Hz, Furan-2), 7.52 (s, 1H, H2),
7.34–7.14 (m, 6H, Ph, H7), 6.73 (dd, 1H, J = 1.8–0.9 Hz, Furan-
4), 4.03 (s, 2H, CH2), 2.84 (m, 2H, CH2), 2.69 (s, 3H, CH3), 2.64 (s,
3H, CH2). 13C NMR (CDCl3 ) d: 146.60 (C8a), 144.66 (Furan-2),
140.64 (Ph-1), 139.33 (Furan-5), 133.44 (C2), 129.14 (Ph-3,5*),
129.07 (Ph-2,6*), 128.26 (C8), 127.05 (Ph-4), 123.78 (C6), 123.59

J.-B. Véron et al. / Bioorg. Med. Chem. 16 (2008) 9536–9545
9541
(C7), 120.19 (C3), 118.78 (Furan-3), 118.74 (C5), 109.23 (Furan-
4), 36.54 (CH2), 33.04 (CH2), 25.86 (CH2), 17.61 (CH3). Anal. Calcd
for C21H20N2OS: C, 72.38; H, 5.79; N, 8.04. Found: C, 72.47; H,
5.74; N, 8.03.
were added successively by syringe. The tube was sealed with a
teflon-lined cap and the reaction mixture was heated at 112 °C.
After cooling at room temperature, the suspension was diluted
with CH2Cl2 and was filtered through Celite. Solvent was evapo-
rated and residue was purified by column chromatography.
4.2.3.8.
3-Benzylthiomethyl-6-methyl-8-(thien-3-yl)imidazo-
4.2.4.1.
8-Methyl-6-(morpholin-1-yl)-3-(phenethylthiometh-
[1,2-a]pyridine (30). The compound was obtained following the
general procedure using 9 (394 mg, 1 mmol), thien-3-ylboronic acid
(154 mg, 1.2 mmol). After 3 h at 85 °C and usual treatment, pure
product was obtained by column chromatography on neutral
alumina eluted with CH2Cl2/petroleum ether (50:50). 37% yield.
Mp 90–91 °C. 1H NMR (CDCl3) d: 8.55 (dd, 1H, J = 3–1.3 Hz, Thio-2),
7.78–7.75 (m, 2H, Thio-4, H5), 7.55 (s, 1H, H2), 7.46 (dd, 1H, J = 5.1–
3 Hz, Thio-5), 7.38–7.29 (m, 6H, Ph, H7), 3.94 (s, 2H, CH2), 3.63 (s, 2H,
CH2), 2.43 (s, 3H, CH3). 13C NMR (CDCl3) d: 144.25 (C8a), 138.21 (Ph-
1), 137.05 (Thio-3), 133.69 (C2), 129.64 (Ph-2,6*), 129.17 (Ph-3,5*),
127.79 (Ph-4), 127.38 (Thio-4), 126.03 (Thio-2*), 126.00 (Thio-5*),
125.07 (C7), 124.77 (C8), 122.33 (C6), 121.05 (C5), 119.34 (C3), 35.91
(CH2), 24.81 (CH2), 19.12 (CH3). Anal. Calcd for C20H18N2S2: C, 68.53;
H, 5.18; N, 7.99. Found: C, 68.69; H, 5.21; N, 7.95.
yl)imidazo[1,2-a]pyridine (17). The compound was obtained
following the general procedure using 5 (361 mg, 1 mmol) and
morpholine (130 lL, 1.5 mmol). The tube was heated for 20 h at
112 °C. Pure product was obtained by column chromatography on
neutral alumina eluted with ethyl acetate/petroleum ether (40:60).
87% yield. Mp 76–77 °C. 1H NMR (CDCl3) d: 7.46 (s, 1H, H2), 7.42
(m, 1H, H5), 7.35–7.22 (m, 3H, Ph-3,4,5), 7.16 (m, 2H, Ph-2,6), 6.97
(m, 1H, H7), 3.98 (s, 2H, CH2), 3.93 (t, 4H, J = 4.7 Hz, Morpholine),
3.12 (t, 4H, J = 4.7 Hz, Morpholine), 2.82 (m, 2H, CH2), 2.63 (m, 2H,
CH2), 2.60 (s, 3H, CH3). 13C NMR (CDCl3) d: 144.24 (C8a), 140.48
(Ph-1*), 140.07 (C6*), 132.85 (C2), 128.91 (Ph-2,6*), 128.82 (Ph-
3,5*), 127.75 (C8), 126.78 (Ph-4), 120.00 (C7, C3), 108.15 (C5),
67.15 (Morpholine), 51.10 (Morpholine), 36.29 (CH2), 32.72 (CH2),
25.73 (CH2), 17.54 (CH3). Anal. Calcd for C21H25N3OS: C, 68.63; H,
6.86; N, 11.43. Found: C, 68.60; H, 6.87; N, 11.46.
4.2.3.9. 8-(Furan-2-yl)-6-methyl-3-(phenethylthiomethyl)imi-
dazo[1,2-a]pyridine (31). The compound was obtained follow-
ing the general procedure using 7 (408 mg, 1 mmol), fur-2-
ylboronic acid (135 mg, 1.2 mmol). After 3 h at 85 °C, boronic acid
was again added (56 mg, 0.5 mmol). After 3 h more at 85 °C and
usual treatment, pure product was obtained by column chroma-
tography on neutral alumina eluted with ethyl acetate/petroleum
ether (10:90). 80% yield. Mp 95–96 °C. 1H NMR (CDCl3) d: 7.85 (m,
1H, H5), 7.74 (d, 1H, J = 3.4 Hz, Furan-3), 7.61–7.59 (m, 2H, H7,
Furan-5), 7.55 (s, 1H, H2), 7.36–7.15 (m, 5H, Ph), 6.64 (dd, 1H, J =
3.4–1.8 Hz, Furan-4), 4.00 (s, 2H, CH2), 2.86 (m, 2H, CH2), 2.66
(m, 2H, CH2), 2.45 (s, 3H, CH3). 13C NMR (CDCl3) d: 149.51 (C8a),
143.06 (Furan-5), 141.92 (Furan-2), 140.49 (Ph-1), 133.09 (C2),
128.98 (Ph-2,6*), 128.89 (Ph-3,5*), 126.87 (Ph-4), 122.19 (C8),
122.06 (C7), 120.85 (C5), 119.68 (C3*), 119.45 (C6*), 112.65 (Furan-
3*), 112.50 (Furan-4*), 36.32 (CH2), 32.82 (CH2), 25.55 (CH2), 18.95
(CH3). Anal. Calcd for C21H20N2OS: C, 72.38; H, 5.79; N, 8.04. Found:
C, 72.46; H, 5.80; N, 8.07.
4.2.4.2.
8-Methyl-3-phenethylthiomethyl-6-(pyrrolidin-1-yl)-
imidazo[1,2-a]pyridine (18). The compound was obtained fol-
lowing the general procedure using 5 (361 mg, 1 mmol) and
pyrrolidine (123 lL, 1.5 mmol). The tube was heated for 20 h at
112 °C. Pure product was obtained by column chromatography on
neutral alumina eluted with ethyl acetate/petroleum ether (40:60).
84% yield. Mp 131–132 °C. 1H NMR (CDCl3) d: 7.42 (s, 1H, H2),
7.35–7.14 (m, 5H, Ph), 7.09 (m, 1H, H5), 6.80 (q, 1H, J = 1.1 Hz,
H7), 3.99 (s, 2H, CH2), 3.31 (m, 4H, Pyrrolidine), 2.83 (m, 2H, CH2),
2.62 (s, 3H, CH3), 2.63 (m, 2H, CH2), 2.08 (m, 4H, Pyrrolidine). 13C
NMR (CDCl3) d: 143.00 (C8a), 140.66 (Ph-1), 137.59 (C6), 132.20
(C2), 128.95(Ph-2,6*), 128.82 (Ph-3,5*), 127.23 (C8), 126.74 (Ph-4),
118.83 (C3), 116.77 (C7), 101.81 (C5), 48.68 (Pyrrolidine), 36.39
(CH2), 32.70 (CH2), 25.91 (CH2), 25.66 (Pyrrolidine), 17.64 (CH3).
