Synthesis, biological activity and structure-activity relationship of 4,5-dimethoxybenzene derivatives inhibitor of rhinovirus 14 infection

Article abstract of DOI:10.1016/j.ejmech.2014.01.034

Human rhinoviruses are a common cause of respiratory infections, and thus constitute an important target for medicinal chemistry. Still, no drug has been approved for clinical use. We report herein the discovery of dibenzenic derivatives with potent and s

Full text of DOI:10.1016/j.ejmech.2014.01.034

European Journal of Medicinal Chemistry 76 (2014) 445e459
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, biological activity and structureeactivity relationship of
4,5-dimethoxybenzene derivatives inhibitor of rhinovirus 14 infection
,
Manon Roche a, Céline Lacroix b, Omar Khoumeri a, David Franco b, Johan Neyts b
**
,
,
Thierry Terme a, Pieter Leyssen b, Patrice Vanelle a
*
a Aix-Marseille Univ, Institut de Chimie Radicalaire, UMR 7273, CNRS 27, Boulevard Jean Moulin Marseille, France
b Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Human rhinoviruses are a common cause of respiratory infections, and thus constitute an important
target for medicinal chemistry. Still, no drug has been approved for clinical use. We report herein the
discovery of dibenzenic derivatives with potent and specific in vitro anti-rhinoviral 14 activity. A total of
99 structural analogues were synthesized by an original synthesis method, i.e. through one organic agent
Tetrakis(DimethylAmino)Ethylene (TDAE) and a structureeactivity relationship was established. It was
shown that 4,5-dimethoxy scaffold and the presence of a C-4 substituted aromatic moiety were
necessary to the in vitro activity of these original agents. However, modifications on liker were not
convincing. The benzonitrile derivative 23 was identified as the most potent and selective inhibitor of
Received 20 November 2013
Received in revised form
14 January 2014
Accepted 18 January 2014
Available online 17 February 2014
Keywords:
Human rhinovirus 14
Tetrakis(DimethylAmino)Ethylene
4,5-Dimethoxybenzenes
Antiviral activity
rhinovirus replication in these series (EC50 of 2 ꢀ 0.5
m
M, CC50 of 184
mM, selectivity index of 92).
Ó 2014 Elsevier Masson SAS. All rights reserved.
1. Introduction
clinical development for the treatment of asthma exacerbations and
has completed phase II clinical trials with a positive outcome [14].
In this paper, we explore the use of Tetrakis(DimethylAmino)
Ethylene (TDAE)-based chemistry in a medicinal setting [15,16]
(Chart 1). TDAE is an organic reducing agent [17] which reacts
with haloalkyl derivatives to generate an anion under mild condi-
tions via two sequential transfers of one electron (Scheme 1) [18].
This carbanion is able to react with various electrophiles such as
Human rhinoviruses (HRV) are single-stranded, positive-sense
RNA viruses of the Picornaviridae family. They are responsible for at
least 50% of the common colds [1,2], a mild, self-limiting upper
respiratory tract illness, nonetheless with major economic impact
through loss of productivity [1,3,4]. Furthermore, rhinovirus in-
fections have frequently been associated with more severe lower
respiratory tract disease such as exacerbations of asthma or chronic
obstructive pulmonary disease (COPD) [5,6]. Prevention through
vaccination is not feasible because there exist more than 150
different rhinovirus types with low antibody cross-reactivity [7]. To
lower the burden of rhinovirus infection in patients with asthma or
COPD, urgent development of agents with broad-spectrum antiviral
activity against the three genetic clades of HRV (A, B and C) is needed
[8]. In the past, several small-molecule inhibitors have been in
(clinical) development to treat the common cold [9e11]. However,
none of these candidates reached the market because the side-
effects of the treatment did not outweigh the burden of a common
cold itself or no efficacy was observed in a setting with natural
occurring rhinovirus infections [12,13]. Currently, capsid binder
vapendavir (BTA-798, Biota Pharmaceuticals Incorporated) is under
aromatic aldehydes, a-ketoester, ketomalonate, a-ketolactam and
sulfonimine derivatives [19e27]. Since the development of TDAE
methodology, a chemical library was constituted and evaluated for
the antiviral effect in a virus-cell-based assay on different viruses.
This first screening revealed a specificity of the compounds for HRV.
For the initial structureeactivity relationship, we evaluated the
inhibitory activity of the compounds in a virus-cell-based assay for
HRV 14. Subsequently, active compounds from this SAR were
evaluated against a panel of 13 genetically diverse human rhino-
virus strains.
2. Results and discussion
2.1. First topological exploration with nitrobenzyl chloride
derivatives
* Corresponding author. Tel.: þ33 4 91835580; fax: þ33 4 91 79 46 77.
** Corresponding author. Tel.: þ32 16 332883; fax: þ33 16 337340.
E-mail addresses: johan.neyts@rega.kuleuven.be (J. Neyts), patrice.vanelle@
univ-amu.fr (P. Vanelle).
The first homogenous series of compounds that have been
evaluated for antiviral activity, were the products derived from the
0223-5234/$ e see front matter Ó 2014 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2014.01.034

446
M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
O
F
O
O
F
F
N
N
N
N
N
O
N
O
O
N
Pleconaril
Disoxaril
N
N
O
O
NH2
N
N
O
S
N
O
OEt
HO
Me
Enviroxime
Vapendavir
Chart 1. Molecules with anti-HRV activity.
CH3 CH3
H3C N
N CH3
H3C N
N CH3
CH3 CH3
NO2
NO2
O
DMF
R2
R1
+
R
R
Cl
R2
R1
1) 1 h, -20 °C
2) 2 h, rt
HO
R1, R2 = H, Aryl, Alkyl, ...
Scheme 1. TDAE methodology: general procedure.
TDAE-initiated reaction of various nitrobenzyl chloride derivatives
(1e5) with p-nitrobenzaldehyde (most reactive aldehyde) of which
the reaction scheme is shown in Scheme 2 and of which the yield of
the reaction products together with the antiviral activity against
HRV 14 are listed in Table 1.
seeking to produce other compounds with higher activity and less
toxicity, as well as to define a structureeactivity relationship (SAR).
Our strategy involved a topological exploration of the diarylethanol
derivative described, examining three targets of this molecule: the
linker, R1 and R2 substituents (Chart 2).
In this homogenous series, the most active compound was the 2-
(4,5-dimethoxy-2-nitrophenyl)-1-(4-nitrophenyl)ethanol 6, which
was formed from TDAE-initiated reaction on 1-(chloromethyl)-4,5-
dimethoxy-2-nitrobenzene 1. This compound 6 proved to be a se-
2.2. Pharmacomodulation of substituent R1
First, we changed electrophiles, selecting aldehydes with
different physicochemical and steric characters. Thus, the synthesis
started with the reaction of 1-(chloromethyl)-4,5-dimethoxy-2-
nitrobenzene 1 with various aldehydes under classical TDAE
lective (EC50 of 4.3 ꢀ 1.0
mM, CC50 of 95 mM, selectivity index of 23)
inhibitor of virus replication. These first results led us to direct our
research towards the 4,5-dimethoxy-2-nitrobenzene derivatives,
O
H
NO2
TDAE
DMF
NO2
+
R
R
NO2
Cl
1) 1 h, -20 °C
2) 2 h, rt
HO
NO2
6 -10
H3CO
H3CO
NO2
Cl
NO2
O2N
NO2
Cl
NO2
Cl
NO2
Cl
O
R
=
Cl
Cl
O
H3C
1
2
3
5
4
Scheme 2. First homogenous series with p-nitrobenzaldehyde.

