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

Article abstract of DOI:10.1016/j.bmc.2007.03.061

The synthesis of original imidazo[1,2-a]pyridines bearing a phenethylthiomethyl side chain at the 3 position and a (hetero)aryl substituent on the 6 or 8 position, and their antiviral activities are reported. From the synthesized compounds, the 6-halogeno

Full text of DOI:10.1016/j.bmc.2007.03.061

Bioorganic & Medicinal Chemistry 15 (2007) 7209–7219
Influence of 6 or 8-substitution on the antiviral activity
of 3-phenethylthiomethylimidazo[1,2-a]pyridine against human
cytomegalovirus (HCMV) and varicella-zoster virus (VZV)
a
a
b
b
´
´
Jean-Baptiste Veron, Cecile Enguehard-Gueiffier, Robert Snoeck, Graciela Andrei,
Erik De Clercqb and Alain Gueiffiera,*
aLaboratoire de chimie the´rapeutique, Faculte´ de pharmacie, EA 3857, 31 avenue Monge, 37200 Tours, France
bRega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
Received 10 October 2006; revised 13 March 2007; accepted 20 March 2007
Available online 24 March 2007
Abstract—The synthesis of original imidazo[1,2-a]pyridines bearing a phenethylthiomethyl side chain at the 3 position and a (het-
ero)aryl substituent on the 6 or 8 position, and their antiviral activities are reported. From the synthesized compounds, the 6-halo-
geno and 6-phenylimidazo[1,2-a]pyridine derivatives 4c–d and 5b were the most potent against human cytomegalovirus (CMV) and/
or varicella-zoster virus (VZV), whereas several other congeners (i.e., 5e, 5g, 5i, 5l, 5n, 5p, 5q, and 5t), while less potent, were equally
or more selective in their inhibitory activity against both VZV and CMV. These compounds showed similar activity against thymi-
dine kinase competent (TK+) and deficient (TKꢀ) VZV strains, demonstrating a mechanism of action independent of the viral thy-
midine kinase.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
by neuralgic pain that occurs most commonly in older
persons.4
Varicella-zoster virus (VZV) and human cytomegalovi-
rus (HCMV) belong to the a- and b-herpesviridae,
respectively. Like other herpesviruses, primary infection
is followed by persistence of the virus in a latent form.1
The HCMV primary infection rarely causes disease in
immunocompetent individuals with the exception of a
mononucleosis-like illness in some patients.2 However,
reactivation of the virus is of significant concern in
immunocompromised individuals, such as HIV-infected
or patients under immunosuppressive therapy after solid
organ or allogeneic bone marrow transplantation.3 Pri-
mary infection with VZV results in varicella (chicken-
pox), a common and extremely contagious acute
infection, mild in healthy children but more severe in
adults and immunocompromised persons. VZV estab-
lishes latency in neural tissues. Reactivation of latent
VZV from dorsal root ganglia results in herpes zoster
(shingles), a localized cutaneous eruption accompanied
Currently, five compounds are officially licensed for
treatment of HCMV infection.5 The principal indica-
tion for all these agents is HCMV retinitis in AIDS
patients. Unfortunately, all these derivatives suffer
from a number of drawbacks that limit their clinical
usefulness. Thus, oral ganciclovir (GCV) was
approved only as maintenance therapy and prophy-
laxis as the low bioavailability (around 5%) of the oral
formulation was considered insufficient for induction
therapy. There were concerns that inadequate viral
suppression resulting from the lower systemic exposure
from oral GCV could lead to emergence of drug resis-
tance.6 The side effects of GCV include hematologic
abnormalities (primarily neutropenia, anemia, and
thrombocytopenia) secondary to bone marrow sup-
pression and probable long-term reproductive toxic-
ity.7 Valganciclovir (VGV), a prodrug of ganciclovir,
has an improved oral bioavailability of around
60%.8 Cidofovir (CDV) is available only as an IV for-
mulation as its oral bioavailability is less than 5%.
The drug needs only one administration per 1 or 2
weeks, as a result of its long intracellular half-life.
The major limitation of CDV is severe renal toxicity.
Keywords: Antiviral drugs; Human cytomegalovirus (HCMV); Vari-
cella-zoster virus (VZV); Imidazo[1,2-a]pyridine.
*
Corresponding author. Tel.: +33 247 367 138; fax: +33 247 367
288; e-mail: alain-gueiffier@univ-tours.fr
0968-0896/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2007.03.061

´
J.-B. Veron et al. / Bioorg. Med. Chem. 15 (2007) 7209–7219
7210
Patients receiving iv CDV (always as a second line
therapy) must be given oral probenecid to protect
against kidney failure and must be prehydrated before
infusion.6 The major dose-limiting toxicity of foscarnet
(FOS) is renal impairment, underscoring the impor-
tance of adequate hydration and frequent monitoring
of serum creatinine levels in patients receiving FOS.
Renal impairment may lead to a number of cardiac
or neurologic disorders, including seizures, that in sev-
eral cases resulted in death.7 FOS must be given intra-
venously three times daily.5 Finally, fomivirsen has to
be injected intraocularly, as a second-line therapy for
local treatment of CMV retinitis in AIDS patients.
The most frequent adverse effect is ocular inflamma-
tion (uveitis).6,7
term GCV or ACV therapy. Suppression of TK-defi-
cient strains of VZV can only be achieved with TK-inde-
pendent drugs such as FOS or CDV. These two drugs
also retain full antiviral activity against GCV-resistant
CMV strains carrying mutations in the CMV UL97
gene.
The extensive studies on the emergence of HCMV drug
resistance strongly underscore that cross-resistance and
drug-related toxicity can severely limit the therapeutic
alternatives. Thus, development of new anti-HCMV
drugs with novel mechanisms of action, less toxic, more
effective, and orally bioavailable is urgently needed.9,10
The human herpesvirus inhibitors in development have
been recently largely reviewed.9,11–14
As regards the treatment of VZV infections, four com-
pounds are officially licensed: acyclovir, valaciclovir,
famciclovir, and brivudin.5 Famciclovir is an oral pro-
drug of penciclovir that presents a safety profile and
antiviral activity spectrum largely similar to those of
acyclovir. Finally, the in vitro inhibitory effect of brivu-
din on VZV by far exceeds that of acyclovir. In addition,
brivudin has favorable oral bioavailability allowing only
once-daily dosing.6
In our search in the chemistry and pharmacology of
bridgehead heterocycles, we have reported that 7- and
8-methyl-3-phenylmethylthiomethylimidazo[1,2-a]pyri-
dines I–II (Fig. 1) are potent inhibitors of HCMV and
VZV.15 We have now further investigated the influence
of the thioether side chain and showed that phenethylth-
iomethyl group enhances the activity and diminishes the
toxicity.16 We have then demonstrated that many func-
tionalities are tolerated in position 2 but in all cases, the
unsubstituted compound remained the best inhibitor.17
At this time, optimization of the pyridinic moiety was
made problematic because of the lack of efficient meth-
ods of functionalization. Interestingly, in the past few
years, optimization of various metallo-catalyzed cou-
pling reactions in our laboratory18–23 allowed us to
introduce new functionalities on the pyridinic part of
the scaffold, notably aryl and heteroaryl groups in posi-
tion 618 and 822 via Suzuki–Miyaura cross-coupling
reaction. The synthesis and biological evaluation of this
new series of compounds is subject of the present article.
The antiviral activity and selectivity of acyclovir, ganci-
clovir, and related compounds is based on their specific
activation by herpesvirus-encoded kinases (thymidine
kinase TK for VZV and UL97 protein kinase for
CMV) that convert these nucleoside analogues to their
monophosphate metabolites. After initial conversion
of the purine nucleoside analogues to their monophos-
phate, further activation to the di- and triphosphate is
catalyzed by cellular enzymes involved in nucleotide
metabolism. For brivudin, the monophosphate is con-
verted to the diphosphate by HSV TK or VZV TK.
These compounds after phosphorylation act as compet-
itive inhibitor/alternate substrate with the substrate
binding site of the DNA polymerase, resulting in inhibi-
tion of viral DNA synthesis.6,9
2. Results and discussion
2.1. Chemistry
FOS and CDV are the only two antiherpes drugs known
to inhibit viral DNA synthesis in a manner that is inde-
pendent of viral thymidine kinase or protein kinase.
FOS requires no metabolic activation; it interacts di-
rectly with the pyrophosphate binding site of the DNA
polymerase. CDV requires a two-step activation by cel-
lular kinases; its diphosphate inhibits the viral DNA
polymerase.
As shown in Scheme 1, the suitably halogenated 2-
aminopyridines 1a–e24,25 were refluxed with chloroacet-
aldehyde in ethanol to give the imidazo[1,2-a]pyridines
2a–e16,25 in around 85% yields. Hydroxymethylation in
position 3 of this scaffold was previously described using
formaldehyde in acetic acid media in the presence of
sodium acetate. In initial procedures, the reaction was
performed in a Parr apparatus and isolation of the at-
tempted product was made difficult because of the for-
mation of a dimeric compound. Recently, we have
shown that the reaction has to be performed at specific
Fomivirsen does not interfere with viral DNA synthesis
but is a unique antiviral agent that inhibits CMV repli-
cation by an antisense mechanism. It prevents viral rep-
lication by binding to a complementary CMV mRNA
sequence, thereby inhibiting translation of several
CMV immediate early proteins.6,9
N
R
N
S
Thus, the main approved systemic drugs share a similar
mechanism of action, targeting the viral DNA polymer-
ase. The emergence of drug-resistant virus strains that
carry alterations in the viral TK (VZV) or UL97 protein
kinase (CMV) affects predominantly patients after long-
I R = 7-CH3
II R = 8-CH3
Figure 1. Potent inhibitors of HCMV and VZV.