Anal. Calcd for C21H25N3S: C, 71.75; H, 7.17; N, 11.95. Found: C,
71.73; H, 7.18; N, 11.94.
4.2.4.3. 6-Methyl-8-(morpholin-1-yl)-3-(phenethylthiomethyl)-
imidazo[1,2-a]pyridine (33). The compound was obtained fol-
lowing the general procedure using 8 (361 mg, 1 mmol) and
4.2.3.10. 8-(Furan-3-yl)-6-methyl-3-(phenethylthiomethyl)imi-
dazo[1,2-a]pyridine (32). The compound was obtained following
the general procedure using 7 (300 mg, 0.74 mmol), fur-3-ylboronic
acid (91 mg, 0.81 mmol). After 3 h at 85 °C, boronic acid was again
added (56 mg, 0.5 mmol). After 3 h more at 85 °C and usual
treatment, pure product was obtained by column chromatography
on neutral alumina eluted with ethyl acetate/petroleum ether
(10:90). 65% yield. Mp 92–93 °C. 1H NMR (CDCl3) d: 8.76 (m, 1H,
Furan-5), 7.79 (m,1H, H5), 7.54 (t,1H, J = 1.7 Hz, Furan-2), 7.50 (s,1H,
H2), 7.33–7.13 (m, 6H, Ph, H7), 6.94 (dd, 1H, J = 1.7–0.8 Hz, Furan-4),
morpholine (130 lL, 1.5 mmol). The tube was heated for 48 h at
112 °C. Pure product was obtained by column chromatography on
neutral alumina eluted by CH2Cl2. 30% yield. Mp 108–110 °C. 1H
NMR (CDCl3) d: 7.58 (m, 1H, H5), 7.41 (s, 1H, H2), 7.35–7.22 (m, 3H,
Ph-3,4,5), 7.16 (m, 2H, Ph-2,6), 6.34 (d, 1H, J = 1 Hz, H7), 4.00 (t, 4H,
J = 4.7 Hz, Morpholine), 3.95 (s, 2H, CH2), 3.54 (t, 4H, J = 4.7 Hz,
Morpholine), 2.83 (m, 2H, CH2), 2.62 (m, 2H, CH2), 2.35 (s, 3H, CH3).
13C NMR (CDCl3 ) d: 141.35 (C8a), 140.94 (Ph-1*), 140.76 (C8*),
131.62 (C2), 129.20 (Ph-2,6*), 129.14 (Ph-3,5*), 127.10 (Ph-4),
122.89 (C6), 119.56 (C3), 116.11 (C5), 110.77 (C7), 67.60 (Mor-
pholine), 50.71 (Morpholine), 36.58 (CH2), 32.98 (CH2), 25.81
(CH2), 19.48 (CH3). Anal. Calcd for C21H25N3OS: C, 68.63; H, 6.86; N,
11.43. Found: C, 68.69; H, 6.87; N, 11.41.
3.96 (CH2), 2.82 (m, 2H, CH2), 2.62 (m, 2H, CH2), 2.38 (s, 3H, CH3). 13
C
NMR (CDCl3) d: 143.80 (Furan-5), 143.58 (C8a), 143.45 (Furan-2),
140.53 (Ph-1), 132.98 (C2), 129.00 (Ph-2,6*), 128.91 (Ph-3,5*),
126.88 (Ph-4), 123.86 (C7), 122.14 (Furan-3*), 121.67 (C8*), 121.25
(C6*), 120.56 (C5), 119.42 (C3), 108.77 (Furan-4), 36.34 (CH2),
32.85 (CH2), 25.60 (CH2), 18.94 (CH3). Anal. Calcd for C21H20N2OS:
C, 72.38; H, 5.79; N, 8.04. Found: 72.35; H, 5.79; N, 8.02.
4.2.4.4.
6-Methyl-3-phenethylthiomethyl-8-(pyrrolidin-1-yl)-
imidazo[1,2-a]pyridine (34). The compound was obtained fol-
lowing the general procedure using 8 (361 mg, 1 mmol) and
4.2.4. General procedure for palladium-catalysed aminations
pyrrolidine (123 lL, 1.5 mmol). The tube was heated for 48 h at
Halogenated imidazo[1,2-a]pyridines 5,
8 or 9 (1 mmol),
112 °C. Pure product was obtained by column chromatography on
neutral alumina eluted with diethyl ether/petroleum ether (40:60).
80% yield. Mp 68–69 °C. 1H NMR (CDCl3) d: 7.39 (s, 1H, H2), 7.34–
7.16 (m, 6H, Ph, H5), 5.93 (s, 1H, H7), 3.95 (s, 2H, CH2), 3.81 (t, 4H,
J = 6.7 Hz, Pyrrolidine), 2.82 (m, 2H, CH2), 2.65 (m, 2H, CH2), 2.32 (s,
Pd2(dba)3 (9 mg, 0.01 mmol), t-BuONa (135 mg, 1.4 mmol), rac-
BINAP (19 mg, 0.03 mmol), and amine if solid (1.5 mmol) were
added to a screw-capped test tube. The tube was evacuated and
back-filled with N2. Amine if liquid (1.5 mmol), toluene (2 mL)

9542
J.-B. Véron et al. / Bioorg. Med. Chem. 16 (2008) 9536–9545
on neutral alumina eluted with CH2Cl2. 90% yield. Mp 144–
145 °C. 1H NMR (CDCl3) d: 8.49 (dd, 1H, J = 2–0.7 Hz, H5), 7.52 (s,
1H, H2), 7.34–7.22 (m, 4H, H7, Ph-3,4,5), 7.16 (m, 2H, Ph-2,6),
4.01 (s, 2H, CH2), 3.92 (t, 2H, J = 7 Hz, Pyrrolidinone), 2.84 (m, 2H,
CH2), 2.72–2.58 (m, 7H, CH2, CH3, Pyrrolidinone), 2.26 (m, 2H, Pyr-
rolidinone). 13C NMR (CDCl3) d: 174.85 (C = O), 144.94 (C8a),
140.52 (Ph-1), 133.56 (C2), 128.94 (Ph-2,6*), 128.86 (Ph-3,5*),
127.86 (C6*), 127.29 (C8*), 126.80 (Ph-4), 120.45 (C3), 118.82
(C7), 114.81 (C5), 49.41 (Pyrrolidinone), 36.32 (CH2), 32.91
(CH2*), 32.65 (Pyrrolidinone*), 25.63 (CH2), 18.49 (Pyrrolidinone),
17.55 (CH3). Anal. Calcd for C21H23N3OS: C, 69.01; H, 6.34; N,
11.50. Found: C, 69.03; H, 6.31; N, 11.54.
3H, CH3), 2.04 (m, 4H, Pyrrolidine). 13C NMR (CDCl3) d: 140.70 (C8*),
140.50 (C8a*), 138.24 (Ph-1), 130.99 (C2), 129.00 (Ph-2,6*), 128.88
(Ph-3,5*), 126.80 (Ph-4), 123.62 (C6), 118.94 (C3), 111.14 (C5),
104.01 (C7), 50.38 (Pyrrolidine), 36.47 (CH2), 32.83 (CH2), 25.80
(Pyrrolidine, CH2), 19.33 (CH3). Anal. Calcd for C21H25N3S: C, 71.25;
H, 7.17; N, 11.95. Found: C, 71.20; H, 7.19; N, 11.96.