M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
447
Table 1
SAR of the first homogenous series.a,b
No
Code
Structure
Yield
85%
CC50
EC50
EC90
H
H
CO
CO
NO
OH
6
W6
95.1 ꢀ 16.2
4.3 ꢀ 1.02
8.8 ꢀ 0.9
>301
NO
NO
OH
O
7
8
M012618b
M0168
O
65%
85%
11.4
347
>301
>347
NO
NO
OH
NO
>347
NO
OH
9
M0186
68%
85%
67.8
134
>331
>347
>331
>347
H C
O N
NO
OH
10
M017418a
NO
CC50 ¼ 50% Cytostatic/Cytotoxic Concentration (concentration at which 50% adverse effect is observed on the host cell).
EC50 ¼ 50% Effective Concentration (concentration at which 50% inhibition of virus replication is observed).
EC90 ¼ 90% Effective Concentration (concentration at which 90% inhibition of virus replication is observed).
a
All values are in
In assay conditions: Pleconaril EC50 ¼ 0.2 ꢀ 0.1
m
M, expressed as median ꢀ Med. Abs. Dev.
b
m
M; Pleconaril CC50 ¼ 50.2 ꢀ 5
mM.
(compounds 17, 18 and 22) or C-2 phenyl (like compound 16 for
example) group of R1 substitutions of chemical entities decreased or
abolished the hRV 14 activity in vitro. The 4-[1-hydroxy-2-(4,5-
dimethoxy-2-nitrophenyl)-1-hydroxyethyl]benzonitrile 23 was
H3CO
H3CO
NO2
OH
R2
R1
identified as the most potent (EC50 of 2.19 ꢀ 0.49
m
M) and selective
(CC50 of 184 ꢀ 30
mM, selectivity index of 92) inhibitor of virus
Chart 2. First topological exploration of 4,5-dimethoxy-2-nitrobenzene derivative.
replication.
conditions [19] i.e. with 3 equiv of aldehyde in the presence of
1.1 equiv of TDAE in DMF, at ꢁ20 ꢂC for 1 h followed by 2 h at room
temperature and yielded diarylethanols 11e30 in 35%e85% yield
(Scheme 3). Yields varied according to functional group of elec-
trophiles. As observed in previous studies [19e30], an electron-
withdrawing group in ortho or para positions promotes the attack
of carbanion, thus increasing yield. The biological activities of these
molecules are described in Table 2.
2.3. Secondary alcohol function explorations
For the purposes of the SAR study and to confirm our hit
scaffold, we investigated the importance of the secondary alcohol
function. Thus, we synthesized and evaluated a series of tertiary
alcohols prepared under initial TDAE procedure from 1 and ke-
tone derivatives such as
a-ketoesters [21], a-diketones [29],
acetophenones and isatine [28] as electrophiles (Scheme 4 and
Table 3). Tertiary alcohols 31e37 were obtained in 28%e87%
yield.
Biological assays showed five molecules (6, 13, 14, 23, 24) with
interesting anti-HRV 14 activities (EC50 around 2 mM). Thesemolecules
were also selective (selectivity index from 6 to 92). All these products
presented a phenyl group moiety as R1. The substitution and various
replacements of the C-4 phenyl group (compounds 6,14, 23 and 24) of
R1 moiety led to slightly more active derivatives (isosteric and non
isosteric). In addition, R1 biphenyl structure 1-(biphenyl-4-yl)-2-(4,5-
dimethoxy-2-nitrophenyl)ethanol 13 increased the lipophilic char-
All modifications on scaffold, presented in Table 3, clearly
showed the importance of secondary alcohol versus tertiary
alcohol. In fact, modifications of CeOH substituents for compounds
31e37 greatly affected biological activity, suggesting that steric
hindrance is correlated with activity. Moreover, the modification of
the more active compounds 6 and 23 by a methyl group as R2
(compounds 33 and 34) led to a total loss of inhibitory activity
against HRV 14.
acter and provided good activity, with a EC50 of 1.97 ꢀ 0.13
mM.
Moreover, thesubstitutionandvariousreplacementsoftheC-3phenyl
NO2
TDAE
NO2
DMF
O
H3CO
+
H3CO
H3CO
R1
H
R1
Cl
HO
1) 1 h, -20 °C
2) 2 h, rt
H3CO
1
11-30
Scheme 3. Pharmacomodulation of R1.

448
M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
Table 2
SAR: nature of R1.a,b
No
Code
W6
R1
Yield
85%
CC50
EC50
EC90
6
95.1 ꢀ 16.2
4.3 ꢀ 1.0
8.8 ꢀ 0.9
NO2
11
12
M090
M092
68%
50%
78.7 ꢀ 12.7
65.8 ꢀ 4.1
9.8 ꢀ 0.1
6.0 ꢀ 0.5
15.7 ꢀ 0.3
10.3 ꢀ 1.1
Cl
Br
13
14
M0108
M0110
70%
35%
12 ꢀ 5.6
1.97 ꢀ 0.1
2.8 ꢀ 0.6
3.13 ꢀ 0.1
5.2 ꢀ 1.1
56 ꢀ 16.0
SCH3
F
F
F
F
15
16
M0122
M0140
25%
36%
ND
ND
>254
>287
>254
>287
F
NO2
NO2
CN
17
18
M0142
M0144
52%
70%
380
15.8 ꢀ 3.3
29 ꢀ 6.9
27.5 ꢀ 5.4
160 ꢀ 38.8
66.7 ꢀ 11.8
Br
19
20
21
M0146
M0148
M0164
50%
39%
85%
ND
>262
>262
33.3
Br
52.4 ꢀ 13.5
98.7 ꢀ 11.4
28.1 ꢀ 3.1
>311
F
>311
F
22
23
M0166
W5
85%
81%
89.8 ꢀ 9.6
184 ꢀ 30
43.2 ꢀ 1.3
2.19 ꢀ 0.4
ND
3.83 ꢀ 0.8
CN
24
25
W46
W47
85%
62%
49.7 ꢀ 18.1
2.04 ꢀ 0.1
60.4 ꢀ 9.3
3.28 ꢀ 0.1
134 ꢀ 15
CF3
112
F