´
J.-B. Veron et al. / Bioorg. Med. Chem. 15 (2007) 7209–7219
7211
R2 R2
R2
NH2
N
i
N
ii
N
N
N
R1
R1
R1
CH2OH
1a-e
2a-e
3a-e
R2
a R1 = Br, R2 = H
N
b R1 = CH3, R2 = I
c R1 = I, R2 = CH3
d R1 = Br, R2 = CH3
e R1 = CH3, R2 = Br
iii
N
R1
S
4a-e
N
N
N
N
iv
Br
S
S
4a
5b
CH3
CH3
N
N
iv
N
N
Br
S
R
S
4d
5a R = Ph
5m R = 3-CH3OPh
5o R = 4-CH3OPh
5q R = 3-NO2Ph
5s R = 3-CNPh
5t R = 4-CNPh
5d R = thien-3-yl
5f R = thien-2-yl
5h R = 2-OHPh
5i R = 3-OHPh
5k R = 4-OHPh
Br
R
N
N
iv
N
N
H3C
H3C
S
S
4e
5c R = Ph
5n R = 3-CH3OPh
5p R = 4-CH3OPh
5r R = 3-NO2Ph
5u R = 3-FPh
5e R = thien-3-yl
5g R = thien-2-yl
5j R = 3-OHPh
5l R = 4-OHPh
Scheme 1. Reagents: (i) ClCH2CHO, C2H5OH; (ii) HCHO, CH3COONa, CH3COOH; (iii) Ph(CH2)2SH, CH3COOH; (iv) RB(OH)2, Pd(PPh3)4,
NaOH or Na2CO3/DME, H2O.
temperature depending upon the nature of substituent in
position 2 in order to avoid the formation of the dimeric
side product.17 Concerning the 2-unsubstituted deriva-
tives 2a–e, a reaction temperature of 40 °C was
required to give the corresponding alcohols 3a–e within
24 h in about 80% yield. The thioether side chain was
introduced using phenethylthiol in acetic media at
80 °C giving 4a–e in moderate to good yield (41–90%).
dimethoxyethane.18,22 In this work, NaOH or Na2CO3
was used as base. The corresponding aryl or heteroa-
ryl compounds 5a–u were obtained in moderate to
good yields, with the exception of the hydroxyphenyl
compounds which were obtained in 35–51% yields,
probably due to their poor solubility and the succes-
sive chromatographies required for the purification
step.
In our previous studies on metallo-catalyzed coupling
reactions, we reported that Suzuki reaction on 6 or 8-
halogenoimidazo[1,2-a]pyridine occurred in various
conditions. The reaction was efficient starting from
the bromo or iodo derivatives using tetrakis(triphenyl-
phosphine)palladium(0) as catalyst, and different
bases, that is, NaOH, Na2CO3 or K3PO4 in 1,2-
2.2. Antiviral activity
All the synthesized compounds were inactive against
parainfluenza-3 virus, reovirus-3, Sindbis virus, Cox-
sackie virus B4, Punta Toro virus in Vero cell cultures,
against vesicular stomatitis virus, Coxsackie virus B4,
and respiratory syncytial virus in HeLa cell cultures,

´
J.-B. Veron et al. / Bioorg. Med. Chem. 15 (2007) 7209–7219
7212
and against herpes simplex virus type 1 (HSV-1) (KOS)
and thymidine kinase-deficient (TKꢀ) (KOS) acyclovir-
resistant (ACVr) strains, HSV-2, and vesicular stomati-
tis in E6SM cell cultures.
However, these compounds inhibited VZV plaque for-
mation at concentrations similar to those that alter cell
morphology.
On the other hand, among compounds that inhibited
VZV plaque formation at concentrations that resulted
in no alteration of cell morphology, viz. 5e, 5g, 5i, 5j,
5l, 5n, 5p, 5q, and 5t, while less potent (EC50 > 1.0 lg/mL)
than 4c and 5b, had selectivity indexes (ratio of CC50
to EC50) equal to or higher than 5.
Compounds 5c, 5f, 5j, and 5p showed moderate activi-
ties against vaccinia virus [EC50 (50% effective concen-
tration) = 9.6 lg/mL and
a
minimal cytotoxic
concentration (MCC) of 80 lg/mL in E6SM cell
cultures].
The most interesting antiviral activities were obtained
against CMV and VZV in human embryonic lung
HEL cells (Table 1).
2.2.2. Anti-CMV activity. As seen in table, the tested
compounds can be classified in three groups depending
on their range of anti-CMV activities: a group of totally
inactive compounds (5h, 5k, and 5r) with an
EC50 > 100 lg/mL, a group of moderately active com-
pounds (4b, 5a, 5d–5g, 5i, 5j, 5l, 5m, 5o–5q, 5s–5u) with
an EC50 between 2 and 4 lg/mL, and a group of two ac-
tive compounds (4c and 4d) with an EC50 < 1 lg/mL. It
should be noted that some of the compounds inhibited
mostly the Davis strain and not the AD-169 strain.
The compounds (5h,k,n,r) that were inactive against
CMV are also totally inefficient against VZV; thus, an
ortho- or para-hydroxyphenyl group in the 6 position
is deleterious for the antiviral activity as well as a
3-methoxy- or 3-nitrophenyl in the 8 position. Although
compounds 4c and 4d showed the lowest EC50 values,
compound 4c only showed activity against the Davis
strain but at concentrations close to those that altered
cell morphology (MCC P 0.8). Compound 4d
showed EC50 values that were about 10-fold lower than
MCC values, and the highest selectivity index
(SI = 124).
2.2.1. Anti-VZV activity. At first, it should be noted that
contrarily to acyclovir and brivudin which require phos-
phorylation to exert their antiviral activity, our com-
pounds showed the same range of activity against TK+
and TKꢀ VZV strains, demonstrating a mechanism of
action independent of the virus-encoded thymidine
kinase.
With regard to the structure–activity relationship
(SAR), the influence of the substitution position de-
pends on the nature of the substituent. For the haloge-
nated compounds 4b–d, halogen atom is preferred in
position 6 over position 8 for antiviral activity. How-
ever, these three compounds were rather cytotoxic since
the MCC (minimum cytotoxic concentration that causes
a microscopically detectable alteration of cell morphol-
ogy) values for those compounds were in the same range
as their EC50 values. This toxicity seems to be dimin-
ished with the presence of a substituent in position 8
(methyl or phenyl) as seen with phenyl derivatives 5a–
c, when comparing 5b with 5a or 5c. However, the 8-
methyl also decreased the anti-VZV activity, that is,
EC50 = 0.74 lg/mL (compound 5b) compared to
EC50 = 3.6 lg/mL (compound 5a) against TK+ VZV
strains. Similar results were observed with the thienyl
compounds 5d–g, with the 6-thienyl derivatives, that
is, 5d and 5f (EC50 = 1.7–4 lg/mL), being more potent
than the 8-thienyl analogues, that is, 5e and 5g
(EC50 = 7.8–8.9 lg/mL). A highly decreased toxicity
The compounds showing the highest anti-CMV potency
(4c, 4d and 5b) (EC50 < 1.0 lg/mL) were also the most
cytotoxic (MCC values of the same order as EC50 val-
ues). On the other hand, a wealth of compounds, viz.
5a, 5e–5g, 5i, 5m, 5o–5q, 5s, and 5u, which showed an
EC50 of 2–4 lg/mL, had selectivity indexes (ratio CC50
to EC50) similar to or in excess of 5.
3. Conclusion
was noted with
a thienyl group in position 8
(MCC = 100 lg/mL for 5e and 5g compared to
MCC P 4 and 20 lg/mL for 5d and 5f).
In this work, we have shown that the substituent at the 6
or 8 position strongly influences the activity of these
compounds against human cytomegalovirus and vari-
cella-zoster virus as well as their cytotoxicity. From
the synthesized compounds, the 6-halogeno and
6-phenylimidazo[1,2-a]pyridine derivatives 4c, 4d and
5b were the most potent agents against CMV and/or
VZV, whereas various other compounds, viz. 5e, 5g,
5i, 5n, 5p, 5q, and 5t, were the most selective in their
inhibitory activity against both VZV and CMV. All
compounds showed similar activity against TK+ and
TKꢀ VZV strains, demonstrating a mechanism of action
that is independent of the viral thymidine kinase.
With regard to the 6-phenyl substitution pattern, a hy-
droxyl group was tolerated only in meta position (5i:
EC50 = 2.4 lg/mL for TK+ strain) while a total loss of
activity was observed with the hydroxyl in ortho (5h)
or para (5k) positions (EC50 > 20 lg/mL). On the con-
trary, the methoxy and cyano groups are preferred in
para position (EC50 = 2.2–2.4 lg/mL for TK+ strain) in-
stead of meta (EC50 > 4 and 100 lg/mL for the TK+
strain, respectively).
The compounds showing the highest anti-VZV potency
(EC50 < 1.0 lg/mL) were the 6-iodo and 6-phenyl deriv-
atives 4c and 5b, with EC50 values against TK+ strain in
the same range as acyclovir but with much higher poten-
cies against the TKꢀ strain than the two references.