4.2.4.5.
dazo[1,2-a]pyridine (35). The compound was obtained follow-
ing the general procedure using (394 mg, 1 mmol) and
pyrrolidine (123 L, 1.5 mmol). The tube was heated for 48 h at
3-Benzylthiomethyl-6-methyl-8-(pyrrolidin-1-yl)imi-
9
l
112 °C. Pure product was obtained by column chromatography on
neutral alumina eluted with CH2Cl2/petroleum ether (70:30). 60%
yield. Mp 86–87 °C. 1H NMR (CDCl3) d: 7.38–7.29 (m, 5H, Ph), 7.36
(s, 1H, H2), 7.22 (s, 1H, H5), 5.91 (s, 1H, H7), 3.85 (s, 2H, CH2), 3.80
(m, 4H, Pyrrolidine), 3.61 (s, 2H, CH2), 2.29 (s, 3H, CH3), 2.04 (m,
4H, Pyrrolidine). 13C NMR (CDCl3) d: 140.46 (C8a), 137.94 (Ph-1),
130.93 (C2), 129.22 (Ph-2,6*), 128.66 (Ph-3,5*), 127.22 (Ph-4),
123.24 (C6), 118.49 (C3), 110.81 (C5), 103.67 (C7), 50.08 (Pyrrol-
idine), 35.34 (CH2), 25.50 (Pyrrolidine), 24.50 (CH2), 19.01 (CH3).
C8 not found. Anal. Calcd for C20H23N3S: C, 71.18; H, 6.87; N, 12.45.
Found: C, 71.25; H, 6.84; N, 12.49.
4.2.5.3.
8-Methyl-3-phenethylthiomethyl-6-(pyrrol-1-yl)imi-
dazo[1,2-a]pyridine (21). The compound was obtained follow-
ing the general procedure using 4 (408 mg, 1 mmol), CuI (10 mg,
0.05 mmol), K3PO4 (447 mg, 2.1 mmol), pyrrole (84
lL, 1.2 mmol),
N,N 0-dimethylethylenediamine (16
l
L, 0.15 mmol) and toluene
(2 mL). The tube was heated for 48 h at 112 °C. Pure product was
obtained by column chromatography on neutral alumina eluted
with diethylether/petroleum ether (50:50). 96% yield. Mp 58–
60 °C. 1H NMR (CDCl3) d: 8.11 (m, 1H, H5), 7.56 (s, 1H, H2), 7.35–
7.23 (m, 4H, H7, Ph-3,4,5), 7.18 (m, 2H, Ph-2,6), 7.07 (t, 2H,
J = 2.1 Hz, pyrrole-2,5), 6.43 (t, 2H, J = 2.1 Hz, pyrrole-3,4), 4.01 (s,
2H, CH2), 2.84 (m, 2H, CH2), 2.72 (s, 3H, CH3), 2.66 (m, 2H, CH2). 13
C
4.2.5. General procedure for copper-catalysed couplings of
amines, lactam, azoles or thiophenols
NMR (CDCl3) d: 145.81 (C8a), 140.59 (Ph-1), 134.12 (C2), 129.69
(C6), 129.12 (C8, Ph-2,3,5,6), 127.11 (Ph-4), 120.85 (C3, Pyrrole-
2,5), 120.59 (C7), 114.96 (C5), 111.38 (Pyrrole-3,4), 36.54 (CH2),
33.16 (CH2), 25.90 (CH2), 17.75 (CH3). Anal. Calcd for C21H21N3S: C,
72.59; H, 6.09; N, 12.09. Found: C, 72.64; H, 6.11; N, 12.12.
Halogenated imidazo[1,2-a]pyridines 4, 6, 7 or 9 (1 mmol), cop-
per (I) iodide, base, and amine or azole or thiophenol if solids were
added to a screw-capped test tube. The tube was evacuated and
back-filled with N2. N,N0-Dimethylethylenediamine (11
lL,
0.1 mmol) or ethylene glycol (111
lL, 2 mmol), amine or azole or
4.2.5.4. 3-Benzylthiomethyl-8-methyl-6-(pyrrol-1-yl)imidazo-
[1,2-a]pyridine (22). The compound was obtained following
the general procedure using 6 (394 mg, 1 mmol), CuI (10 mg,
thiophenol if liquids (1.2 mmol) and isopropanol (1 mL) or toluene
(2 mL) were added successively by syringe. The tube was sealed with
a teflon-lined cap and the reaction mixture was heated at 85 °C with
isopropanol or 112 °C with toluene. After cooling at room tempera-
ture, the suspension was diluted with CH2Cl2 and filtered through
Celite. Solvent was evaporated and residue was purified by column
chromatography.
0.05 mmol), K3PO4 (447 mg, 2.1 mmol), pyrrole (84
lL, 1.2 mmol),
N,N 0-dimethylethylenediamine (16
l
L, 0.15 mmol) and toluene
(2 mL). The tube was heated for 48 h at 112 °C. Pure product was
obtained by column chromatography on neutral alumina eluted
with CH2Cl2/petroleum ether (70:30). 93% yield. Mp 75–77 °C. 1H
NMR (CDCl3) d: 8.01 (m, 1H, H5), 7.54 (s, 1H, H2), 7.35–7.26 (m, 5H,
Ph), 7.21 (m, 1H, H7), 7.04 (t, 2H, J = 2.2 Hz, Pyrrole-2,5), 6.43 (t, 2H,
J = 2.2 Hz, Pyrrole-3,4), 3.94 (s, 2H, CH2), 3.62 (s, 2H, CH2), 2.71 (s,
3H, CH3). 13C NMR (CDCl3) d: 145.72 (C8a), 138.03 (Ph-1), 134.30
(C2), 129.61 (C6), 129.48 (Ph-2,6*), 129.15 (Ph-3,5*), 129.00 (C8),
127.79 (Ph-4), 120.81 (Pyrrole-2,5), 120.75 (C3), 120.45 (C7),
114.86 (C5), 111.31 (Pyrrole-3,4), 35.99 (CH2), 24.84 (CH2), 17.68
(CH3). Anal. Calcd for C20H19N3S: C, 72.04; H, 5.74; N, 12.60. Found:
C, 72.11; H, 5.71; N, 12.61.
4.2.5.1.
omethylimidazo[1,2-a]pyridine (19). The compound was
obtained following the general procedure using (408 mg,
1 mmol), CuI (28 mg, 0.15 mmol), K3PO4 (447 mg, 2.1 mmol),
ethylene glycol (111 L, 2 mmol), N-methylpiperazine (133 L,
8-Methyl-6-(4-methylpiperazin-1-yl)-3-phenethylthi-
4
l
l
1.2 mmol) and isopropanol (1 mL). The tube was heated for 48 h at
85 °C. Pure product was obtained by column chromatography on
neutral alumina eluted with CH2Cl2. 62% yield. Mp 84–85 °C. 1H
NMR (CDCl3) d: 7.44 (s, 1H, H2), 7.42 (m, 1H, H5), 7.33–7.22 (m, 3H,
Ph-3,4,5), 7.15 (m, 2H, Ph-2,6), 6.97 (m, 1H, H7), 3.98 (s, 2H, CH2),
3.16 (t, 4H, J = 4.8 Hz, Piperazine), 2.82 (m, 2H, CH2), 2.68–2.58 (m,
6H, CH2, Piperazine), 2.61 (s, 3H, CH3), 2.42 (s, 3H, CH3). 13C NMR
(CDCl3) d: 144.35 (C8a), 140.61 (Ph-1*), 140.14 (C6*), 132.93 (C2),
129.01 (Ph-2,6*), 128.92 (Ph-3,5*), 127.68 (C8), 126.87 (Ph-4),
120.50 (C7), 120.00 (C3), 108.31 (C5), 55.46 (Piperazine), 50.91
(Piperazine), 46.60 (CH3), 36.44 (CH2), 32.83 (CH2), 25.88 (CH2),
17.59 (CH3). Anal. Calcd for C22H28N4S: C, 69.44; H, 7.42; N, 14.72.