M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
449
Table 2 (continued )
No
Code
W48
R1
Yield
49%
CC50
ND
EC50
EC90
OCH3
OCH3
26
>306
>306
O2N
27
28
M0130
M0132
86%
33%
171 ꢀ 44.4
221 ꢀ 32.9
58.9 ꢀ 3.4
117 ꢀ 28.8
100 ꢀ 2.7
N
N
313
N
O
29
30
M0134
M052
70%
85%
276
ND
>329
>334
>329
>334
CH2CH3
O
ND ¼ not determined.
CC50 ¼ 50% Cytostatic/Cytotoxic Concentration (concentration at which 50% adverse effect is observed on the host cell).
EC50 ¼ 50% Effective Concentration (concentration at which 50% inhibition of virus replication is observed).
EC90 ¼ 90% Effective Concentration (concentration at which 90% inhibition of virus replication is observed).
a
All values are in
In assay conditions: Pleconaril EC50 ¼ 0.2 ꢀ 0.1
m
M, expressed as median ꢀ Med. Abs. Dev.
b
m
M; Pleconaril CC50 ¼ 50.2 ꢀ 5
mM.
H3CO
H3CO
NO2
Cl
O
H3CO
H3CO
NO2
R
i
OH
R2
+
R1
R2
1
R1 = COOEt and R2
=
COOEt
CH3
31 R1 = COOEt and R2
=
COOEt
CH3
R1 = COOEt and R2 = CH3
32 R1 = COOEt and R2 = CH3
R1 = pC6H4CN and R2
=
33 R1 = pC6H4CN and R2
=
R1 = pC6H4NO2 and R2
=
CH3
34 R1 = pC6H4NO2 and R2
=
CH3
O
H3CO
H3CO
NO2
Cl
CH3
O
O
H3CO
H3CO
NO2
HO
N
i
+
CH3
N
1
3518d
O
O
H3CO
H3CO
NO2
HO
H3CO
H3CO
NO2
Cl
O
ii
+
1
3618h
O
H3CO
H3CO
NO2
HO
O
H3CO
H3CO
NO2
Cl
ii
+
O
3718h
1
aAll yields refer to the chromatographically isolate products and are relative to substrate.
b Reagents and conditions: (i) electrophile (3 equiv), TDAE (1.1 equiv), extra dry DMF, -20 °C,1 h; rt, 2 h; H2O;
31 (72%), 32 (59%), 33 (78%), 34 (34%), 35 (87%), (ii) electrophile (3 equiv), TDAE (1.0 equiv), extra dry
DMF, -20 °C,1 h; 80°C, 2 h; H2O; 36 (32 %), 37 (28%).
Scheme 4. Pharmacomodulation of R1 and R2.a,b

450
M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
Table 3
1-ol 42 in 32% yield from the reaction of 1-(3-chloroprop-1-ynyl)-
SAR: R1 and R2 modification.a,b
4-nitrobenzene 41 (prepared via a Sonogashira cross coupling re-
action) [27] with 3 equiv of 4,5-dimethoxy-2-nitrobenzaldehyde in
the presence of 1.1 equiv of TDAE in DMF, at ꢁ50 ꢂC for 1 h followed
by 2 h at 60 ꢂC [20].
The reaction of the 1-(dichloromethyl)-4,5-dimethoxy-2-
nitrobenzene 43 with 3 equiv of aldehydes (presented in Scheme
5) in the presence of 1.1 equiv of TDAE in DMF, at ꢁ20 ꢂC for 1 h,
followed by 2 h at rt yielded oxirane derivatives 44e49 in 35%e80%
yield. These reactions were performed under light catalysis
(Table 4).
OH functional group reversal was explored with the biological
evaluation of compound 39. The potent activity was abolished in
the case of inversion of the OH functional group position on the
linker. Moreover, the expected effect of rigidifying the linker was to
decrease the number of conformations and thus potentially in-
crease selectivity. Product 1-(4,5-dimethoxy-2-nitrophenyl)-4-(4-
nitrophenyl)but-3-yn-1-ol 42 presented interesting anti-
rhinoviral activity but also significant toxicity on the Hela cells
No Code
Structure
Yield CC50
EC50
EC90
H CO
H CO
NO
HO
COOEt
COOEt
31 OUA34
72%
59%
78%
ND
ND
107
>269 >269
>319 >319
>292 >292
H CO
H CO
MeO
NO
HO
COOEt
CH
32 M056
33 M096
NO
OH
MeO
H C
NO
CN
NO
MeO
MeO
OH
O
34 M0112
34%
87%
138
>276 >276
H C
H CO
H CO
NO
HO
CH
N
35 W001818d
152 ꢀ 44.9 >279 >279
(CC50 ¼ 17.2
mM). An increased linker length might be more inter-
esting without a triple bond. Rigidification without elongation (38,
40, 44e49) led to a complete loss of anti-HRV 14 activity.
O
H CO
H CO
NO
HO
The next step in our pharmacomodulation process was the
derivatization of the linker. All substitutions are described in
Scheme 6 [31e35]. The substitution reactions were carried out for
products 6, 13, 23 and 28 by the action of 3 equiv of thionyl chloride
in CH2Cl2, for 4 h. This reaction led to chloride derivatives 50e53 in
90%e95% yield. 1-(Azido-2-(4-nitrophenyl)ethyl)-4,5-dimethoxy-
36 W003718h
32%
28%
ND
ND
>329 >329
301 >307
H CO
H CO
NO
HO
O
37 W003818h
2-nitrobenzene
54
and
4-(1-azido-2-(4,5-dimethoxy-2-
ND ¼ not determined.
nitrophenyl)ethyl)benzonitrile 55 were obtained by using 3 equiv
of NaN3 and respectively the 1-(2-chloro-2-(4-nitrophenyl)ethyl)-
4,5-dimethoxy-2-nitrobenzene 50 and the 4-(1-chloro-2-(4,5-
dimethoxy-2-nitrophenyl)ethyl)biphenyl 51 in solution in ethanol
for 6 h (Yields: 54, 37%; 55, 30%). The conversion of 1-(azido-2-(4-
nitrophenyl)ethyl)-4,5-dimethoxy-2-nitrobenzene 54 to 2-(4,5-
dimethoxy-2-nitrophenyl)-1-(4-nitrophenyl)ethanamine 56 was
accomplished by treatment with 1 equiv of PPh3 according to
Staudinger reaction conditions.
CC50 ¼ 50% Cytostatic/Cytotoxic Concentration (concentration at which 50% adverse
effect is observed on the host cell).
EC50 ¼ 50% Effective Concentration (concentration at which 50% inhibition of virus
replication is observed).
EC90 ¼ 90% Effective Concentration (concentration at which 90% inhibition of virus
replication is observed).
a
All values are in
m
M, expressed as median ꢀ Med. Abs. Dev.
In assay conditions: Pleconaril EC50 0.2 0.1
CC50 ¼ 50.2 ꢀ 5 M.
b
¼
ꢀ
mM; Pleconaril
m
4-[2-(4,5-Dimethoxy-2-nitrophenyl)-1-hydroxy-ethyl]benzoni-
trile 23 was then treated with diethylaminosulfur trifluoride to
yield the 4-(2-(4,5-dimethoxy-2-nitrophenyl)-1-fluoroethyl)ben-
zonitrile 57. To check the effect of steric hindrance in this scaffold
moiety on biological activity, mesylation of the hydroxyl group of 4-
[2-(4,5-dimethoxy-2-nitrophenyl)-1-hydroxy-ethyl]benzonitrile
23 was performed with 1.5 equiv of methane sulfonyl chloride in
chloroform at 60 ꢂC for 48 h leading to 1-(4-cyanophenyl)-2-(4,5-
dimethoxy-2-nitrophenyl)ethyl methanesulfonate 58 in 25% yield
(Table 5).
2.4. Linker modifications
Next, variations on the linker moiety were introduced to further
expand the SAR. Different approaches were considered: effect of
linker elongation, modification of hydroxyl group and linker
rigidification (Scheme 5). However, TDAE methodology was not
sufficient for all these purposes: our first strategy was to somewhat
modify the TDAE methodology (substrate, experimental condi-
tions) to obtain products with a modified linker.
The reaction of chloride 1 and p-nitrobenzaldehyde under
classical TDAE conditions but with heating at 70 ꢂC for 2 h in the
second phase of the protocol enabled us to isolate the (E)-1,2-
dimethoxy-4-nitro-5-(4-nitrostyryl)benzene 38 in 15% yield. In
parallel, the reaction of chloride 5 with 3 equiv of 4,5-dimethoxy-2-
nitrobenzaldehyde under classical TDAE conditions [19] led to 1-
(4,5-dimethoxy-2-nitrophenyl)-2-(4-nitrophenyl)ethanol 39 in
36% yields. In this case, the position of OH group was modified
compared with hit 6.
Modification of hydroxyl function changed the biological activ-
ity but not significantly. In fact, in the case of 50, 51, 52, 56 and 57,
anti-HRV 14 activity was retained. However, modification of steric
hindrance significantly decreased EC50 value. In fact, 1-(4-
cyanophenyl)-2-(4,5-dimethoxy-2-nitrophenyl)ethyl methanesul-
fonate 58 did not show any antiviral activity in vitro.
2.5. First C-2 substituent exploration
Moreover, a carbonyl function in the linker should promote
rigidifying. So, a solution of 4-[1-hydroxy-2-(4,5-dimethoxy-2-
nitrophenyl)-1-hydroxyethyl]benzonitrile 23 in acetone was
treated with 3 equiv CrO3 solubilized in 10 equiv of H2SO4. The
Our final aim here was to determine the real impact of the C-2
group on biological activity. This group, present on dimethox-
ybenzene substrate, is very important for TDAE reactivity. From a
biological point of view, it is very lipophilic and promotes mem-
brane crossing. The effect of “nitro” substituent at the 2- position of
the dimethoxybenzene core on anti-HRV 14 activity was exami-
nated by comparison with unsubstituted or acetamido derivatives.
reaction was stirred during 0.5
h to obtain ketone 2-(4,5-
dimethoxy-2-nitrophenyl)-1-(4-nitrophenyl)ethanone 40 in 80%
yield. To explore more linker modifications, we synthesized prod-
uct 1-(4,5-dimethoxy-2-nitrophenyl)-4-(4-nitrophenyl)but-3-yn-