Based on their potency and/or selectivity, any of the fol-
lowing compounds deserves to be further pursued in fol-
low-up studies for their potential in the treatment of
VZV and/or HCMV infections: 4c, 4d, 5a, 5b, 5e–5g,

´
J.-B. Veron et al. / Bioorg. Med. Chem. 15 (2007) 7209–7219
7213
Table 1. Anti-CMV and -VZV activities and cytotoxic properties in human embryonic lung (HEL) cells
a
Compound
Antiviral activity EC50 (lg/mL)
Cytotoxicity (lg/mL)
Cell morphology (MCC)b
Cell growth (CC50)
c
VZV
CMV
AD-169 strain
OKA strain TK+
07/1 strain TKꢀ
Davis strain
4b
4c
2.6
0.68
0.48
3.6
2.6
0.43
1.1
>0.8
>0.16
0.32
2.0
1.8
0.12
0.13
2.2
P4
P0.8
P2
20
>50
>50
28
4d
5a
>4
31
5b
5c
0.74
>4
1.7
>0.8
>4
>0.8
>4
>0.8
>4
4
20
9.9
33
>50
>50
32
5d
5e
1.8
8.6
>0.8
2.5
1.8
2.5
P4
100
20
8.9
5f
5g
4
7.8
>4
4
2.2
2.5
2.2
2.2
100
100
20
>50
>50
50
5h
5i
>20
2.4
1.6
>20
3.7
2.9
>100
2.2
>4
>100
2.2
>100
2.2
>4
5j
5k
20
P100
20
11.4
>50
13.7
>20
1.7
>4
>100
2.7
>4
>100
2.2
2.5
5l
5m
2.2
10.9
3.1
20
100
36
>50
5n
5o
8.3
2.4
10.3
>4
10.9
2.2
20
20
25.8
5p
5q
2.0
5.6
3.1
8.3
2.2
7.6
2.2
4
19.6
43
P100
100
5r
>20
>100
2.2
>20
81
>100
>100
2.5
2.5
47
>50
5s
2.2
1.8
2.2
>100
P20
20
5t
5u
2.0
10.6
35
>4
>4
28
2.2
Acyclovir
Brivudin
Ganciclovir
Cidofovir
0.70
0.0038
NDd
NDd
NDd
NDd
0.51
0.10
NDd
NDd
0.80
0.12
>400
>400
100
>200
362
NDd
NDd
NDd
146
47
P100
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.
c Cytotoxic concentration required to reduce cell growth by 50%.
d Not determined.
5i, 5j, 5m–5q, and 5s–5u. This abundance of possibilities
will have to be narrowed down in the light of the future
demands for antivirals (for anti-CMV compared to anti-
VZV drugs), their in vivo efficacy and pharmacokinetics,
and, eventually, safety/toxicity profile.
6-bromo-3-hydroxymethylimidazo[1,2-a]pyridine 3a,16
6-bromo-3-hydroxymethyl-8-methylimidazo[1,2-a]pyri-
dine
3d,16
8-bromo-3-hydroxymethyl-6-methylimi-
dazo[1,2-a]pyridine 3e.16
4.2. Chemistry
4. Experimental
4.2.1. General procedure for cyclization (2a–e). The
appropriate 2-aminopyridine 1a–e (27 mmol) and an
aqueous solution of chloroacetaldehyde 45% (4.3 mL,
29,4 mmol) were refluxed in 50 mL of ethanol for 24 h.
After cooling, the solution was concentrated to dryness,
then diluted in water. The solution was made basic by
addition of sodium carbonate and extracted with dichlo-
romethane. The dried organic layers were evaporated to
dryness and chromatographed on silica gel eluting with
diethyl ether.
4.1. General details
The melting points were determined in a capillary appa-
ratus and are uncorrected. NMR experiments were per-
formed at 200 MHz (1H) and 50 MHz (13C) in CDCl3 or
DMSO-d6 on Bruker DPX 200 instruments. Possible
inversion of two values in the NMR spectra is expressed
by an asterisk ( ). Tetrakis(triphenylphosphine)palla-
*
dium(0) was prepared as described in the literature.26
The starting halogenated aminopyridine derivatives
1a–e were prepared by iodination24 or bromination25
of commercially available aminopyridines. Previously
reported imidazo[1,2-a]pyridines synthesized by the de-
scribed procedure were 6-bromoimidazo[1,2-a]pyridine
2a,25 6-bromo-8-methylimidazo[1,2-a]pyridine 2d,16
4.2.1.1. 8-Iodo-6-methylimidazo[1,2-a]pyridine (2b).
Yield 85%. Mp 171–172 °C. 1H NMR (CDCl3) d
7.90 (m, 1H, H5), 7.62 (m, 2H, H2, H3), 7.53 (d,
1H, J = 1.3 Hz, H7), 2.28 (s, 3H, CH3); 13C NMR
(CDCl3) d 144.31 (C8a), 137.20 (C7), 133.92 (C2),
124.23 (C5), 123.36 (C6), 114.48 (C3), 84.06 (C8),
18.04 (CH3).
and
8-bromo-6-methylimidazo[1,2-a]pyridine
2e,25

´
J.-B. Veron et al. / Bioorg. Med. Chem. 15 (2007) 7209–7219
7214
4.2.1.2. 6-Iodo-8-methylimidazo[1,2-a]pyridine (2c).
Yield 89%. Mp 138 °C. H NMR (CDCl3) d 8.27 (s,
1H, H5), 7.57 (d, 1H, J = 1.2 Hz, H2), 7.52 (d, 1H,
J = 1.2 Hz, H3), 7.16 (s, 1H, H7), 2.59 (s, 3H, CH3);
13C NMR (CDCl3) d 144.81 (C8a), 133.46 (C2), 131.17
(C7), 129.28 (C8), 128.88 (C5), 112.92 (C3), 75.89
(C6), 17.16 (CH3).
(d, 1H, J = 1.3 Hz, H7), 7.53 (s, 1H, H2), 7.41–7.22 (m,
3H, Ph-3,4,5), 7.16 (m, 2H, Ph-2,6), 3.93 (s, 2H, CH2),
2.84 (m, 2H, CH2), 2.62 (m, 2H, CH2), 2.37 (s, 3H,
CH3); 13C NMR (CDCl3) d 147.12 (C8a), 140.35 (Ph-
1), 136.94 (C7), 133.83 (C2), 128.95 (Ph-2,6*), 128.88
(Ph-3,5*), 126.88 (Ph-4), 123.19 (C6), 122.66 (C5),
121.06 (C3), 84.46 (C8), 36.27 (CH2), 32.84 (CH2),
25.74 (CH2), 18.41 (CH3). Anal. Calcd for C17H17IN2S:
C, 50.01; H, 4.20; N, 6.86. Found: C, 49.85; H, 4.29; N,
6.93.
1
4.2.2. General procedure for hydroxymethylation (3a–e).
To a solution of imidazo[1,2-a]pyridine 2a–e (32 mmol)
in 8.5 mL of acetic acid was added sodium acetate (9.7 g,
0.118 mol) and then an aqueous solution of formalde-
hyde 37% (16 mL, 0.224 mol). The reaction mixture
was stirred for 24 h at 40 °C. After cooling, the reaction
mixture was diluted with water and made basic with so-
dium carbonate. The precipitate was filtered off and
chromatographed on neutral alumina eluting with a
mixture of CH2Cl2 and methanol (95:5).
4.2.3.3. 6-Iodo-8-methyl-3-phenethylthiomethylimi-
1
dazo[1,2-a]pyridine (4c). Yield 74%. Mp 99–100 °C. H
NMR (CDCl3) d 8.26 (d, 1H, J = 0.8 Hz, H5), 7.44 (s,
1H, H2), 7.35–7.22 (m, 4H, H7, Ph-3,4,5), 7.17 (m, 2H,
Ph-2,6), 3.94 (s, 2H, CH2), 2.82 (m, 2H, CH2), 2.71–
2.59 (m, 5H, CH2, CH3); 13C NMR (CDCl3) d 147.75
(C8a), 140.38 (Ph-1), 133.10 (C2), 131.46 (C7), 129.45
(C8), 128.95 (Ph-2,3,5,6), 127.57 (C5), 126.92 (Ph-4),
119.83 (C3), 76.11 (C6), 36.36 (CH2), 33.00 (CH2),
25.53 (CH2), 17.09 (CH3). Anal. Calcd for C17H17IN2S:
C, 50.01; H, 4.20; N, 6.86. Found: C, 49.88; H, 4.19; N,
6.90.
4.2.2.1. 3-Hydroxymethyl-8-iodo-6-methylimidazo[1,
2-a]pyridine (3b). Yield 81%. Mp 176–178 °C. 1H
NMR (DMSO-d6) d 8.23 (m, 1H, H5), 7.67 (d, 1H,
J = 1.2 Hz, H7), 7.47 (s, 1H, H2), 4.72 (s, 2H, CH2),
3.38 (s, 1H, OH), 2.27 (s, 3H, CH3); 13C NMR
(DMSO-d6) d 144.40 (C8a), 136.94 (C7), 132.66 (C2),
127.37 (C3), 123.79 (C5), 123.05 (C6), 85.19 (C8),
53.61 (CH2), 18.00 (CH3).
4.2.3.4. 6-Bromo-8-methyl-3-phenethylthiomethylimi-
1
dazo[1,2-a]pyridine (4d). Yield 89%. Mp 66–68 °C. H
NMR (CDCl3) d 8.17 (m, 1H, H5), 7.50 (s, 1H, H2),
7.36–7.24 (m, 3H, Ph-3,4,5), 7.19–7.15 (m, 3H, Ph-2,6,
H7), 3.96 (s, 2H, CH2), 2.84 (m, 2H, CH2), 2.65 (s,
3H, CH3), 2.64 (m, 2H, CH2); 13C NMR (CDCl3) d
145.59 (C8a), 140.37 (Ph-1), 133.47 (C2), 129.16 (C8),
128.92 (Ph-2,3,5,6), 126.92 (Ph-4, C7), 122.62 (C5),
120.24 (C3), 107.47 (C6), 36.35 (CH2), 32.97 (CH2),
25.53 (CH2), 17.22 (CH3). Anal. Calcd for
C17H17BrN2S: C, 56.51; H, 4.74; N, 7.75. Found: C,
56.77; H, 4.86; N, 7.81.