Found: C, 69.48; H, 7.38; N, 14.69.
4.2.5.5. 6-(Imidazol-1-yl)-8-methyl-3-phenethylthiomethylimi-
dazo[1,2-a]pyridine (23). The compound was obtained following
the general procedure using 4 (408 mg, 1 mmol), CuI (10 mg,
0.05 mmol), K3PO4 (447 mg, 2.1 mmol), imidazole (82 mg,
1.2 mmol), N,N0-dimethylethylenediamine (16
lL, 0.15 mmol) and
toluene (2 mL). The tube was heated for 48 h at 112 °C. Pure product
was obtained by column chromatography on neutral alumina eluted
with CH2Cl2. 20% yield. Mp 130–132 °C. 1H NMR (CDCl3) d: 8.15 (m,
1H, H5), 7.84 (br s, 1H, Imidazole-2), 7.60 (s, 1H, H2), 7.34–7.22 (m,
5H, H7, Imidazole-5, Ph-3,4,5), 7.17–7.12 (m, 3H, Imidazole-4, Ph-
2,6), 4.01 (s,2H, CH2), 2.85 (m,2H, CH2), 2.73 (s,3H, CH3), 2.68 (m,2H,
CH2). 13C NMR (CDCl3 ) d: 145.83 (C8a), 140.27 (Ph-1), 136.76
(Imidazole-2), 134.36 (C2), 131.08 (Imidazole-5), 129.65 (C6),
128.91 (Ph-2,3,5,6), 126.94 (Ph-4), 125.78 (C8), 121.06 (C3), 120.12
(Imidazole-4), 119.66 (C7), 116.25 (C5), 36.24 (CH2), 32.95 (CH2),
25.63 (CH2), 17.52 (CH3).Anal. Calcd for C20H20N4S: C, 68.93; H, 5.79;
N, 16.08. Found: C, 68.98; H, 5.82; N, 16.11.
4.2.5.2. N-(8-Methyl-3-phenethylthiomethylimidazo[1,2-a]pyri-
din-6-yl)pyrrolidin-2-one (20).
following the general procedure using 4 (408 mg, 1 mmol), CuI
The compound was obtained
(28 mg, 0.15 mmol), K3PO4 (447 mg, 2.1 mmol), pyrrolidin-2-one
(116
l
L,
1.5 mmol),
N,N0-dimethylethylenediamine
(16 lL,
0.15 mmol) and toluene (2 mL). The tube was heated for 48 h at
112 °C. Pure product was obtained by column chromatography

J.-B. Véron et al. / Bioorg. Med. Chem. 16 (2008) 9536–9545
9543
4.2.5.6.
6-(Indol-1-yl)-8-methyl-3-phenethylthiomethylimi-
neutral alumina eluted with CH2Cl2. 96% yield. Mp 86–87 °C. 1H
NMR (CDCl3) d: 8.24 (m, 1H, H5), 7.53 (s, 1H, H2), 7.34–7.19 (m, 7H,
Ph-3,4,5, PhCl-2,3,5,6), 7.15 (m, 2H, Ph-2,6), 7.01 (m, 1H, H7), 3.96
(s, 2H, CH2), 2.83 (m, 2H, CH2), 2.65 (m, 2H, CH2), 2.60 (s, 3H, CH3).
13C NMR (CDCl3) d: 146.25 (C8a), 140.40 (Ph-1), 135.43 (PhCl-1),
133.59 (C2), 133.10 (PhCl-4), 130.50 (PhCl-2,6), 129.77 (PhCl-3,5),
129.12 (C8), 128.96 (Ph-2,3,5,6), 128.31 (C7), 126.95 (Ph-4), 126.16
(C5), 120.54 (C3), 118.47 (C6), 36.40 (CH2), 33.10 (CH2), 25.59
(CH2), 17.35 (CH3). Anal. Calcd for C23H21ClN2S2: C, 65.00; H, 4.98;
N, 6.59. Found: C, 65.12; H, 4.96; N, 6.64.
dazo[1,2-a]pyridine (24). The compound was obtained follow-
ing the general procedure using 4 (408 mg, 1 mmol), CuI (28 mg,
0.15 mmol), K3PO4 (447 mg, 2.1 mmol), indole (175 mg, 1.5 mmol),
N,N0-dimethylethylenediamine (16
lL, 0.15 mmol) and toluene
(2 mL). The tube was heated for 48 h at 112 °C. Pure product was
obtained by column chromatography on neutral alumina eluted
with CH2Cl2. 62% yield. Mp 63–65 °C. 1H NMR (CDCl3) d: 8.24 (m,
1H, H5), 7.76 (m, 1H, Indole), 7.62 (s, 1H, H2), 7.53 (m, 1H, Indole),
7.35 (d, 1H, J = 3.3 Hz, Indole), 7.34–7.14 (m, 8H, Ph, H7, 2 H
Indole), 6.77 (dd, 1H, J = 3.3–0.8 Hz, Indole), 4.01 (s, 2H, CH2), 2.85
(m, 2H, CH2), 2.76 (s, 3H, CH3), 2.68 (m, 2H, CH2). 13C NMR (CDCl3)
d: 145.71 (C8a), 140.37 (Ph-1), 136.85 (Indole quat.), 133.91 (C2),
129.56 (C6*), 128.95 (Ph-2,3,5,6), 128.59 (Indole), 127.59 (Indole
quat.*), 126.94 (Ph-4), 123.21 (Indole), 122.66 (C7), 121.75 (Indole),
121.13 (Indole), 120.81 (C3), 118.46 (C5), 110.63 (Indole), 104.51
(Indole), 36.36 (CH2), 33.05 (CH2), 25.74 (CH2), 17.57 (CH3). C8 not
found. Anal. Calcd for C25H23N3S: C, 75.53; H, 5.83; N, 10.57.
Found: C, 75.62; H, 5.87; N, 10.55.
4.2.5.10.
omethylimidazo[1,2-a]pyridine (28). The compound was
obtained following the general procedure using (408 mg,
6-(4-Hydroxyphenylthio)-8-methyl-3-phenethylthi-
4
1 mmol), CuI (10 mg, 0.05 mol), K2CO3 (198 mg, 2 mmol), 4-
hydroxythiophenol (190 mg, 1.5 mmol), N,N0-dimethylethylenedi-
amine (16 lL, 0.15 mmol) and isopropanol (1 mL). The tube was
heated for 24 h at 85 °C. Pure product was obtained by column
chromatography on neutral alumina eluted with CH2Cl2. 60% yield.
Mp 139–140 °C. 1H NMR (DMSO) d: 9.81 (s, 1H, OH), 8.40 (s, 1H,
H5), 7.55 (s, 1H, H2), 7.31–7.19 (m, 7H, Ph, PhOH-2,6), 6.99 (s, 1H,
H7), 6.80 (d, 2H, J = 8.2 Hz, Ph-3,5), 4.21 (s, 2H, CH2), 2.74 (m, 2H,
CH2), 2.57 (m, 2H, CH2), 2.44 (s, 3H, CH3). 13C NMR (DMSO) d:
158.45 (PhOH-4), 145.47 (C8a), 141.22 (Ph-1), 134.10 (PhOH-2,6),
133.57 (C2), 129.35 (Ph-2,6), 129.12 (Ph-3,5), 128.13 (PhOH-1),
126.99 (Ph-4, C7), 125.04 (C5), 123.63 (C8*), 121.81 (C6*), 120.68
(C3), 117.40 (PhOH-3,5), 36.01 (CH2), 32.87 (CH2), 24.55 (CH2),
17.24 (CH3). Anal. Calcd for C23H22N2OS2: C, 67.95; H, 5.45; N, 6.89.