M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
451
O
H
MeO
MeO
NO2
H3CO
H3CO
NO2
Cl
i
+
NO2
NO2
1
38
O2N
MeO
MeO
NO2
OH
H3CO
H3CO
NO2
O
ii
+
Cl
H
5
NO2
39
NO2
O
H3CO
H3CO
NO2
OH
MeO
MeO
iii
CN
CN
40
23
Cl
H
O
OMe
O
MeO
MeO
NO2
iv
NO2
HO
MeO
NO2
4218l
NO2
41
H
R
MeO
MeO
NO2
O
H3CO
H3CO
NO2
Cl
v
+
R
Cl
43
44 R = 4-Br
45 R = 4-CN
46 R = 4-NO2
47 R = 4-Cl
48 R = 3-NO2
49 R = 2-Br
R = 4-Br
R = 4-CN
R = 4-NO2
R = 4-Cl
R = 3-NO2
R = 2-Br
a Reagents and Conditions: (i) p-nitrobenzaldehyde (3 equiv), TDAE (1.1 equiv), extra dry DMF, -20° C,1 h; 70 °C, 2 h;
H2O; 38 (15%). (ii) 4,5-dimethoxy-2-nitrobenzaldehyde (3 equiv), TDAE (1.1 equiv), extra dry DMF, -20 °C, 1 h; rt, 2 h;
H2O; 39 (36%). (iii) CrO3 (3 equiv) in H2SO4 (10 equiv), C3H6O, rt, 0.5 h; 40 (80%). (iv) 4,5-dimethoxy-2-nitrobenzaldehyde
(3 equiv), TDAE (1.1 equiv), extra dry DMF, -50 °C,1 h; 60 °C, 2 h; H2O; 42 (32%). (v) electrophile (3 equiv), TDAE (1.1
equiv), extra dry DMF, -20 °C, 1 h, hν; rt, 2 h, hν.; H2O; 44 (52%), 45 (40%), 46 (58%), 47 (40%), 48 (40%), 49 (38%).
bAll yields refer to the chromatographically isolate products and are relative to substrate.
Scheme 5. Modifications of the linker.a,b
The preparation of the non-nitrated analogue 4-(2-(3,4-
dimethoxyphenyl)-1-hydroxyethyl)benzonitrile 60 of compound
23 was realized from 4-[2-(4,5-dimethoxy-2-nitrophenyl)-1-
hydroxy-ethyl]benzonitrile 23 via a reduction of the nitro group,
diazotation of amine and reduction of diazonium salt by hypo-
phosphorus acid (H3PO2). In this context, the formation of 4-(2-
(3,4-dimethoxyphenyl)-1-hydroxyethyl)benzonitrile 60 (10%) was
accompanied by N-(2-(2-(4-cyanophenyl)-2-hydroxyethyl)-4,5-
dimethoxyphenyl)acetamide 59 (15%). This procedure is pre-
sented in Scheme 7.
2.6. Integrated SAR guidelines
The aim of the present study was to provide some elements to
analyse the effect of different structural elements on in vitro ac-
tivity. To date, all these results could be summarized; the guidelines
of integrated SAR and following synthesis strategy are represented
in Scheme 8.
Subsequently, a subset of compounds that were selected based
on their potency against HRV 14 were evaluated for selective
antiviral activity in virus-cell-based assays of thirteen HRV sero-
types, including major and minor group serotypes (HRV 2, HRV 9,
HRV 15, HRV 29, HRV 41, HRV 59, HRV 63, HRV 85 and HRVA89
from HRV clade A; HRV 42, HRV 70, HRV 72 and HRV 86 from
HRV clade B). This analysis revealed that the antiviral activity of
As 60 showed some activity (Table 6), the “nitro” group seems to
promote anti-HRV 14 activity. Moreover, steric hindrance at this
position significantly decreased EC50 value which is evident from
compound 59 that did not present any antiviral activity in vitro.