4.2.2.2. 3-Hydroxymethyl-6-iodo-8-methylimidazo[1,
2-a]pyridine (3c). Yield 84%. Mp 218–220 °C. 1H
NMR (DMSO-d6) d 8.55 (s, 1H, H5), 7.45 (s, 1H, H2),
7.33 (s, 1H, H7), 5.30 (t, 1H, J = 5.4 Hz, OH), 4.79 (d,
2H, J = 5.4 Hz, CH2), 2.47 (s, 3H, CH3); 13C NMR
(50 MHz, DMSO-d6) d 144.99 (C8a), 132.30 (C2),
130.93 (C7), 129.02 (C8), 128.41 (C5), 126.11 (C3),
76.91 (C6), 53.35 (CH2), 16.96 (CH3).
4.2.3. General procedure to obtain thioether derivatives
(4a–e). To a solution of imidazo[1,2-a]pyridine 3a–e
(12.4 mmol) in 12 mL of acetic acid was added pheneth-
ylmercaptan (1.5 mL, 11.2 mmol). The mixture was
heated at 80 °C overnight. After cooling, the solution
was diluted with water, made basic with sodium carbon-
ate, and extracted with dichloromethane. The organic
layers were dried and evaporated to dryness. The residue
was chromatographed on neutral alumina eluting with
dichloromethane.
4.2.3.5. 8-Bromo-6-methyl-3-phenethylthiomethylimi-
dazo[1,2-a]pyridine (4e). Yield 90%. Mp 80–82 °C. H
1
NMR (CDCl3) d 7.87 (m, 1H, H5), 7.52 (s, 1H, H2),
7.37 (d, 1H, J = 1.6 Hz, H7), 7.33–7.21 (m, 3H, Ph-
3,4,5), 7.15 (m, 2H, Ph-2,6), 3.94 (s, 2H, CH2), 2.82
(m, 2H, CH2), 2.62 (m, 2H, CH2), 2.37 (s, 3H, CH3);
13C NMR (CDCl3) d 143.63 (C8a), 140.34 (Ph-1),
133.92 (C2), 130.10 (C7), 128.92 (Ph-2,6*), 128.88 (Ph-
3,5*), 126.88 (Ph-4) 122.63 (C6), 121.79 (C5), 120.97
(C3), 111.66 (C8), 36.27 (CH2), 32.88 (CH2), 25.63
(CH2), 18.59 (CH3). Anal. Calcd for C17H17BrN2S: C,
56.51; H, 4.74; N, 7.75. Found: C, 56.84; H, 4.89; N,
7.83.
4.2.3.1. 6-Bromo-3-phenethylthiomethylimidazo[1,2-
1
a]pyridine (4a). Yield 41%. Mp 107–109 °C. H NMR
(CDCl3) d 8.30 (m, 1H, H5), 7.58 (d, 1H, J = 9.5 Hz,
H8), 7.52 (s, 1H, H2), 7.37–7.24 (m, 4H, H7, Ph-3,4,5),
7.17 (m, 2H, Ph-2,6), 3.97 (s, 2H, CH2), 2.80 (m, 2H,
CH2), 2.64 (m, 2H, CH2); 13C NMR (CDCl3) d 145.10
(C8a), 140.32 (Ph-1), 134,26 (C2), 128.95 (Ph-2,3,5,6),
128.18 (C7), 126.96 (Ph-4), 124.86 (C5), 119.98 (C3),
118.95 (C8), 107.51 (C6), 36.32 (CH2), 33.02 (CH2),
25.43 (CH2). Anal. Calcd for C16H15BrN2S: C, 55.34;
H, 4.35; N, 8.07. Found: C, 55.12; H, 4.43; N, 8.17.
4.2.4. General procedure for Suzuki cross coupling
reactions (5a–u). Into a three-necked round-bottomed
flask were introduced under argon, 4a or 4d–e (1 mmol),
tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol),
the boronic acid (1.2 mmol), 8 mL of 1,2-dimethoxye-
thane, and NaOH (80 mg, 2 mmol) or Na2CO3 (212 mg,
2 mmol) solubilized in 8 mL of water. The reaction
mixture was heated at 85 °C for 3 h. Reaction was
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
dryness.
4.2.3.2. 8-Iodo-6-methyl-3-phenethylthiomethylimi-
dazo[1,2-a]pyridine (4b). Yield 78%. Mp 105–107 °C.
1H NMR (CDCl3) d 7.89 (d, 1H, J = 1.3 Hz, H5), 7.63

´
J.-B. Veron et al. / Bioorg. Med. Chem. 15 (2007) 7209–7219
7215
4.2.4.1. 8-Methyl-6-phenyl-3-phenethylthiomethylimi-
dazo[1,2-a]pyridine (5a). Compound 5a was obtained
following the general procedure using 4d (362 mg,
1 mmol), phenylboronic acid (134 mg, 1.1 mmol), and
NaOH as base. Pure product was obtained by column
chromatography on neutral alumina eluting with
tained following the general procedure using 4d
(362 mg, 1 mmol), thien-3-ylboronic acid (141 mg,
1.1 mmol), and NaOH as base. Pure product was ob-
tained by column chromatography on neutral alumina
eluting with CH2Cl2. Yield 89%. Mp 108 °C. 1H
NMR (CDCl3) d 8.22 (m, 1H, H5), 7.53 (s, 1H, H2),
7.49 (m, 2H, Thio-2,4), 7.40 (dd, 1H, J = 3.9–2.5 Hz,
Thio-5), 7.34–7.22 (m, 4H, Ph-3,4,5, H7), 7.16 (m,
2H, Ph-2,6), 4.04 (s, 2H, CH2), 2.84 (m, 2H, CH2),
2.70 (s, 3H, CH3), 2.65 (m, 2H, CH2); 13C NMR
(CDCl3) d 146.53 (C8a), 140.47 (Ph-1), 138.94 (Thio-
3), 133.52 (C2), 128.95 (Ph-2,6*), 128.88 (Ph-3,5*),
127.83 (C8), 127.25 (Thio-2), 126.85 (Ph-4), 126.33
(Thio-5), 123.75 (C7), 121.94 (C6), 121.08 (Thio-4),
120.09 (C3), 119.19 (C5), 36.35 (CH2), 32.87 (CH2),
25.62 (CH2), 17.51 (CH3). Anal. Calcd for
C21H20N2S2: C, 69.19; H, 5.53; N, 7.68. Found: C,
69.47; H, 5.48; N, 7.71.
1
CH2Cl2. Yield 91%. Mp 72–73 °C. H NMR (CDCl3)
d 8.19 (m, 1H, H5), 7.62 (m, 2H, Ph0-2,6), 7.55 (s, 1H,
H2), 7.52-7.39 (m, 3H, Ph0-3,4,5), 7.34–7.15 (m, 6H,
H7, Ph), 4.05 (s, 2H, CH2), 2.83 (m, 2H, CH2), 2.73 (s,
3H, CH3), 2.67 (m, 2H, CH2); 13C NMR (CDCl3) d
146.51 (C8a), 140.49 (Ph-1), 138.20 (Ph0-1), 133.50
(C2), 129,48 (Ph0-3,5), 128.97 (Ph-2,6*), 128.900 (Ph-
3,5*), 128.20 (Ph0-4), 127.86 (C8), 127.56 (Ph -2,6),
127.15 (C6), 126.87 (Ph-4), 124.47 (C7), 120.09 (C3),
119.89 (C5), 36.38 (CH2), 32.93 (CH2), 25.76 (CH2),
17.55 (CH3). Anal. Calcd for C23H22N2S: C, 77.06; H,
6.19; N, 7.81. Found: C, 77.38; H, 6.23; N, 7.99.
4.2.4.2. 6-Phenyl-3-phenethylthiomethylimidazo[1,2-
a]pyridine (5b). Compound 5b was obtained following
the general procedure using 4a (347 mg, 1 mmol), phen-
ylboronic acid (134 mg, 1.1 mmol), and NaOH as base.
Pure product was obtained by column chromatography
on neutral alumina eluting with CH2Cl2. Yield 58%. Oil.
1H NMR (CDCl3) d 8.32 (dd, 1 H, J = 1.7–0.9 Hz, 1H,
H5), 7.74 (dd, 1H, J = 9.4–0.9 Hz, H8), 7.63 (m, 2H, Ph0-
2,6), 7.56 (s, 1H, H2), 7.55–7.40 (m, 3H, Ph0-3,4,5), 7.34–
7.14 (m, 6H, H7, Ph), 4.05 (s, 2H, CH2), 2.84 (m, 2H,
CH2), 2.66 (m, 2H, CH2); 13C NMR (CDCl3) d 146.09
(C8a), 140.46 (Ph-1), 137.88 (Ph0-1), 134.27 (C2),
129,56 (Ph0-3,5), 128.93 (Ph-2,3,5,6), 128.34 (Ph0-4),
127.54 (Ph0-2,6), 127.00 (C6), 126.90 (Ph-4), 125.40
(C7), 122,03 (C5), 119.79 (C3), 118,17 (C8), 36.35
(CH2), 32.97 (CH2), 25.61 (CH2). Anal. Calcd for
C22H20N2S: C, 76.71; H, 5.85; N, 8.13. Found: C,
76.85; H, 5.81; N, 8.33.
4.2.4.5.