Found: C, 97.93; H, 5.46; N, 6.89.
4.2.5.7. 8-Methyl-3-phenethylthiomethyl-6-(pyrrolo[2,3-b]pyri-
din-1-yl)imidazo[1,2-a]pyridine (25). The compound was
obtained following the general procedure using
4 (408 mg,
1 mmol), CuI (10 mg, 0.05 mmol), K3PO4 (447 mg, 2.1 mmol), 7-
azaindole (142 mg, 1.2 mmol), N,N 0-dimethylethylenediamine
(16 lL, 0.15 mol) and toluene (2 mL). The tube was heated for
48 h at 112 °C. Pure product was obtained by column chromatog-
raphy on neutral alumina eluted with CH2Cl2. 93% yield. Mp 90–
94 °C. 1H NMR (CDCl3) d: 8.52 (m, 1H, H5), 8.40 (dd, 1H, J = 4.7–
1.5 Hz, azaindole), 8.02 (dd, 1H, J = 7.9–1.5 Hz, azaindole), 7.58 (s,
1H, H2), 7.49 (d, 1H, J = 3.6 Hz, azaindole), 7.42 (m, 1H, azaindole),
7.32–7.14 (m, 6H, Ph, H7), 6.69 (d, 1H, J = 3.6 Hz, azaindole), 4.03 (s,
4.2.5.11. 6-(4-Aminophenylthio)-8-methyl-3-phenethylthiome-
thylimidazo[1,2-a]pyridine (29). The compound was obtained
following the general procedure using 4 (408 mg, 1 mmol), CuI
(38 mg, 0.20 mmol), K2CO3 (198 mg, 2 mmol), 4-aminothiophenol
2H, CH2), 2.83 (m, 2H, CH2), 2.73 (s, 3H, CH3), 2.64 (m, 2H, CH2). 13
NMR (CDCl3 d: 148.22 (azaindole), 145.56 (C8a), 144.24
(azaindole), 140.45 (Ph-1), 133.64 (C2), 129.80 (azaindole),
C
)
(188 mg, 1.5 mmol), N,N 0-dimethylethylenediamine (22
lL,
0.20 mmol) and isopropanol (1 mL). The tube was heated for 48 h
at 85 °C. Pure product was obtained by column chromatography on
neutral alumina eluted with CH2Cl2. 47% yield. Oil. 1H NMR (CDCl3)
d: 7.99 (m, 1H, H5), 7.47 (s, 1H, H2), 7.34–7.23 (m, 3H, Ph-3,4,5),
7.29 (d, 2H, J = 8.7 Hz, PhNH2-2,6), 7.16 (m, 2H, Ph-2,6), 6.96 (m,
1H, H7), 6.65 (d, 2H, J = 8.7 Hz, PhNH2-3,5), 3.92 (s, 2H, CH2), 2.82
(m, 2H, CH2), 2.63 (m, 2H, CH2), 2.56 (s, 3H, CH3). 13C NMR (CDCl3)
d: 147.60 (PhNH2-4), 145.98 (C8a), 140.54 (Ph-1), 134.73 (PhNH2-
2,6), 133.11 (C2), 128.99 (Ph-2,6*), 128.95 (Ph-3,5*), 128.06
(PhNH2-1), 126.91 (Ph-4), 126.73 (C7), 123.16 (C8*), 122.34 (C5),
121.35 (C6*), 120.16 (C3), 116.18 (PhNH2-3,5), 36.40 (CH2), 33.09
(CH2), 25.57 (CH2), 17.37 (CH3). Anal. Calcd for C23H23N3S2: C,
68.11; H, 5.72; N, 10.36. Found: C, 68.24; H, 5.69; N, 10.34.
128.96 (Ph-2,6*), 128.90 (Ph-3,5*), 128.48 (azaindole), 128.41
(azaindole), 126.88 (Ph-4), 126.42 (C8), 122.32 (azaindole), 121.81
(C6), 120.82 (azaindole, C3), 118.33 (C5), 117.46 (C7), 102.52
(azaindole), 36.30 (CH2), 33.00 (CH2), 25.63 (CH2), 17.64 (CH3).
Anal. Calcd for C24H22N4S: C, 72.33; H, 5.56; N, 14.06. Found: C,
12.45; H, 5.64; N, 14.13.
4.2.5.8.
8-Methyl-3-phenethylthiomethylimidazo[1,2-a]pyri-
din-6-carbonitrile (26). The compound was obtained following
the general procedure using 4 (408 mg, 1 mmol), CuI (19 mg,
0.10 mmol), sodium cyanide (59 mg, 1.2 mmol), N,N0-dimethyleth-
ylenediamine (106 lL, 1 mmol) and toluene (2 mL). The tube was
heated for 24 h at 112 °C. Pure product was obtained by column
chromatography on neutral alumina eluted with CH2Cl2. 94% yield.
Mp 75–76 °C. 1H NMR (CDCl3) d: 8.48 (m, 1H, H5), 7.60 (s, 1H, H2),
7.37–7.24 (m, 3H, Ph-3,4,5), 7.18 (m, 3H, H7, Ph-2,6), 3.98 (s, 2H,
CH2), 2.85 (m, 2H, CH2), 2.65 (m, 5H, CH2, CH3). 13C NMR (CDCl3) d:
145.99 (C8a), 139.91 (Ph-1), 134.49 (C2), 129.15 (C8), 128.89 (C5),
128.57 (Ph-2,6*), 128.49 (Ph-3,5*), 126.53 (Ph-4), 122.37 (C7),
121.33 (C3), 117.11 (CN), 98.21 (C6), 35.82 (CH2), 32.67 (CH2),
24.84 (CH2), 16.89 (CH3). Anal. Calcd for C18H17N3S: C, 70.33; H,
5.57; N, 13.67. Found: C, 70.42; H, 5.53; N, 13.68.
4.2.5.12. 6-Methyl-8-(4-methylpiperazin-1-yl)-3-phenethylthi-
omethylimidazo[1,2-a]pyridine (36). The compound was
obtained following the general procedure using 7 (408 mg, 1 mmol),
CuI (28 mg, 0.15 mmol), K3PO4 (447 mg, 2.1 mmol), ethylene glycol
(111 lL, 2 mmol), N-methylpiperazine (133 lL, 1.2 mmol) and
isopropanol (1 mL). The tube was heated for 48 h at 85 °C. Pure
product was obtained by column chromatography on neutral
alumina eluted with CH2Cl2. 35% yield. Mp 63–65 °C. 1H NMR
(CDCl3) d: 7.56 (m, 1H, H5), 7.41 (s, 1H, H2), 7.35–7.15 (m, 5H, Ph),
6.36 (m, 1H, H7), 3.95 (s, 2H, CH2), 3.59 (br s, 4H, Piperazine), 2.87–
2.74 (m, 6H, Piperazine, CH2), 2.62 (m, 2H, CH2), 2.44 (s, 3H, CH3),
2.35 (s, 3H, CH3). RMN 13C (CDCl3) d: 141.42 (C8a*), 140.76 (Ph-1*),
140.57 (C8*), 131.63 (C2), 128.98 (Ph-2,6*), 128.89 (Ph-3,5*), 126.84
(Ph-4), 122.54 (C6), 119.15 (C3), 115.66 (C5), 110.58 (C7), 55.44
(Piperazine), 49.84 (Piperazine), 46.54 (CH3), 36.36 (CH2), 32.71
(CH2), 25.62 (CH2), 19.26 (CH3). Anal. Calcd for C22H28N4S: C, 69.44;
H, 7.42; N, 14.72. Found: 69.49; H, 7.41; N, 14.76.