452
M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
Table 4
4. Experimental section
SAR: linker modifications.a,b
4.1. Chemistry
No Code
Structure
Yield CC50
65% 152
EC50
EC90
MeO
MeO
NO
Reagents were purchased from Sigma Aldrich Chemical Co.,
Fisher Scientific SAS and Alfa Aesar Co. VWR international and Carlo
Erba grade solvents were routinely used. Melting points were
determinated on a Buchi capillary melting point apparatus and are
uncorrected. Elemental analysis or Mass spectrometries were per-
formed by Spectropole centre, Aix-Marseille University. The 1H and
13C NMR spectra were determinated on a Bruker AC 200 spec-
trometer. The 1H chemical shifts are reported as parts per million
downfield from tetramethylsilane (Me4Si), the 13C chemical shifts
were referenced to the solvent peak. (CDCl3: 76.9 ppm and Me2SO-
d6 39.6 ppm.) Coupling constants (J) are in Hertz.
Absorptions are reported with the following notations: s,
singlet; d, doublet; t, triplet; q, quartet; m, a more complex mul-
tipletor overlapping multiplets. The following absorbents were
used for column chromatography: silica gel 60 (Merck, particle size
0.0063e0.200, 70e230 mesh ASTM).
38 M3036
>303
>303
NO
NO
NO
MeO
MeO
NO
39 W3618a
40 OM1616
42 M311018l
36% ND
10% ND
>359
>306
>359
>306
OH
NO
MeO
MeO
O
O
N
OH
32% 17.2 ꢀ 3.5 6.8 ꢀ 1.1
9.7
NO
H
CO
OCH
MeO
MeO
NO
Br
44 W1
45 W2
46 W22
52% ND
40% ND
58% ND
>263
>306
>289
>263
>306
>289
O
TLC was performed on 5 cm ꢃ 10 cm aluminium plates coated
MeO
MeO
NO
CN
with silica gel 60 F-254 (Merck) in an appropriate solvent.
O
4.1.1. General procedure for TDAE reaction with various
electrophiles
MeO
MeO
NO
NO
All materials were dried for one day at 120 ꢂC. Chloride and
carbonyl derivatives were introduced into a Schlenk of 30 mL.
Products were put in vacuo, then under nitrogen. An appropriate
volume of anhydrous DMF was added after 10 min of nitrogen
bubbling. The solution was vigorously stirred for 20 min at ꢁ20 ꢂC.
TDAE was added slowly under inert atmosphere. The reaction was
stirred for one hour. The second reaction phase was performed at rt
or at temperature according to procedure of synthesis. The reaction
was hydrolysed with distilled water after TLC analysis clearly
showed that the chloride 1 had been totally consumed. The
aqueous solution was extracted with dichloromethane and the
combined organic layers washed with brine then dried on MgSO4.
O
MeO
MeO
NO
Cl
47 W21
48 W4
40% 109
>298
>298
O
MeO
MeO
NO
40% 144 ꢀ 55.6 98.3
ND
NO
O
MeO
MeO
NO
49 W3
38% ND
>263
>263
O
Br
ND ¼ not determined.
CC50 ¼ 50% Cytostatic/Cytotoxic Concentration (concentration at which 50% adverse
effect is observed on the host cell).
4.1.1.1. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(4-nitrophenyl)ethanol
(6). Yellow solid. Yield, 85%. Mp (recrystallized from ethanol)
EC50 ¼ 50% Effective Concentration (concentration at which 50% inhibition of virus
157 ꢂC. 1H NMR (200 MHz, CDCl3)
d
8.24 (d, 2H, J ¼ 8.7), 7.66 (s, 1H),
replication is observed).
7.64 (d, 2H, J ¼ 8.7), 6.66 (s, 1H), 5.21 (dd, 1H, J ¼ 8.8, 3.6), 3.96 (s,
3H), 3.90 (s, 3H), 3.53 (dd, 1H, J ¼ 13.5, 3.6), 3.04 (dd, 1H, J ¼ 13.5,
EC90 ¼ 90% Effective Concentration (concentration at which 90% inhibition of virus
replication is observed).
a
8.8), 2.42 (s, 1H). 13C NMR (50 MHz, CDCl3)
d 152.9, 151.4, 147.9,
All values are in
m
M, expressed as median ꢀ Med. Abs. Dev.
In assay conditions: Pleconaril EC50 0.2 0.1
CC50 ¼ 50.2 ꢀ 5 M.
b
¼
ꢀ
mM; Pleconaril
147.3, 141.4, 127.9, 126.5, 123.6, 115.0, 108.2, 73.1, 56.4, 56.3, 43.8.
Anal (C16H16N2O7) C, H, N.
m
4.1.1.2. 2-(2-Nitrophenyl)-1-(4-nitrophenyl)ethanol
(8). Yellow
8.19 (d, 1H,
solid. Yield, 85%. Mp 122 ꢂC. 1H MR (200 MHz, CDCl3)
d
this class of compounds was highly specific against HRV 14
(Table 7).
J ¼ 8.8), 7.98 (m, 1H), 7.58 (d, 2H, J ¼ 8.8), 7.29e7.55 (m, 3H), 5.20
(m, 1H), 3.42 (dd, 1H, J ¼ 13.3, 3.8), 3.11 (dd, 1H, J ¼ 13.3, 8.6), 2.46
(d, 1H, J ¼ 3.8). 13C NMR (50 MHz, CDCl3)
d 151.0, 149.7, 147.5, 133.7,
3. Conclusion
133.1, 132.5, 128.2, 126.5, 125.1, 123.8, 73.3, 43.0. Anal (C14H12N2O5)
C, H, N.
A new compound library was established by using original TDAE
methodology. A total of 99 molecules were synthesized and eval-
uated for selective antiviral activity in a virus-cell-based assay for
HRV 14 replication. Exploration of the SAR of this class of com-
pounds showed that the dibenzenic structure was allowed to
possess various groups on the C-4 phenyl moiety. The compound 4-
[1-hydroxy-2-(4,5-dimethoxy-2-nitrophenyl)-1-hydroxyethyl]
benzonitrile 23 was identified as the most potent and selective
inhibitor of the replication of this virus. Currently, studies are
ongoing to unravel the precise molecular mechanism-of-action of
this compound.
4.1.1.3. 2-(5-Methyl-2-nitrophenyl)-1-(4-nitrophenyl)ethanol
(9).
Yellow solid. Yield, 68%. Mp 132 ꢂC. 1H NMR (200 MHz, CDCl3)
d
8.24e8.20 (m, 2H), 7.95 (d, 1H, J ¼ 8.4), 7.62 (d, 2H, J ¼ 8.4), 7.25e
7.21 (m, 1H), 7.13 (s, 1H), 5.20e5.16 (m, 1H), 3.45 (dd, 1H, J ¼ 13.4,
3.5), 3.03 (dd, 1H, J ¼ 13.4, 9.0), 2.41 (s, 3H). 13C NMR (50 MHz,
CDCl3)
d 151.1, 147.4, 147.2, 144.5, 134.2, 132.7, 128.8, 126.5, 125.4,
123.7, 73.3, 43.3, 21.4. Anal (C15H12N2O5) C, H, N.
4.1.1.4. 1-(4-Chlorophenyl)-2-(4,5-dimethoxy-2-nitrophenyl)ethanol
(11). Brown solid. Yield, 68%. Mp 108 ꢂC. 1H NMR (200 MHz, CDCl3)