6-Methyl-3-phenethylthiomethyl-8-(thien-3-
yl)imidazo[1,2-a]pyridine (5e). Compound 5e was ob-
tained following the general procedure using 4e
(362 mg, 1 mmol), thien-3-ylboronic acid (154 mg,
1.2 mmol), and Na2CO3 as base. Pure product was ob-
tained by column chromatography on neutral alumina
eluting with CH2Cl2. Yield 89%. Mp 91–92 °C. 1H
NMR (CDCl3) d 8.55 (dd, 1H, J = 3–1.3 Hz, Thio-2),
7.88 (m, 1H, H5), 7.77 (dd, 1H, J = 5.1–1.3 Hz, Thio-
4), 7.56 (s, 1H, H2), 7.46 (dd, 1H, J = 5.1–3 Hz, Thio-
5), 7.38–7.16 (m, 6H, H7, Ph), 4.02 (s, 2H, CH2), 2.86
(m, 2H, CH2), 2.66 (m, 2H, CH2), 2.45 (s, 3H, CH3);
13C NMR (CDCl3) d 144.13 (C8a), 140.54 (Ph-1),
136.91 (Thio-3), 133.39 (C2), 129.00 (Ph-2,6*), 128.92
(Ph-3,5*), 127.21 (Thio-4), 126.89 (Ph-4), 125.88 (Thio-
2*), 125.83 (Thio-5*), 124.86 (C7), 124.59 (C8), 122.16
(C6), 120.93 (C5), 119.28 (C3), 36.39 (CH2), 32.86
(CH2), 25.66 (CH2), 18.98 (CH3). Anal. Calcd for
C21H20N2S2: C, 69.19; H, 5.53; N, 7.68. Found: C,
69.38; H, 5.49; N, 7.63.
4.2.4.3. 6-Methyl-8-phenyl-3-phenethylthiomethylimi-
dazo[1,2-a]pyridine (5c). Compound 5c was obtained fol-
lowing the general procedure using 4e (362 mg, 1 mmol),
phenylboronic acid (134 mg, 1.1 mmol), and NaOH as
base. The reaction mixture was heated at 85 °C for 3 h
and then phenylboronic acid (13 mg, 0.1 mmol) was
again added. The heating was maintained for 3 h and
the reaction mixture was stirred at room temperature
overnight. Pure product was obtained by column chro-
matography on neutral alumina eluting with CH2Cl2.
Yield 92%. Mp 55–56 °C. 1H NMR (CDCl3) d 7.99
(m, 2H, Ph0-2,6), 7.93 (m, 1H, H5), 7.58–7.40 (m, 4H,
H2, Ph0-3,4,5), 7.36–7.16 (m, 6H, H7, Ph), 4.03 (s, 2H,
CH2), 2.86 (m, 2H, CH2), 2.66 (m, 2H, CH2), 2.47 (s,
3H, CH3); 13C NMR (CDCl3) d 144.22 (C8a), 140.47
(Ph-1), 136.61 (Ph0-1), 133.12 (C2), 130.25 (C8), 129.35
(Ph0-2,6), 129.01 (Ph-2,6* and Ph0-3,5), 128.92 (Ph-
3,5*), 128.79 (Ph0-4), 126.97 (C7), 126.89 (Ph-4),
122.73 (C6), 121.43 (C5), 119.35 (C3), 36.37 (CH2),
32.89 (CH2), 25.67 (CH2), 18.97 (CH3). Anal. Calcd
for C23H22N2S: C, 77.06; H, 6.19; N, 7.81. Found: C,
77.32; H, 6.17; N, 7.70.
4.2.4.6.
8-Methyl-3-phenethylthiomethyl-6-(thien-2-
yl)imidazo[1,2-a]pyridine (5f). Compound 5f was ob-
tained following the general procedure using 4d
(362 mg, 1 mmol), thien-2-ylboronic acid (154 mg,
1.2 mmol), and Na2CO3 as base. Pure product was ob-
tained by column chromatography on neutral alumina
eluting with diethyl ether/petroleum ether (70:30). Yield
1
92%. Mp 72 °C. H NMR (CDCl3) d 8.23 (s, 1H, H5),
7.52 (s, 1H, H2), 7.35 (dd, 1H, J = 5.1–1.2 Hz, Thio-5),
7.33–7.12 (m, 8H, H7, Ph, Thio-3,4), 4.02 (s, 2H,
CH2), 2.84 (m, 2H, CH2), 2.69 (s, 3H, CH3), 2.65 (m,
2H, CH2); 13C NMR (CDCl3) d 146.38 (C8a), 140.89
(Thio-2), 140.47 (Ph-1), 133.50 (C2), 128.97 (Ph-2,6*),
128.91 (Ph-3,5*), 128.57 (C8), 128.10 (Thio-5), 126.88
(Ph-4), 125.57 (Thio-3*), 124.33 (Thio-4*), 123.71 (C7),
121,04 (C6), 120.26 (C3), 118.78 (C5), 36.39 (CH2),
32.95 (CH2), 25.67 (CH2), 17.46 (CH3). Anal. Calcd
for C21H20N2S2: C, 69.19; H, 5.53; N, 7.68. Found: C,
69.51; H, 5.59; N, 7.66.
4.2.4.7.
6-Methyl-3-phenethylthiomethyl-8-(thien-2-
4.2.4.4. 8-Methyl-3-phenethylthiomethyl-6-(thien-3-
yl)imidazo[1,2-a]pyridine (5d). Compound 5d was ob-
yl)imidazo[1,2-a]pyridine (5g). Compound 5g was ob-
tained following the general procedure using 4e

´
J.-B. Veron et al. / Bioorg. Med. Chem. 15 (2007) 7209–7219
7216
(362 mg, 1 mmol), thien-2-ylboronic acid (154 mg,
1.2 mmol), and Na2CO3 as base. Pure product was ob-
tained by column chromatography on neutral alumina
eluting with ether/petroleum ether (70:30). Yield 52%.
Mp 85–86 °C. 1H NMR (CDCl3) d 8.13 (dd, 1H,
J = 3.8–1.2 Hz, Thio-3), 7.85 (m, 1H, H5), 7.57 (s, 1H,
H2), 7.46 (dd, 1H, J = 5.1–1.2 Hz, Thio-5), 7.42 (d,
1H, J = 1.3 Hz, H7), 7.36–7.16 (m, 6H, Thio-4, Ph),
4.00 (s, 2H, CH2), 2.86 (m, 2H, CH2), 2.66 (m, 2H,
CH2), 2.43 (s, 3H, CH3); 13C NMR (CDCl3) d 143.07
(C8a), 140.45 (Ph-1), 138.30 (Thio-2), 133.13 (C2),
128.97 (Ph-2,6*), 128.89 (Ph-3,5*), 128.07 (Thio-4),
127.72 (Thio-3), 126.94 (Thio-5), 126.87 (Ph-4), 124.33
(C7), 123.59 (C8*), 122.31 (C6*), 121.02 (C5), 119.54
(C3), 36.34 (CH2), 32.84 (CH2), 25.64 (CH2), 18.91
(CH3). Anal. Calcd for C21H20N2S2: C, 69.19; H, 5.53;
N, 7.68. Found: C, 69.25; H, 5.52; N, 7.70.
4.2.4.10. 8-(3-Hydroxyphenyl)-6-methyl-3-phenethyl-
thiomethylimidazo[1,2-a]pyridine (5j). Compound 5j
was obtained following the general procedure using
4e (362 mg, 1 mmol), 3-hydroxyphenylboronic acid
(151 mg, 1.1 mmol), and Na2CO3 as base. Pure product
was obtained by column chromatography on neutral
alumina eluting with CH2Cl2 and then with a mixture
of CH2Cl2 and MeOH (98:2). Yield 51%. Mp 78 °C.
1H NMR (DMSO-d6) d 9.51 (s, 1H, OH), 8.21 (s, 1H,
H5), 7.64 (s, 1H, PhOH-2), 7.56 (s, 1H, H2), 7.46 (d,
1H, J = 7.8 Hz, PhOH-6), 7.35–7.16 (m, 7H, H7, Ph
and PhOH-5), 6.84 (d, 1H, J = 7.5 Hz, PhOH-4), 4.20
(s, 2H, CH2), 2.78 (m, 2H, CH2), 2.58 (m, 2H, CH2),
2.39 (s, 3H, CH3); 13C NMR (DMSO-d6) d 157.98
(PhOH-3), 143.73 (C8a), 141.27 (Ph-1), 138.17 (PhOH-
1), 133.51 (C2), 130.04 (C8), 129.36 (Ph-2,6*), 129.13
(Ph-3,5*), 128.96 (PhOH-5), 127.01 (Ph-4), 126.13
(C7), 122.58 (C5), 122.03 (C6), 120.66 (C3), 120.55
(PhOH-6), 116.85 (PhOH-2), 115.97 (PhOH-4), 36.03
(CH2), 32.88 (CH2), 24.74 (CH2), 18.70 (CH3). Anal.
Calcd for C23H22N2OS: C, 73.76; H, 5.92; N, 7.48.
Found: C, 73.94; H, 5.95; N, 7.47.