4.2.5.9. 6-(4-Chlorophenylthio)-8-methyl-3-phenethylthiome-
thylimidazo[1,2-a]pyridine (27). The compound was obtained
following the general procedure using 4 (408 mg, 1 mmol), CuI
(10 mg, 0.05 mmol), K2CO3 (198 mg, 2 mmol), 4-chlorothiophenol
(175 mg, 1.2 mmol), N,N 0-dimethylethylenediamine (16
lL,
0.15 mmol) and isopropanol (1 mL). The tube was heated for 24 h
at 85 °C. Pure product was obtained by column chromatography on

9544
J.-B. Véron et al. / Bioorg. Med. Chem. 16 (2008) 9536–9545
4.2.5.13.
N-(6-methyl-3-phenethylthiomethylimidazo[1,2-
(br s, 1H, Imidazole-4), 7.54 (s, 1H, H2), 7.36–7.23 (m, 4H, H7, Ph-
3,4,5), 7.20–7.14 (m, 3H, Imidazole-5, Ph-2,6), 4.01 (s, 2H, CH2),
2.87 (m, 2H, CH2), 2.68 (m, 2H, CH2), 2.47 (s, 3H, CH3). 13C NMR
(CDCl3 ) d: 140.35 (C8a*), 139.89 (Ph-1*), 137.63 (Imidazole-2),
133.77 (C2), 130.23 (Imidazole-5), 128.91 (Ph-2,3,5,6), 126.90 (Ph-
4), 126.52 (C8), 121.96 (C6), 120.87 (C5), 120.82 (C3), 119.20
(Imidazole-4), 117.73 (C7), 36.31 (CH2), 33.01 (CH2), 25.53 (CH2),
18.89 (CH3). Anal. Calcd for C20H20N4S: C, 68.93; H, 5.79; N, 16.08.
Found: C, 69.02; H, 5.81; N, 16.06.
a]pyridin-8-yl)pyrrolidin-2-one (37). The compound was
obtained following the general procedure using (408 mg,
1 mmol), CuI (28 mg, 0.15 mmol), K3PO4 (447 mg, 2.1 mmol),
ethylene glycol (111 L, 2 mmol), pyrrolidin-2-one (116 L,
7
l
l
1.5 mmol) and isopropanol (1 mL). The tube was heated for 48 h
at 85 °C. Pure product was obtained by column chromatography on
neutral alumina eluted with ethyl acetate/petroleum ether (20:80).
54% yield. Mp 106–107 °C. 1H NMR (CDCl3) d: 7.83 (m, 1H, H5), 7.44
(s, 1H, H2), 7.36 (d, 1H, J = 1.3 Hz, H7), 7.35–7.24 (m, 3H, Ph-3,4,5),
7.18 (m, 2H, Ph-2,6), 4.31 (m, 2H, Pyrrolidinone), 3.97 (s, 2H, CH2),
2.86 (m, 2H, CH2), 2.65 (m, 4H, CH2, Pyrrolidinone), 2.41 (s, 3H,
CH3), 2.29 (m, 2H, Pyrrolidinone). 13C NMR (CDCl3 ) d: 175.82
(C@O), 141.67 (C8a), 140.46 (Ph-1), 132.74 (C2), 128.96 (Ph-2,6*),
128.91 (Ph-3,5*), 127.50 (C8), 126.89 (Ph-4), 124.01 (C7), 122.18
(C6), 120.65 (C5), 119.74 (C3), 50.29 (Pyrrolidinone), 36.31 (CH2),
32.88 (CH2*), 32.10 (Pyrrolidinone*), 25.53 (CH2), 19.25 (Pyrrolid-
inone), 18.86 (CH3). Anal. Calcd for C21H23N3OS: C, 69.01; H, 6.34;
N, 11.50. Found: C, 69.05; H, 6.32; N, 11.48.
4.2.5.17.
8-(Indol-1-yl)-6-methyl-3-phenethylthiomethylimi-
dazo[1,2-a]pyridine (41). The compound was obtained follow-
ing the general procedure using 7 (408 mg, 1 mmol), CuI (28 mg,
0.15 mmol), K3PO4 (447 mg, 2.1 mmol), indole (175 mg, 1.5 mmol),
ethylene glycol (111 lL, 2 mmol) and isopropanol (1 mL). The tube
was heated for 60 h at 85 °C. Pure product was obtained by column
chromatography on silica gel eluted with CH2Cl2/methanol
(99.5:0.5). 37% yield. Mp 102–104 °C. 1H NMR (CDCl3) d: 7.94 (m,
1H, H5), 7.90 (d, 1H, J = 3.4 Hz, indole), 7.73 (m, 1H, indole), 7.60
(m, 1H, indole), 7.54 (s, 1H, H2), 7.37–7.17 (m, 8H, Ph, H7, 2 H
indole), 6.79 (dd, 1H, J = 3.4–0.8 Hz, indole), 4.03 (s, 2H, CH2), 2.89
(m, 2H, CH2), 2.69 (m, 2H, CH2), 2.50 (s, 3H, CH3). 13C NMR (CDCl3)
d: 141.85 (C8a), 140.49 (Ph-1), 136.60 (indole quat.), 133.81 (C2),
130.05 (indole quat.), 129.49 (indole), 129.03 (Ph-2,6*), 128.99 (Ph-
3,5*), 128.74 (C8), 126.97 (Ph-4), 122.79 (indole), 122.10 (C7*),
121.69 (C6*), 121.31 (indole*), 121.24 (indole*), 120.42 (C5), 111.34
(indole), 104.58 (indole), 36.42 (CH2), 33.02 (CH2), 25.62 (CH2),
19.03 (CH3). C3 not found. Anal. Calcd for C25H23N3S: C, 75.53; H,
5.83; N, 10.57. Found: C, 75.51; H, 5.84; N, 10.52.
4.2.5.14. 6-Methyl-3-phenethylthiomethyl-8-(pyrrol-1-yl)imi-
dazo[1,2-a]pyridine (38). The compound was obtained follow-
ing the general procedure using 7 (408 mg, 1 mmol), CuI (10 mg,
0.05 mmol), K3PO4 (447 mg, 2.1 mmol), pyrrole (84
lL, 1.2 mmol),
0
N,N -dimethylethylenediamine (16
lL, 0.15 mmol) and toluene
(2 mL). The tube was heated for 60 h at 112 °C. Pure product was
obtained by column chromatography on neutral alumina eluted
with ethyl acetate/petroleum ether (20:80). 94% yield. Mp 109–
110 °C. 1H NMR (CDCl3) d: 7.82 (m, 1H, H5), 7.65 (t, 2H, J = 2.2 Hz,
Pyrrole-2,5), 7.55 (s, 1H, H2), 7.37–7.23 (m, 3H, Ph-3,4,5), 7.18 (m,
2H, Ph-2,6), 7.09 (d, 1H, J = 1.3 Hz, H7), 6.44 (t, 2H, J = 2.2 Hz,
Pyrrole-3,4), 4.01 (s, 2H, CH2), 2.87 (m, 2H, CH2), 2.75 (m, 2H, CH2),
2.45 (s, 3H, CH3). 13C NMR (CDCl3) d: 140.76 (C8a*), 140.65 (Ph-1*),
133.74 (C2), 130.09 (C6), 129.14 (Ph-2,3,5,6), 127.13 (Ph-4), 122.41
(C8*), 121.76 (Pyrrole-2,5), 120.35 (C3*), 119.63 (C5), 117.35 (C7),
110.99 (Pyrrole-3,4), 36.57 (CH2), 33.13 (CH2), 25.80 (CH2), 19.22
(CH3). Anal. Calcd for C21H21N3S: C, 72.59; H, 6.09; N, 12.09. Found:
C, 72.64; H, 6.17; N, 12.05.