M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
453
H3CO
H3CO
NO2
OH
H3CO
H3CO
NO2
Cl
H3CO
H3CO
NO2
NH2
H3CO
H3CO
NO2
N3
iii
i
ii
X
X
NO2
R
50 X=C-NO2
56
54 R = NO2
55 R =CN
6
X=C-NO2
51 X=C-C6H10
52 X=C-CN
53 X=N
13 X=C-C6H10
23 X=C-CN
27 X=N
H3CO
H3CO
NO2
OH
H3CO
H3CO
NO2
F
iv
57
CN
CN
23
H3CO
H3CO
NO2
OH
H3CO
H3CO
NO2
OSO2CH3
v
CN
58
CN
23
aAll yields refer to the chromatographically isolate products and are relative to substrate.
bReagents and conditions: (i) SOCl2 (3 equiv), CH2Cl2, 0 °C then 50 °C, 4 h, (50- 53) 85-95%; (ii) NaN3 (2 equiv), EtOH, 70
°C, 24 h, 37% (54), 30% (55); (iii) 1) PPh3 (1 equiv), 2) H2O (2mL), THF, rt, 24 h, (73) 20%; (iv) N(Et)2SF3 (1.5 equiv), N2,
CH2Cl2, 0 °C then rt, 10 min, (57) 90%; (v) Methane sulfonylchloride (1.5 equiv), CHCl3, 60 °C, 48 h, (58) 25 %.
Scheme 6. Synthesis of 50e58 and evaluation of the OH substitution.a,b
d
7.58 (s, 1H), 7.30 (s, 4H), 6.51 (s, 1H), 5.01 (dd, 1H, J ¼ 8.2, 4.3), 3.91
(s, 3H), 3.82 (s, 3H), 3.38 (dd, 1H, J ¼ 13.3, 4.3), 3.10 (dd, 1H, J ¼ 13.3,
8.2), 2.36 (s, 1H). 13C NMR (50 MHz, CDCl3)
152.7, 147.7, 142.4,
(50 MHz, CDCl3) d 153.2, 148.1, 141.6, 127.1, 114.2, 108.3, 66.5, 56.5,
56.4, 40.4. HRMS m/z calcd for C16H12F5NO5, 394.0708, (M þ H);
d
found: 394.0714.
141.6, 133.3, 128.6, 128.3, 127.2, 115.0, 108.2, 73.5, 56.3, 73.4, 43.7.
Anal (C16H16ClNO5) C, H, N.
4.1.1.9. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(2-nitrophenyl)ethanol
(16). Brown solid. Yield, 36%. Mp 121 ꢂC. 1H NMR (200 MHz, CDCl3)
4.1.1.5. 1-(4-Bromophenyl)-2-(4,5-dimethoxy-2-nitrophenyl)ethanol
d
8.0 (dd, 1H, J ¼ 8.1, 1.1), 7.90e7.86 (m, 1H), 7.73e7.65 (m, 1H), 7.52
(12). Brown solid. Yield, 50%. Mp 134 ꢂC. 1H NMR (200 MHz, CDCl3)
(s, 1H), 7.53e742 (m, 1H), 6.88 (s, 1H), 5.62e5.56 (m, 1H), 3.94 (s,
6H), 3.50 (dd, 1H, J ¼ 13.3, 8.8), 3.06 (dd, 1H, J ¼ 13.7, 3.7), 1.58 (bs,
d
7.61 (s, 1H), 7.47 (d, 2H, J ¼ 8.4), 7.27 (d, 2H, J ¼ 8.4), 6.52 (s, 1H),
5.03 (dd, 1H, J ¼ 8.1, 4.3), 3.93 (s, 3H), 3.84 (s, 3H), 3.39 (dd, 1H,
1H). 13C NMR (50 MHz, CDCl3)
d 153.2, 147.8, 142.6, 139.6, 133.8,
J ¼ 13.3, 4.3), 3.10 (dd, 1H, J ¼ 13.3, 8.1), 2.11 (s, 1H). 13C NMR
128.5, 128.5, 127.7, 124.6, 113.7, 107.9, 71.1, 56.4, 40.6. Anal
(C16H16N2O7) C, H, N.
(50 MHz, CDCl3) d 152.7, 147.7, 142.9, 141.6, 131.5, 128.2, 127.5, 121.4,
114.9, 108.2, 73.5, 56.3, 43.7. Anal (C16H16BrNO5) C, H, N.
4.1.1.10. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(3-nitrophenyl)ethanol
4.1.1.6. 1-(Biphenyl-4-yl)-2-(4,5-dimethoxy-2-nitrophenyl)ethanol
(17). Yellow solid. Yield, 52%. Mp 151 ꢂC. 1H NMR (200 MHz, CDCl3)
(13). Brown solid. Yield, 70%. Mp 101 ꢂC. 1H NMR (200 MHz, CDCl3)
d
8.36 (s, 1H), 8.15 (dd, 1H, J ¼ 2.2, 1.2), 7.78 (d, 1H, J ¼ 7.9), 7.65 (s,
d
7.61e7.55 (m, 5H), 7.47e7.31 (m, 5H), 6.54 (s, 1H), 5.10 (dd, 1H,
1H), 7.55 (t, 1H, J ¼ 7.9), 6.68 (s, 1H), 5.25e5.17 (m, 1H), 3.95 (s, 3H),
3.91 (s, 3H), 3.53 (dd, 1H, J ¼ 13.4, 3.6), 3.08 (dd, 1H, J ¼ 13.4, 3.7),
J ¼ 8.0, 4.6), 3.91 (s, 3H), 3.79 (s, 3H), 3.45 (dd, 1H, J ¼ 13.2, 4.6), 3.25
(dd, 1H, J ¼ 13.2, 8.0), 2.53 (s, 1H). 13C NMR (50 MHz, CDCl3)
d
152.5,
2.44 (d, 1H, J ¼ 3.6). 13C NMR (50 MHz, CDCl3)
d 152.9, 148.5, 148.0,
147.5, 142.9, 141.6, 140.6, 140.5, 128.7, 128.4, 127.3, 127.0, 126.9,
146.1, 141.5, 132.0, 129.4, 127.8, 122.6, 120.6, 114.9, 108.3, 73.1, 56.4,
43.8. Anal (C16H16N2O7) C, H, N.
126.2, 114.9, 108.0, 73.8, 56.2, 43.5. HRMS for
C22H21NO2
[M þ NH4]þ ¼ 397.1758. Found: [M þ H]þ ¼ 397.1758.
4.1.1.11. 3-[2-(4,5-Dimethoxy-2-nitrophenyl)-1-hydroxyethyl]benzo-
4.1.1.7. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-[4-(methylthio)phenyl]
nitrile (18). Brown solid. Yield, 70%. Mp 148 ꢂC. 1H NMR (200 MHz,
ethanol (14). Brown solid. Yield, 35%. Mp 96 ꢂC. 1H NMR (200 MHz,
CDCl3) d 7.78e7.43 (m, 4H), 7.64 (s, 1H), 6.63 (s, 1H), 5.12 (dd, 1H,
CDCl3)
d
7.57 (s, 1H), 7.25 (dd, 4H, J ¼ 15.9, 8.4), 6.51 (s, 1H), 5.10 (dd,
J ¼ 8.6, 3.5), 3.94 (s, 3H), 3.89 (s, 3H), 3.48 (dd, 1H, J ¼ 13.4, 3.5), 3.04
1H, J ¼ 8.0, 4.5), 3.90 (s, 3H), 3.80 (s, 3H), 3.35 (dd, 1H, J ¼ 13.2, 4.6),
(dd, 1H, J ¼ 13.4, 8.6), 2.48 (s, 1H). 13C NMR (50 MHz, CDCl3)
d 152.9,
3.15 (dd, 1H, J ¼ 13.2, 8.0), 2.45 (s, 3H). 13C NMR (50 MHz, CDCl3)
147.9, 145.5, 141.5, 131.3, 130.3, 129.3, 127.9, 118.8, 115.0, 112.5, 108.3,
73.1, 56.4, 43.8. Anal (C17H16N2O5) C, H, N.
d
152.6, 147.6, 141.6, 140.9, 137.8, 128.5, 126.6, 126.3, 115.0, 108.1,
73.7, 56.3, 43.5, 15.9. Anal (C17H19NO5S) C, H, N.
4.1.1.12. 1-(2-Bromophenyl)-2-(4,5-dimethoxy-2-nitrophenyl)
4.1.1.8. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(perfluorophenyl)ethanol
(15). Yellow solid. Yield, 25%. Mp 87 ꢂC. 1H NMR (200 MHz, CDCl3)
ethanol (19). Brown solid. Yield, 50%. Mp 117 ꢂC. 1H NMR (200 MHz,
CDCl3) d 7.56e7.48 (m, 2H), 7.53 (s,1H), 7.38e7.30 (m,1H), 7.18e7.11
d
7.62 (s, 1H), 6.74 (s, 1H), 5.40e5.42 (m, 1H), 3.95 (s, 3H), 3.94 (s,
(m, 1H), 6.47 (s, 1H), 5.48e5.40 (m, 1H), 3.92 (s, 3H), 3.77 (s, 3H),
3.46 (dd, 1H, J ¼ 13.5, 7.2), 3.32 (dd, 1H, J ¼ 13.5, 5.1), 2.88 (d, 1H,
3H), 3.35 (dd, 1H, J ¼ 13.2, 8.0), 3.15 (dd, 1H, J ¼ 13.2, 4.6). 13C NMR