4.2.4.8. 6-(2-Hydroxyphenyl)-8-methyl-3-phenethylthi-
omethylimidazo[1,2-a]pyridine (5h). Compound 5h was
obtained following the general procedure using 4d
(362 mg, 1 mmol), 2-hydroxyphenylboronic acid
(165 mg, 1.2 mmol), and Na2CO3 as base. Pure product
was obtained by column chromatography on neutral
alumina eluting with CH2Cl2, then by a mixture of
CH2Cl2 and MeOH (99:1 then 98:2). Yield 66%. Mp
4.2.4.11. 6-(4-Hydroxyphenyl)-8-methyl-3-phenethyl-
thiomethylimidazo[1,2-a]pyridine (5k). Compound 5k
was obtained following the general procedure using
4d (362 mg, 1 mmol), 4-hydroxyphenylboronic acid
(165 mg, 1.2 mmol), and Na2CO3 as base. Pure product
was obtained by column chromatography on neutral
alumina eluting with a mixture of CH2Cl2 and MeOH
1
189–190 °C. H NMR (DMSO-d6) d 9.83 (s, 1H, OH),
8.38 (s, 1H, H5), 7.54 (s, 1H, H2), 7.37 (m, 2H, PhOH-
4 and H7), 7.30–7.15 (m, 6H, PhOH-6, Ph), 7.01 (d,
1H, J = 7.9 Hz, PhOH-3), 6.93 (t, 1H, J = 7.4 Hz,
PhOH-5), 4.24 (s, 2H, CH2), 2.78 (m, 2H, CH2), 2.58
(m, 2H, CH2), 2.52 (s, 3H, CH3); 13C NMR (50 MHz,
DMSO-d6) d 155.60 (PhOH-2), 145.66 (C8a), 141.28
(Ph-1), 133.32 (C2), 131.22 (PhOH-4), 129.82 (PhOH-
6), 129.38 (Ph-2,6*), 129.13 (Ph-3,5*), 126.99 (Ph-4),
126.21 (C7), 125.95 (C8*), 125.14 (PhOH-1*), 123.97
(C6*), 122.52 (C5), 121.23 (C3), 120.33 (PhOH-5),
116.93 (PhOH-3), 36.06 (CH2), 32.92 (CH2), 24.79
(CH2), 17.47 (CH3). Anal. Calcd for C23H22N2OS: C,
73.76; H, 5.92; N, 7.48. Found: C, 73.84; H, 5.83; N,
7.52.
1
(98:2). Yield 35%. Mp 210 °C. H NMR (DMSO-d6) d
9.66 (s, 1H, OH), 8.40 (s, 1H, H5), 7.60 (d, 2H,
J = 8.5 Hz, PhOH-2,6), 7.53 (s, 1H, H2), 7.40 (s, 1H,
H7), 7.30–7.16 (m, 5H, Ph), 6.90 (d, 2H, J = 8.5 Hz,
PhOH-3,5), 4.30 (s, 2H, CH2), 2.76 (m, 2H, CH2), 2.56
(m, 2H, CH2), 2.55 (s, 3H, CH3); 13C NMR (DMSO-
d6) d 158.13 (PhOH-4), 145.64 (C8a), 141.29 (Ph-1),
133.42 (C2), 129.36 (Ph-2,6*), 129.12 (Ph-3,5*), 128.75
(PhOH-2,6), 128.60 (PhOH-1), 127.20 (C8), 126.99
(Ph-4), 125.89 (C6), 123.74 (C7), 121.48 (C3), 119.74
(C5), 116.69 (PhOH-3,5), 36.01 (CH2), 32.79 (CH2),
24.68 (CH2), 17.50 (CH3). Anal. Calcd for C23H22N2OS:
C, 73.76; H, 5.92; N, 7.48. Found: C, 73.82; H, 5.93; N,
7.46.
4.2.4.9. 6-(3-Hydroxyphenyl)-8-methyl-3-phenethylthi-
omethylimidazo[1,2-a]pyridine (5i). Compound 5i was
obtained following the general procedure using 4d
(362 mg, 1 mmol), 3-hydroxyphenylboronic acid
(151 mg, 1.1 mmol), and Na2CO3 as base. Pure product
was obtained by column chromatography on neutral
alumina eluting with a mixture of CH2Cl2 and MeOH
4.2.4.12. 8-(4-Hydroxyphenyl)-6-methyl-3-phenethyl-
thiomethylimidazo[1,2-a]pyridine (5l). Compound 5l
was obtained following the general procedure using
4e (362 mg, 1 mmol), 4-hydroxyphenylboronic acid
(165 mg, 1.2 mmol), and Na2CO3 as base. Pure product
was obtained by column chromatography on neutral
alumina eluting with a mixture of CH2Cl2 and MeOH
1
(98:2). Yield 37%. Mp 75 °C. H NMR (DMSO-d6) d
8.47 (s, 1H, H5), 7.56 (s, 1H, H2), 7.41 (s, 1H, H7),
7.36–7.14 (m, 8H, Ph, PhOH-2,5,6), 6.83 (d, 1H,
J = 7.8 Hz, PhOH-4), 4.30 (s, 2H, CH2), 2.75 (m, 2H,
CH2), 2.56 (m, 2H, CH2), 2.71 (s, 3H, CH3), OH not
found; 13C NMR (DMSO-d6) d 158.80 (PhOH-3),
145.89 (C8a), 141.25 (Ph-1), 139.36 (PhOH-1), 133.59
(C2), 130.91 (PhOH-5), 129.35 (Ph-2,6*), 129.11 (Ph-
3,5*), 127.36 (C8), 126.98 (Ph-4), 125.91 (C6), 123.73
(C7), 121.70 (C3), 120.84 (C5), 118.39 (PhOH-6*),
115.52 (PhOH-4), 114.48 (PhOH-2*), 36.02 (CH2),
32.80 (CH2), 24.67 (CH2), 17.49 (CH3). Anal. Calcd
for C23H22N2OS: C, 73.76; H, 5.92; N, 7.48. Found:
C, 73.98; H, 5.85; N, 7.51.
1
(98:2). Yield 44%. Mp 184 °C. H NMR (DMSO-d6) d
9.65 (s, 1H, OH), 8.14 (s, 1H, H5), 8.03 (d, 2H,
J = 8.6 Hz, PhOH-2,6), 7.55 (s, 1H, H2), 7.31–7.18 (m,
6H, H7, Ph), 6.88 (d, 2H, J = 8.6 Hz, PhOH-3,5), 4.20
(s, 2H, CH2), 2.79 (m, 2H, CH2), 2.58 (m, 2H, CH2),
2.39 (s, 3H, CH3). 13C NMR (CDCl3) d 158.10
(PhOH-4), 144.69 (C8a), 140.44 (Ph-1), 132.24 (C2),
131.35 (C8), 130.25 (PhOH-2,6), 128.98 (Ph-2,3,5,6),
127.63 (C7), 127.15 (PhOH-1), 126.91 (Ph-4), 123.14
(C6), 120.66 (C5), 119.54 (C3), 117.01 (PhOH-3,5),
36.03 (CH2), 32.81 (CH2), 24.68 (CH2), 18.77 (CH3).

´
J.-B. Veron et al. / Bioorg. Med. Chem. 15 (2007) 7209–7219
7217
Anal. Calcd for C23H22N2OS: C, 73.76; H, 5.92; N, 7.48.
Found: C, 73.78; H, 5.90; N, 7.49.
NMR (CDCl3) d 159.88 (PhOMe-4), 146.33 (C8a),
140.51 (Ph-1), 133.34 (C2), 130.60 (PhOMe-1), 128.97
(Ph-2,6*), 128.89 (Ph-3,5*), 128.62 (PhOMe-2,6),
127.68 (C8), 126.85 (Ph-4), 124.53 (C7), 119.95 (C3),
119.24 (C5), 114.90 (PhOMe-3,5), 55.83 (OMe), 36.37
(CH2), 32.90 (CH2), 25.75 (CH2), 17.55 (CH3). C6 not
found. Anal. Calcd for C24H24N2OS: C, 74.19; H,
6.23; N, 7.21. Found: C, 74.42; H, 6.36; N, 7.25.
4.2.4.13. 6-(3-Methoxyphenyl)-8-methyl-3-phenethyl-
thiomethylimidazo[1,2-a]pyridine (5m). Compound 5m
was obtained following the general procedure using 4d
(362 mg, 1 mmol), 3-methoxyphenylboronic acid
(183 mg, 1.2 mmol), and Na2CO3 as base. Pure product
was obtained by column chromatography on neutral
alumina eluting with CH2Cl2. Yield 87%. Mp 87–
4.2.4.16. 8-(4-Methoxyphenyl)-6-methyl-3-phenethyl-
thiomethylimidazo[1,2-a]pyridine (5p). Compound 5p
was obtained following the general procedure using
4e (362 mg, 1 mmol), 4-methoxyphenylboronic acid
(183 mg, 1.2 mmol), and Na2CO3 as base. Pure product
was obtained by column chromatography on neutral
alumina eluting with a mixture of CH2Cl2 and MeOH
(98:2). Yield 76%. Oil. 1H NMR (CDCl3) d 7.97 (d,
2H, J = 8.9 Hz, PhOMe-2,6), 7.87 (s, 1H, H5), 7.56 (s,
1H, H2), 7.35-7.16 (m, 6H, H7, Ph), 7.07 (d, 2H,
J = 8.9 Hz, PhOMe-3,5), 4.09 (s, 2H, CH2), 3.89 (s,
3H, OCH3), 2.86 (m, 2H, CH2), 2.66 (m, 2H, CH2),
2.44 (s, 3H, CH3); 13C NMR (CDCl3) d 160.16
(PhOMe-4), 147.14 (C8a), 140.54 (Ph-1), 133.44 (C2),
130.56 (PhOMe-2,6), 129.87 (C8*), 129.27 (PhOMe-1*),
128.98 (Ph-2,6*), 128.89 (Ph-3,5*), 126.85 (Ph-4),
125.74 (C7), 122.46 (C6), 120.85 (C5), 119.22 (C3),
114.43 (PhOMe-3,5), 55.80 (OMe), 36.40 (CH2), 32.89
(CH2), 25.71 (CH2), 18.95 (CH3). Anal. Calcd for
C24H24N2OS: C, 74.19; H, 6.23; N, 7.21. Found: C,
74.41; H, 6.26; N, 7.22.