4.2.5.18. 8-(Pyrrolo[2,3-b]pyridin-1-yl)-6-methyl-3-phenethyl-
thiomethylimidazo[1,2-a]pyridine (42). The compound was
obtained following the general procedure using
7 (408 mg,
1 mmol), CuI (10 mg, 0.05 mmol), K3PO4 (447 mg, 2.1 mmol), 7-
azaindole (142 mg, 1.2 mmol), N,N 0-dimethylethylenediamine
(16 lL, 0.15 mmol) and toluene (2 mL). The tube was heated for
48 h at 112 °C. Pure product was obtained by column chromatog-
raphy on neutral alumina eluted with ethyl acetate/petroleum
ether (20:80). 48% yield. Mp 108–109 °C. 1H NMR (CDCl3) d: 8.36
(dd, 1H, J = 4.7–1.6 Hz, azaindole), 8.31 (d, 1H, J = 3.8 Hz, azain-
dole), 7.99 (dd, 1H, J = 7.8–1.6 Hz, azaindole), 7.92 (s, 1H, H5), 7.90
(m, 1H, azaindole), 7.48 (s, 1H, H2), 7.33–7.23 (m, 3H, Ph-3,4,5),
7.21–7.13 (m, 3H, H7, Ph-2,6), 6.70 (d, 1H, J = 3.8 Hz, azaindole),
3.98 (s, 2H, CH2), 2.89–2.82 (m, 2H, CH2), 2.69–2.60 (m, 2H, CH2),
2.50 (s, 3H, CH3). 13C NMR (CDCl3) d: 148.61 (azaindole), 143.59
(azaindole), 141.53 (C8a), 140.49 (Ph-1), 133.37 (C2), 130.23
(azaindole), 129.52 (azaindole), 128.99 (Ph-2,6*), 128.94 (Ph-
3,5*), 127.02 (C8), 126.91 (Ph-4), 122.34 (azaindole), 122.26
(indole, C6), 120.37 (C5), 120.14 (indole, C3), 117.55 (C7), 102.02
(azaindole), 36.38 (CH2), 32.91 (CH2), 25.58 (CH2), 19.12 (CH3).
Anal. Calcd for C24H22N4S: C, 72.33; H, 5.56; N, 14.06. Found: C,
72.54; H, 53.46; N, 14.02.
4.2.5.15.
3-Benzylthiomethyl-6-methyl-8-(pyrrol-1-yl)imi-
dazo[1,2-a]pyridine (39). The compound was obtained follow-
ing the general procedure using 9 (394 mg, 1 mmol), CuI (10 mg,
0.05 mmol), K3PO4 (447 mg, 2.1 mmol), pyrrole (84
lL, 1.2 mmol),
N,N 0-dimethylethylenediamine (16
lL, 0.15 mmol) and toluene
(2 mL). The tube was heated for 48 h at 112 °C. Pure product was
obtained by column chromatography on neutral alumina eluted
with CH2Cl2/petroleum ether (70:30). 87% yield. Mp 95–96 °C. 1H
NMR (CDCl3) d: 7.70 (m, 1H, H5), 7.64 (t, 2H, J = 2.2 Hz, Pyrrole-2,5),
7.52 (s, 1H, H2), 7.38–7.28 (m, 5H, Ph), 7.07 (d, 1H, J = 1.3 Hz, H7),
6.44 (t, 2H, J = 2.2 Hz, Pyrrole-3,4), 3.94 (s, 2H, CH2), 3.64 (s, 2H,
CH2), 2.42 (s, 3H, CH3). 13C NMR (CDCl3) d: 140.66 (C8a), 138.08
(Ph-1), 133.87 (C2), 129.98 (C8), 129.56 (Ph-2,6), 129.13 (Ph-3,5),
127.78 (Ph-4), 122.24 (C6), 121.70 (Pyrrole-2,5), 120.21 (C3),
119.49 (C5), 117.14 (C7), 110.89 (Pyrrole-3,4), 36.00 (CH2), 24.73
(CH2), 19.09 (CH3). Anal. Calcd for C20H19N3S: C, 72.04; H, 5.74; N,
12.60. Found: C, 72.22; H, 5.69; N, 12.64.
4.2.5.19.
8-Cyano-6-methyl-3-phenethylthiomethylimidazo-
[1,2-a]pyridine (43). The compound was obtained following
the general procedure using 7 (408 mg, 1 mmol), CuI (19 mg,
0.10 mmol), sodium cyanide (59 mg, 1.2 mmol), N,N0-dimethyl-
4.2.5.16.
8-(Imidazol-1-yl)-6-methyl-3-phenethylthiomethy-
ethylenediamine (106 lL, 1 mmol) and toluene (2 mL). The tube
limidazo[1,2-a]pyridine (40). The compound was obtained fol-
lowing the general procedure using 7 (408 mg, 1 mmol), CuI
(28 mg, 0.15 mmol), K3PO4 (447 mg, 2.1 mmol), imidazole
was heated for 24 h at 112 °C. Pure product was obtained by
column chromatography on neutral alumina eluted with CH2Cl2/
petroleum ether (80:20). 94% yield. Mp 122–123 °C. 1H NMR
(CDCl3) d: 8.12 (d, 1H, J = 1.4 Hz, H5), 7.59 (s, 1H, H2), 7.55 (d, 1H,
J = 1.4 Hz, H7), 7.35–7.23 (m, 3H, Ph-3,4,5), 7.17 (m, 2H, Ph-2,6),
3.98 (s, 2H, CH2), 2.84 (m, 2H, CH2), 2.63 (m, 2H, CH2), 2.45 (s,
3H, CH3). 13C NMR (CDCl3) d: 143.49 (C8a), 140.43 (Ph-1), 135.10
(102 mg, 1.5 mmol), N,N 0-dimethylethylenediamine (32
lL,
0.30 mmol) and toluene (2 mL). The tube was heated for 48 h at
112 °C. Pure product was obtained by column chromatography on
neutral alumina eluted with CH2Cl2. 42% yield. Mp 85–86 °C. 1H
NMR (CDCl3) d: 8.53 (br s, 1H, Imidazole-2), 7.90 (m, 1H, H5), 7.80

J.-B. Véron et al. / Bioorg. Med. Chem. 16 (2008) 9536–9545
9545
cells were inoculated with 20 PFU/well and the different dilutions
of the tested compounds were added as for CMV. After 5 days incu-
bation at 37 °C in a 5% CO2 atmosphere, the cells were fixed and
stained. Viral plaque formation was recorded and compared to
the untreated control. Acyclovir and brivudin were used as refer-
ence drugs.
(C7*), 134.45 (C2*), 129.16 (Ph-2,3,5,6), 127.21 (C5*), 126.95 (Ph-
4*), 121.85 (C6*), 121.21 (C3*), 115.53 (CN), 102.92 (C8), 36.45
(CH2), 33.20 (CH2), 25.55 (CH2), 18.76 (CH3). Anal. Calcd for
C18H17N3S: C, 70.33; H, 5.57; N, 13.67. Found: C, 70.31; H, 5.54;
N, 13.68.
Antiviral activity is expressed as the concentration of the com-
pound required to inhibit viral cytopathicity by 50% (EC50).