454
M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
Table 5
SAR: evaluation of the OH substitution.a,b
No
Code
Structure
Yield
95%
CC50
137
EC50
EC90
NO
Cl
MeO
MeO
50
M2094
33.1 ꢀ 9.6
69 ꢀ 9.9
NO
NO
Cl
MeO
MeO
51
52
M3028
M3024
87%
90%
14.1
145
3.42 ꢀ 0.7
55.1 ꢀ 3.4
ND
NO
Cl
MeO
MeO
80.2
CN
NO
Cl
MeO
MeO
53
54
M3026
M2104
85%
37%
86.6 ꢀ 69.3
>310
>268
>310
>268
N
NO
N
MeO
MeO
ND
NO
NO
N
MeO
MeO
55
56
M3054
M3022
30%
20%
215
191
33 ꢀ 1
51.5 ꢀ 0.4
71.6 ꢀ 0.2
CN
NO
NH
MeO
MeO
49.5 ꢀ 0.1
NO
MeO
MeO
NO
F
57
58
M3100
M3076
90%
25%
61.9
ND
18.1
28.5
CN
CN
O
CH
O
MeO
MeO
NO
S
O
>308
>308
ND ¼ not determined.
CC50 ¼ 50% Cytostatic/Cytotoxic Concentration (concentration at which 50% adverse effect is observed on the host cell).
EC50 ¼ 50% Effective Concentration (concentration at which 50% inhibition of virus replication is observed).
EC90 ¼ 90% Effective Concentration (concentration at which 90% inhibition of virus replication is observed).
a
All values are in
In assay conditions: Pleconaril EC50 ¼ 0.2 ꢀ 0.1
m
M, expressed as median ꢀ Med. Abs. Dev.
b
m
M; Pleconaril CC50 ¼ 50.2 ꢀ 5
mM.
J ¼ 3.8). 13C NMR (50 MHz, CDCl3)
d
152.6, 147.7, 142.4, 132.6, 129.1,
(200 MHz, CDCl3) d 7.63 (s, 1H), 7.45e7.18 (m, 4H), 6.58 (s, 1H),
127.9, 127.8, 127.4, 122.1, 114.2, 107.9, 73.3, 56.3, 56.2, 40.4. Anal
(C16H16BrNO5) C, H, N.
5.10e5.03 (m, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.45 (dd, 1H, J ¼ 13.4,
4.2), 3.32 (dd, 1H, J ¼ 13.5, 8.3), 2.88 (d, 1H, J ¼ 2.8). 13C NMR
(50 MHz, CDCl3) d 152.7, 147.8, 146.2, 141.6, 130.7, 130.1, 128.8, 128.1,
124.5, 122.6, 120.1, 114.9, 108.2, 73.4, 56.3, 43.6. Anal (C16H16BrNO5)
C, H, N.
4.1.1.13. 1-(3-Bromophenyl)-2-(4,5-dimethoxy-2-nitrophenyl)
ethanol (20). Brown solid. Yield, 39%. Mp 131 ꢂC. 1H NMR
O
H3C
NO2
MeO
MeO
MeO
NH
OH
MeO
MeO
OH
i, ii
OH
MeO
+
CN
CN
23
CN
59
a
60
a All yields refer to the chromatographically isolate products and are relative to substrate.
b Reagents and Conditions: (i) Reaction was performed with 35 equiv of Fe, acetic acid, 115 °C, 0.5h; (ii) H3PO2, 100 °C; 1
equiv of NaNO2, -15 °C; 0 °C 0.75 h, 15% of 59 and 10% of 60.
Scheme 7. Impact of the C-2 group on biological activity.a,b