1
89 °C. H NMR (CDCl3) d 8.18 (m, 1H, H5), 7.54 (s,
1H, H2), 7.41 (t, 1H, J = 8.1 Hz, PhOMe-5), 7.32–7.12
(m, 8H, H7, Ph, PhOMe-2,6), 6.96 (ddd, 1H, J = 8.1–
2.5–0.9 Hz, PhOMe-4), 4.02 (s, 2H, CH2), 3.90 (s, 3H,
OCH3), 2.85 (m, 2H, CH2), 2.66 (m, 2H, CH2), 2.71
(s, 3H, CH3); 13C NMR (CDCl3) d 160.55 (PhOMe-3),
146.48 (C8a), 140.48 (Ph-1), 139.66 (PhOMe-1), 133.38
(C2), 130.52 (PhOMe-5), 128.95 (Ph-2,6*), 128.89
(Ph-3,5*), 127.81 (C8*), 127.08 (C6*), 126.86 (Ph-4),
124.53 (C7), 120.15 (C3), 120.00 (PhOMe-6, C5),
113.58 (PhOMe-2), 113.30 (PhOMe-4), 55.82 (OCH3),
36.38 (CH2), 32.95 (CH2), 25.75 (CH2), 17.52 (CH3).
Anal. Calcd for C24H24N2OS: C, 74.19; H, 6.23; N,
7.21. Found: C, 74.35; H, 6.27; N, 7.29.
4.2.4.14. 8-(3-Methoxyphenyl)-6-methyl-3-phenethylthi-
omethylimidazo[1,2-a]pyridine (5n). Compound 5n was
obtained following the general procedure using 4e
(362 mg, 1 mmol), 3-methoxyphenylboronic acid
(183 mg, 1.2 mmol), and Na2CO3 as base. Pure product
was obtained by column chromatography on silica gel
eluting with
a
mixture of CH2Cl2 and MeOH
4.2.4.17. 8-Methyl-6-(3-nitrophenyl)-3-phenethylthi-
omethylimidazo[1,2-a]pyridine (5q). Compound 5q was
obtained following the general procedure using 4d
(362 mg, 1 mmol), 3-nitrophenylboronic acid (200 mg,
1.2 mmol), and Na2CO3 as base. Pure product was
obtained by column chromatography on silica gel elut-
ing with a mixture of CH2Cl2/MeOH (98:2). 77% yield.
Mp 108–109 °C. 1H NMR (CDCl3) d 8.48 (m, 1H,
PhNO2-2), 8.29 (m, 2H, PhNO2-4*, H5), 7.94 (ddd,
1H, J = 7.9–1.1–0.7 Hz, PhNO2-6), 7.69 (t, 1H,
J = 7.9 Hz, PhNO2-5), 7.58 (s, 1H, H2), 7.34–7.14 (m,
6H, H7, Ph), 4.07 (s, 2H, CH2), 2.85 (m, 2H, CH2),
2.75 (s, 3H, CH3), 2.68 (m, 2H, CH2); 13C NMR
(CDCl3) d 149.24 (PhNO2-3), 146.51 (C8a), 140.38
(Ph-1), 140.01 (PhNO2-1), 133.94 (C2), 133.40
(PhNO2-6), 130.49 (PhNO2-5), 128.92 (Ph-2,6*), 128.88
(Ph-3,5*), 128.73 (C8), 126.88 (Ph-4), 124.85 (C6),
123.47 (C7), 122.92 (PhNO2-4), 122.33 (PhNO2-2),
120.55 (C3), 120.55 (C5), 36.32 (CH2), 32.94 (CH2),
25.71 (CH2), 17.54 (CH3). Anal. Calcd for
C23H21N3O2S: C, 68.46; H, 5.25; N, 10.41. Found: C,
68.64; H, 5.34; N, 10.52.
1
(99.5:0.5). Yield 95%. Oil. H NMR (CDCl3) d 7.92 (s,
1H, H5), 7.59 (m, 2H, PhOMe-2,6), 7.56 (s, 1H, H2),
7.44 (t, 1H, J = 8.1 Hz, PhOMe-5), 7.34–7.16 (m, 6H,
H7, Ph), 6.99 (dd, 1H, J = 8.1–1.7 Hz, PhOMe-4), 4.02
(s, 2H, CH2), 3.91 (s, 3H, OCH3), 2.87 (m, 2H, CH2),
2.68 (m, 2H, CH2), 2.45 (s, 3H, CH3). 13C NMR
(CDCl3) d 160.09 (PhOMe-3), 144.49 (C8a), 140.52
(Ph-1), 138.20 (PhOMe-1), 133.60 (C2), 130.18 (C8),
129.92 (PhOMe-5), 128.98 (Ph-2,6*), 128.90 (Ph-3,5*),
126.87 (Ph-4), 126.58 (C7), 122.37 (C6), 121.90
(PhOMe-6), 121.46 (C5), 119.26 (C3), 115.02 (PhOMe-
2), 114.35 (PhOMe-4), 55.77 (OCH3), 36.39 (CH2),
32.89 (CH2), 25.70 (CH2), 18.93 (CH3). Anal. Calcd
for C24H24N2OS: C, 74.19; H, 6.23; N, 7.21. Found:
C, 74.58; H, 6.34; N, 7.19.
4.2.4.15.
6-(4-Methoxyphenyl)-8-methyl-3-phen-
ethylthiomethylimidazo[1,2-a]pyridine (5o). Compound
5o was obtained following the general procedure using
4d (362 mg, 1 mmol), 4-methoxyphenylboronic acid
(168 mg, 1.1 mmol), and NaOH as base. The reaction
mixture was heated at 85 °C for 3 h and then boronic
acid (16 mg, 0.1 mmol) was again added. The heating
was maintained for 3 h. Pure product was obtained by
column chromatography on silica gel eluting with a mix-
ture of ether and petroleum ether (50:50). Yield 88%.
4.2.4.18. 6-Methyl-8-(3-nitrophenyl)-3-phenethylthi-
omethylimidazo[1,2-a]pyridine (5r). Compound 5r was
obtained following the general procedure using 4e
(362 mg, 1 mmol), 3-nitrophenylboronic acid (200 mg,
1.2 mmol), and Na2CO3 as base. Pure product was ob-
tained by column chromatography on silica gel eluting
with ether and then ethyl acetate. Yield 79%. Mp 141–
142 °C. 1H NMR (CDCl3) d 8.86 (t, 1H, J = 1.9 Hz,
PhNO2-2), 8.49 (ddd, 1H, J = 7.9–1.9–1 Hz, PhNO2-6),
1
Mp 88 °C. H NMR (CDCl3) d 8.14 (s, 1H, H5), 7.55
(d, 2H, J = 8.6 Hz, PhOMe-2,6), 7.53 (s, 1H, H2), 7.34-
7.15 (m, 6H, Ph, H7), 7.06 (d, 2H, J = 8.6 Hz, PhOMe-
3,5), 4.04 (s, 2H, CH2), 3.91 (s, 3H, OMe), 2.85 (m,
2H, CH2), 2.67 (m, 2H,CH2), 2.72 (s, 3H, CH3); 13C

´
J.-B. Veron et al. / Bioorg. Med. Chem. 15 (2007) 7209–7219
7218
8.30 (ddd, 1H, J = 7.9–1.9–1 Hz, PhNO2-4), 8.00 (m,
1H, H5), 7.71 (t, 1H, J = 7.9 Hz, PhNO2-5), 7.57 (s,
1H, H2), 7.34–7.16 (m, 6H, H7, Ph), 4.04 (s, 2H, CH2),
2.87 (m, 2H, CH2), 2.61 (m, 2H, CH2), 2.50 (s, 3H,
CH3); 13C NMR (CDCl3) d 148.87 (PhNO2-3), 143.99
(C8a), 140.43 (Ph-1), 138.48 (PhNO2-1), 135.56
(PhNO2-6), 133.87 (C2), 129.87 (PhNO2-5), 128.97
(Ph-2,3,5,6), 127.64 (C8), 126.93 (Ph-4, C7), 124.15
(PhNO2-2), 123.36 (PhNO2-4), 122.55 (C5), 122.40
(C6), 119.80 (C3), 36.38 (CH2), 32.93 (CH2), 25.63
(CH2), 18.94 (CH3). Anal. Calcd for C23H21N3O2S: C,
68.46; H, 5.25; N, 10.41. Found: C, 68.67; H, 5.32; N,
10.39.
tained by column chromatography on silica gel eluting
with ether/petroleum ether (80:20). Yield 60%. Oil. H
1
NMR (CDCl3) d 7.95 (m, 1H, H5), 7.79 (m, 2H, PhF-
2,6), 7.56 (s, 1H, H2), 7.49 (td, 1H, J = 8 Hz, 6 Hz,
PhF-5), 7.36–7.23 (m, 4H, Ph-3,4,5, H7), 7.20–7.09 (m,
3H, Ph-2,6, PhF-4), 4.02 (s, 2H, CH2), 2.87 (m, 2H,
CH2), 2.67 (m, 2H, CH2), 2.46 (s, 3H, CH3); 13C
NMR (CDCl3) d 163.23 (J = 243.5 Hz, PhF-3), 144.18
(C8a), 140.51 (Ph-1), 138.97 (J = 8 Hz, PhF-1), 133.65
(C2), 130.36 (J = 8 Hz, PhF-5), 128.98 (Ph-2,6*),
128.90 (Ph-3,5*), 126.87 (Ph-4), 126.60 (C8), 125.03
(J = 2 Hz, PhF-6), 122.28 (C5), 121.92 (C6), 119.55
(C3), 116.36 (J = 22.5 Hz, PhF-2), 115.46 (J = 20.5 Hz,
PhF-4), 36.39 (CH2), 32.95 (CH2), 25.62 (CH2), 18.85
(CH3). Anal. Calcd for C23H21FN2S: C, 73.37; H,
5.62; N, 7.44. Found: C, 73.48; H, 5.63; N, 7.42.