4.2.5.20. 8-(4-Chlorophenylthio)-6-methyl-3-phenethylthiome-
thylimidazo[1,2-a]pyridine (44). The compound was obtained
following the general procedure using 7 (408 mg, 1 mmol), CuI
(10 mg, 0.05 mmol), K2CO3 (198 mg, 2 mmol), 4-chlorothiophenol
4.4. Cytostatic activity assays
(175 mg, 1.2 mmol), ethylene glycol (111 lL, 2 mmol) and isopro-
The cytostatic assays were performed as previously de-
panol (1 mL). The tube was heated for 48 h at 80 °C. Pure product
was obtained by column chromatography on neutral alumina
eluted with ethyl acetate/petroleum ether (30:70). 84% yield. Mp
56–58 °C. 1H NMR (CDCl3) d: 7.75 (m, 1H, H5), 7.50–7.45 (m, 3H,
H2, PhCl-2,6), 7.39–7.20 (m, 5H, PhCl-3,5, Ph-3,4,5), 7.13 (m, 2H,
Ph-2,6), 6.59 (d, 1H, J = 1.4 Hz, H7), 3.94 (s, 2H, CH2), 2.80 (m, 2H,
CH2), 2.60 (m, 2H, CH2), 2.25 (s, 3H, CH3). 13C NMR (CDCl3 ) d:
143.36 (C8a), 140.43 (Ph-1), 135.44 (PhCl-2,6), 135.18 (PhCl-4),
133.34 (C2), 130.35 (C8), 130.17 (PhCl-3,5), 128.95 (Ph-2,6*),
128.87 (Ph-3,5*), 127.19 (PhCl-1), 126.85 (Ph-4), 125.46 (C7),
122.29 (C6), 120.42 (C5), 120.05 (C3), 36.31 (CH2), 32.84 (CH2),
25.49 (CH2), 18.88 (CH3). Anal. Calcd for C23H21ClN2S2: C, 65.00; H,
4.98; N, 6.59. Found: C, 64.98; H, 4.95; N, 6.60.
scribed.11–13 Briefly, 100-
l
L aliquots of HEL cell suspensions were
added to the wells of a 96-well microtiter plate containing
100 L of varying concentrations of the test compounds. After 3-
l
days incubation period at 37 °C in a humidified CO2-controlled
incubator, the number of viable cells was determined using a Coul-
ter Counter. Cytostatic activity is expressed as the compound con-
centration that reduced the number of viable cells by 50% (CC50).
The cytotoxicity measurement was based on microscopically visi-
ble morphological alterations of the HEL cell cultures: cytotoxicity
was defined as the minimum cytotoxic concentration (MCC) re-
quired for causing a microscopically detectable alteration of cell
morphology.
Acknowledgments
4.2.5.21.
omethylimidazo[1,2-a]pyridine (45). The compound was
obtained following the general procedure using (408 mg,
1 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (198 mg, 2 mmol), 4-
hydroxythiophenol (152 mg, 1.2 mmol), ethylene glycol (111 L,
8-(4-Hydroxyphenylthio)-6-methyl-3-phenethylthi-
The authors thank SAVIT, Tours (France) for NMR spectrometry.
We thank Mrs. Anita Camps, Frieda de Meyer, Anita van Lierde and
Lies Vandenheurck for excellent technical assistance. This work
was supported by grants from the Belgian Fonds voor Wet-
enschappelijk Onderzoeck (FWO), Vlaanderen, and the Geconcerte-
erde Onderzoeksacties (GOA), Vlaamse Gemeenschap.
7
l
2 mmol) and isopropanol (1 mL). The tube was heated for 48 h at
85 °C. Pure product was obtained by column chromatography on
neutral alumina eluted with ethyl acetate/petroleum ether (70:30).
21% yield. Mp 168–170 °C. 1H NMR (DMSO) d: 10.08 (s, 1H, OH),
8.01 (s, 1H, H5), 7.52 (s, 1H, H2), 7.45 (d, 2H, J = 8.4 Hz, PhOH-2,6),
7.28–7.17 (m, 5H, Ph), 6.94 (d, 2H, J = 8.4 Hz, PhOH-3,5), 6.24 (s,
1H, H7), 4.17 (s, 2H, CH2), 2.77 (m, 2H, CH2), 2.57 (m, 2H, CH2), 2.17
References and notes
1. Gueiffier, A.; Lhassani, M.; Elhakmaoui, A.; Snoeck, R.; Andrei, G.; Chavignon,
O.; Teulade, J.-C.; Kerbal, A.; Essassi, E. M.; Debouzy, J.-C.; Witvrouw, M.;
Blache, Y.; Balzarini, J.; De Clercq, E.; Chapat, J.-P. J. Med. Chem. 1996, 39,
2856.
2. Gueiffier, A.; Mavel, S.; Lhassani, M.; Elhakmoui, A.; Snoeck, R.; Andrei, G.;
Chavignon, O.; Teulade, J.-C.; Witvrouw, M.; Balzarini, J.; De Clercq, E.; Chapat,
J.-P. J. Med. Chem. 1998, 41, 5108.
3. Mavel, S.; Renou, J.-L.; Galtier, C.; Allouchi, H.; Snoeck, R.; Andrei, G.; De Clercq,
E.; Balzarini, J.; Gueiffier, A. Bioorg. Med. Chem. 2002, 10, 941.
4. Véron, J.-B.; Enguehard-Gueiffier, C.; Snoeck, R.; Andrei, G.; De Clercq, E.;
Gueiffier, A. Bioorg. Med. Chem. 2007, 15, 7209.
13
(s, 3H, CH3). C NMR (DMSO) d: 159.88 (PhOH-4), 141.93 (C8a*),
141.26 (Ph-1), 138.19 (PhOH-2,6), 132.77 (C2), 130.03 (PhOH-1),
129.37 (Ph-2,6*), 129.13 (Ph-3,5*), 127.01 (Ph-4), 122.00 (C8*),
121.75 (C7), 121.34 (C6*), 120.08 (C5), 117.98 (PhOH-3,5), 117.74
(C3), 36.00 (CH2), 32.82 (CH2), 24.59 (CH2), 18.80 (CH3). Anal. Calcd
for C23H22N2OS2: C, 67.95; H, 5.45; N, 6.89. Found: C, 98.02; H,
5.44; N, 6.92.
5. Enguehard, C.; Allouchi, H.; Gueiffier, A.; Buchwald, S. L. J. Org. Chem. 2003, 68,
4367.
4.3. Antiviral assays
6. Enguehard, C.; Allouchi, H.; Gueiffier, A.; Buchwald, S. L. J. Org. Chem. 2003, 68,
5614.
7. Enguehard-Gueiffier, C.; Thery, I.; Gueiffier, A.; Buchwald, S. L. Tetrahedron
2006, 6042.
8. Coulson, D. R. Inorg. Synth. 1971, 13, 121.
9. Dolci, L.; Dolle, F.; Valette, H.; Vaufrey, F.; Fuseau, C.; Bottlaender, M.; Crouzel,
C. Bioorg. Med. Chem. 1999, 7, 467.
10. Yamanaka, M.; Miyake, K.; Suda, S.; Ohhara, H.; Ogawa, T. Chem. Pharm. Bull.
1991, 39, 1556.
11. De Clercq, E.; Descamps, J.; Verhelst, G.; Walker, R. T.; Jones, A. S.; Torrence, P.
F.; Shugar, D. J. Infect. Dis. 1980, 141, 563.
Human cytomegalovirus (CMV) AD-169 and Davis strains were
exposed to human embryonic lung (HEL) cell cultures. Briefly, con-
fluent cultures in microtiter plates were inoculated with 100 pla-
que forming units (PFU). After 2 h virus absorption, residual virus
was removed and the cell cultures were incubated in the presence
of varying concentrations of the test compounds. Viral cytopathic-
ity was recorded as soon as it reached completion in the control
virus-infected cell cultures. Inhibition of CMV by the test
compounds was compared with cidofovir and ganciclovir as the
reference compounds. Varicella-zoster virus (VZV) Oka (TK+) and
07/1 (TKꢀ) strains were grown on HEL cells. For VZV, confluent
12. De Clercq, E.; Holy´, A.; Rosenberg, I.; Sakuma, T.; Balzarini, J.; Maudgal, P. C.
Nature 1986, 323, 464.
13. Balzarini, J.; Naesens, L.; Slachmuylders, J.; Niphuis, H.; Rosenberg, I.; Holy´, A.;
Schellekens, H.; De Clercq, E. Aids 1991, 5, 21.