4.2.4.19. 6-(3-Cyanophenyl)-8-methyl-3-phenethylthi-
omethylimidazo[1,2-a]pyridine (5s). Compound 5s was
obtained following the general procedure using 4d
(362 mg, 1 mmol), 3-cyanophenylboronic acid (177 mg,
1.2 mmol), and Na2CO3 as base. Pure product was ob-
tained by column chromatography on silica gel eluting
with a mixture of CH2Cl2 and MeOH (99:1). Yield
83%. Mp 118–119 °C. 1H NMR (CDCl3) d 8.20 (d,
1H, J = 0.9 Hz, H5), 7.87 (s, 1H, PhCN-2), 7.84 (dt,
1H, J = 7.6–1.5 Hz, PhCN-6), 7.70 (dt, 1H, J = 7.67–
1.5 Hz, PhCN-4), 7.63 (t, 1H, J = 7.6 Hz, PhCN-5),
7.56 (s, 1H, H2), 7.32–7.12 (m, 6H, H7, Ph), 4.05 (s,
2H, CH2), 2.85 (m, 2H, CH2), 2.66 (m, 2H, CH2), 2.72
(s, 3H, CH3); 13C NMR (CDCl3) d 146.47 (C8a),
140.37 (Ph-1), 139.58 (PhCN-1), 133.86 (C2), 131.86
(PhCN-6*), 131.58 (PhCN-2*), 131.02 (PhCN-4),
130.34 (PhCN-5), 128.92 (Ph-2*), 128.64 (Ph-3,5*),
128.64 (C8), 126.89 (Ph-4), 125.01 (C6), 123.50 (C7),
120.49 (C5), 118.97 (C3), 113.74 (PhCN-3), 36.30
(CH2), 32.92 (CH2), 25.71 (CH2), 17.54 (CH3). Anal.
Calcd for C24H21N3S: C, 75.16; H, 5.52; N, 10.96.
Found: C, 75.24; H, 5.39; N, 10.87.
4.3. Antiviral assays
Human cytomegalovirus (HCMV) AD169 and Davis
strains were exposed to human embryonic lung
(HEL) cell cultures. Briefly, confluent culture in micro-
titer plates was inoculated with 100 plaque 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 com-
pounds. Viral cytopathicity was recorded as soon as it
reached completion in the control virus-infected cell
cultures. Inhibition of HCMV by the test compounds
was compared with cidofovir and ganciclovir as the ref-
erence compounds. Varicella-zoster virus (VZV) Oka
(TK+) and 07/1 (TKꢀ) strains were grown on HEL
cells. As described for HCMV, confluent cells were
inoculated but with 20 PFU/well and the different dilu-
tions of the tested compounds were added as for
HCMV. After 5 days incubation 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 reference drugs.
4.2.4.20. 6-(4-Cyanophenyl)-8-methyl-3-phenethylthi-
omethylimidazo[1,2-a]pyridine (5t). Compound 5t was
obtained following the general procedure using 4d
(362 mg, 1 mmol), 4-cyanophenylboronic acid (177 mg,
1.2 mmol), and Na2CO3 as base. Pure product was ob-
tained by column chromatography on silica gel eluting
with a mixture of CH2Cl2 and MeOH (99:1). Yield
70%. Mp 102 °C. 1H NMR (CDCl3) d 8.25 (s, 1H,
H5), 7.81 (d, 2H, J = 8.6 Hz, PhCN-3,5), 7.72 (d, 2H,
J = 8.6 Hz, PhCN-2,6), 7.57 (s, 1H, H2), 7.32–7.12 (m,
6H, H7, Ph), 4.05 (s, 2H, CH2), 2.84 (m, 2H, CH2),
2.68 (m, 2H, CH2), 2.74 (s, 3H, CH3); 13C NMR
(CDCl3) d 178.60 (CN), 146.27 (C8a), 142.64 (PhCN-
1), 140.32 (Ph-1), 133.36 (C2), 133.28 (PhCN-3,5),
128.91 (Ph-2,3,5,6), 128.53 (C8), 128.10 (PhCN-2,6),
126.91 (Ph-4), 125.47 (C6), 123.75 (C7), 120.72 (C5),
119.05 (C3), 111.94 (PhCN-4), 36.29 (CH2), 32.96
(CH2), 25.70 (CH2), 17.56 (CH3). Anal. Calcd for
C24H21N3S: C, 75.16; H, 5.52; N, 10.96. Found: C,
75.32; H, 5.56; N, 10.98.
Antiviral activity is expressed as the concentration of the
compound required to inhibit viral cytopathicity by 50%
(IC50).
4.4. Cytostatic activity assays
The cytostatic assays were performed as previously de-
scribed.27–29 Briefly, 100-lL aliquots of HEL cell sus-
pensions were added to the wells of
a 96-well
microtiter plate containing 100 lL of varying concentra-
tions of the test compounds. After 3 days incubation
period at 37 °C in a humidified CO2-controlled incuba-
tor, the number of viable cells was determined using a
Coulter Counter. Cytostatic activity is expressed as the
compound concentration that reduced the number of
viable cells by 50% (CC50). The cytotoxicity measure-
ment was based on microscopically visible morphologi-
cal alterations of the HEL cell cultures: cytotoxicity was
defined as the minimum cytotoxic concentration (MCC)
required for causing a microscopically detectable alter-
ation of cell morphology.
4.2.4.21. 8-(3-Fluorophenyl)-6-methyl-3-phenethylthi-
omethylimidazo[1,2- a]pyridine (5u). Compound 5u was
obtained following the general procedure using 4e
(362 mg, 1 mmol), 3-fluorophenylboronic acid (168 mg,
1.2 mmol), and Na2CO3 as base. Pure product was ob-

´
J.-B. Veron et al. / Bioorg. Med. Chem. 15 (2007) 7209–7219
7219
Balzarini, J.; De Clercq, E.; Chapat, J. P. J. Med. Chem.
1996, 39, 2856–2859.
Acknowledgments
16. Gueiffier, A.; Mavel, S.; Lhassani, M.; Elhakmaoui, 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, 5108–5112.
17. 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, 941–946.
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 Wetenschappelijk
Onderzoeck (FWO), Vlaanderen and the Geconcerteerde
Onderzoeksacties (GOA), Vlaamse Gemeenschap.
´
18. Enguehard, C.; Hervet, M.; Thery, I.; Renou, J.-L.;
Fauvelle, F.; Gueiffier, A. Helv. Chim. Acta 2001, 84,
3610–3615.
19. Enguehard, C.; Allouchi, H.; Gueiffier, A.; Buchwald, S.
L. J. Org. Chem. 2003, 68, 5614–5617.
References and notes
20. Enguehard, C.; Allouchi, H.; Gueiffier, A.; Buchwald, S.
L. J. Org. Chem. 2003, 68, 4367–4370.
1. Stevens, J. G. Microbiol. Rev. 1989, 53, 318–332.
2. Vancikova, Z.; Dvorak, P. Curr. Drug Targets Immune
Endocr. Metabol. Disord. 2001, 1, 179–187.
3. Nichols, W. G.; Boeckh, M. J. Clin. Virol. 2000, 16, 25–40.
4. Gnann, J. W., Jr. J. Infect. Dis. 2002, 186(Suppl. 1), S91–
S98.
5. De Clercq, E. J. Clin. Virol. 2004, 30, 115–133.
6. Naesens, L.; De Clercq, E. Herpes 2001, 8, 12–16.
7. Biron, K. K. Antiviral Res. 2006, 71, 154–163.
8. Baillie, G. M. Am. J. Health Syst. Pharm. 2005, 62, S14–
S17.
´
21. Hervet, M.; Thery, I.; Gueiffier, A.; Enguehard-Gueiffier,
C. Helv. Chim. Acta 2003, 86, 3461–3469.
´
22. Kazock, J.-Y.; Enguehard-Gueiffier, C.; Thery, I.; Gueif-
fier, A. Bull. Chem. Soc. Jpn. 2005, 78, 154–159.
´
23. Enguehard-Gueiffier, C.; Thery, I.; Gueiffier, A.; Buch-
wald, S. L. Tetrahedron 2006, 62, 6042–6049.
24. Dolci, L.; Dolle, F.; Valette, H.; Vaufrey, F.; Fuseau, C.;
Bottlaender, M.; Crouzel, C. Bioorg. Med. Chem. 1999, 7,
467–479.
25. Yamanaka, M.; Miyake, K.; Suda, S.; Ohhara, H.;
Ogawa, T. Chem. Pharm. Bull. (Tokyo) 1991, 39, 1556–
1567.
26. Coulson, D. R. Inorg. Synth. 1971, 13, 121–124.
27. De Clercq, E.; Descamps, J.; Verhelst, G.; Walker, R. T.;
Jones, A. S.; Torrence, P. F.; Shugar, D. J. Infect. Dis.
1980, 141, 563–574.
28. De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.;
Balzarini, J.; Maudgal, P. C. Nature 1986, 323, 464–467.
29. Balzarini, J.; Naesens, L.; Slachmuylders, J.; Niphuis, H.;
Rosenberg, I.; Holy, A.; Schellekens, H.; De Clercq, E.
Aids 1991, 5, 21–28.
9. De Clercq, E. J. Antimicrob. Chemother. 2003, 51, 1079–
1083.
10. Baldanti, F.; Lurain, N.; Gerna, G. Hum. Immunol. 2004,
65, 403–409.
11. Borthwick, A. D. Med. Res. Rev. 2005, 25, 427–452.
12. Wathen, M. W. Rev. Med. Virol. 2002, 12, 167–178.
13. Bogner, E. Rev. Med. Virol. 2002, 12, 115–127.
14. Martinez, A.; Castro, A.; Gil, C.; Perez, C. Med. Res. Rev.
2001, 21, 227–244.
15. 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.;