M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
455
Table 6
4.1.1.16. 4-[2-(4,5-Dimethoxy-2-nitrophenyl)-1-hydroxy-ethyl]ben-
zonitrile (23). Yellow solid. Yield, 81%. Mp (recrystallized from
SAR: C-2 group influence.a,b
ethanol) 159 ꢂC. 1H NMR (200 MHz, CDCl3)
d
7.60 (d, 2H, J ¼ 8.4),
No Code
Structure
Yield CC50 EC50
EC90
7.58 (s, 1H), 7.52 (d, 2H, J ¼ 8.4), 6.60 (s, 1H), 5.10 (dd, 1H, J ¼ 8.6,
O
H3C
3.6), 3.90 (s, 3H), 3.87 (s, 3H), 3.47 (dd, 1H, J ¼ 13.4, 3.6), 3.03 (dd,
MeO
MeO
NH
1H, J ¼ 13.4, 8.6), 2.47 (s, 1H). 13C NMR (50 MHz, CDCl3)
d 152.8,
OH
59 OM1606
15%
10%
ND
>294
>294
149.2, 147.9, 141.5, 132.3, 127.8, 126.4, 118.7, 114.9, 111.3, 108.2, 73.3,
56.4, 56.3, 43.7. Anal (C17H16N2O5) C, H, N.
CN
CN
MeO
MeO
4.1.1.17. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-[4-(trifluoromethyl)
phenyl]ethanol (24). Brown oil. Yield, 85%. 1H NMR (200 MHz,
OH
60 OM1613
>353 96.2 ꢀ 17.8 >353
CDCl3)
d
7.62e7.48 (m, 5H), 6.50 (s, 1H), 5.12 (dd, 1H, J ¼ 8.1, 4.2),
3.91 (s, 3H), 3.80 (s, 3H), 3.44 (dd, 1H, J ¼ 13.1, 4.2), 3.1 (dd, 1H,
J ¼ 13.1, 8.1), 2.48 (s, 1H). 13C NMR (50 MHz, CDCl3)
d
152.7, 147.8,
ND ¼ not determined.
CC50 ¼ 50% Cytostatic/Cytotoxic Concentration (concentration at which 50% adverse
effect is observed on the host cell).
147.7, 141.5, 129.4 (q, C, J ¼ 75.0), 128.0, 126.0, 125.3 (q, 2CH, J ¼ 3.7),
124.1 (q, CF3, J ¼ 271.9), 114.9, 108.1, 73.4, 56.2, 43.6. Anal
(C17H16F3NO5) C, H, N.
EC50 ¼ 50% Effective Concentration (concentration at which 50% inhibition of virus
replication is observed).
EC90 ¼ 90% Effective Concentration (concentration at which 90% inhibition of virus
replication is observed).
4.1.1.18. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(4-fluorophenyl)ethanol
(25). Brown solid. Yield, 62%. Mp 113 ꢂC. 1H NMR (200 MHz, CDCl3)
a
All values are in
m
M, expressed as median ꢀ Med. Abs. Dev.
In assay conditions: Pleconaril EC50 0.2 0.1
CC50 ¼ 50.2 ꢀ 5 M.
b
¼
ꢀ
mM; Pleconaril
m
d
7.60 (s, 1H), 7.38e7.31 (m, 2H), 7.07e6.98 (m, 2H), 6.54 (s, 1H),
5.03 (dd, 1H, J ¼ 8.0, 4.5), 3.92 (s, 3H), 3.83 (s, 3H), 3.38 (dd, 1H,
J ¼ 13.4, 4.5), 3.14 (dd, 1H, J ¼ 13.4, 8.0). 13C NMR (50 MHz, CDCl3)
d
162.2 (d, C, J ¼ 245.5), 152.6, 147.6, 141.6, 139.6, 128.3, 127.4 (d,
4.1.1.14. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(2-fluorophenyl)ethanol
(21). Yellow solid. Yield, 85%. Mp 94 ꢂC. 1H NMR (200 MHz, CDCl3)
2CH, J ¼ 8.0), 115.2 (d, 2CH, J ¼ 21.2), 114.9, 108.1, 73.5, 56.2, 43.7.
Anal (C16H16FNO5) C, H, N.
d
7.57 (s, 1H), 7.50e7.42 (m, 1H), 7.32e7.11 (m, 2H), 7.06e6.96 (m,
1H), 6.48 (s, 1H), 5.42e5.34 (m, 1H), 3.93 (s, 3H), 3.79 (s, 3H), 3.46
4.1.1.19. 1,2-Bis(4,5-dimethoxy-2-nitrophenyl)ethanol
Brown solid. Yield, 49%. Mp 194 ꢂC (dec). 1H NMR (200 MHz, CDCl3)
7.65 (s, 1H), 7.50 (s, 1H), 7.34 (s, 1H), 7.03 (s, 1H), 5.70 (dd, 1H,
(26).
(d, 1H, J ¼ 1.88), 3.32 (s, 1H), 2.58 (d, 1H, J ¼ 3.7). 13C NMR (50 MHz,
CDCl3)
d
159.8 (C, d, J ¼ 245), 152.6, 147.6, 142.1, 130.6 (CH, d,
d
J ¼ 13.0), 129.2 (d, CH, J ¼ 8.4), 127.7, 127.6 (d, CH, J ¼ 8.4), 124.7 (d,
CH, J ¼ 3.66), 115.3 (d, CH, J ¼ 21.6), 114.5, 108.1, 68.8, 56.3, 41.4. Anal
(C16H16FNO5) C, H, N.
J ¼ 8.9, 3.0), 4.01 (s, 3H), 3.99 (s, 3H), 3.97 (s, 3H), 3.95 (s, 3H), 3.52
(dd, 1H, J ¼ 13.9, 8.9), 3.30 (dd, 1H, J ¼ 5.0, 3.0). 13C NMR (50 MHz,
CDCl3)
d 153.9, 153.2, 148.0, 147.8, 142.7, 139.4, 135.5, 127.9, 113.6,
109.2, 108.1, 107.8, 71.5, 56.5, 56.4, 56.3, 40.2. Anal (C18H20N2O9) C,
H, N.
4.1.1.15. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(3-fluorophenyl)ethanol
(22). Yellow solid. Yield 85%. Mp 91 ꢂC. 1H NMR (200 MHz, CDCl3)
d
7.62 (s,1H), 7.3e7.29 (m,1H), 7.19e7.14 (m, 2H), 7.02e6.93 (m,1H),
4.1.1.20. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(pyridin-4-yl)ethanol
6.57 (s, 1H), 5.10e5.06 (m, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 3.45 (dd,
(27). Yellow solid. Yield, 86%. Mp 191 ꢂC. 1H NMR (200 MHz, CDCl3)
1H, J ¼ 13.3, 4.3), 3.32 (dd, 1H, J ¼ 13.3, 8.3), 2.94 (s, 1H). 13C NMR
d
8.60e8.59 (m, 2H), 7.65 (s, 1H), 7.38 (d, 2H, J ¼ 5.4), 6.58 (s, 1H),
(50 MHz, CDCl3)
d
163.0 (d, C, J ¼ 246.2), 152.8, 147.7, 146.6 (d, C,
5.21 (dd, 1H, J ¼ 8.7, 3.9), 3.96 (s, 3H), 3.87 (s, 3H), 3.53 (dd, 1H,
J ¼ 6.59), 141.7, 130.0 (d, CH, J ¼ 8.41), 128.2, 121.5 (d, CH, J ¼ 2.9),
114.9, 114.5 (d, CH, J ¼ 21.2), 112.7 (d, CH, J ¼ 21.9), 108.2, 73.6, 56.3,
43.6. Anal (C16H16FNO5) C, H, N.
J ¼ 13.4, 3.9), 3.06 (dd, 1H, J ¼ 13.4, 8.7). 13C NMR (50 MHz, CDCl3)
d
152.8, 149.8, 147.9, 141.6, 127.8, 120.8, 114.9, 108.3, 72.7, 56.4, 43.4.
Anal (C15H16N2O5) C, H, N.
C-2 : one groupment
necessary for interaction
NO2 as potent groupment ?
Isosteric and bioisosteric remplacement
sudy
NO2
MeO
OH
Extension of substitution work
MeO
R
C-4 substitution increase in vitro activity
Lipophilic groupment ++
R = NO2, CN, CF3, F, phenyl
4,5-dimethoxybenzene :
most potent position of OMe
Secondary alcohol function ++
first rigidifications not probent
Extension of C-4 substitution work
Scheme 8. SAR Guidelines.

456
M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
Table 7
Broad spectrum hRV activities.
EC50
(
m
M)
Human rhinovirus A
Human rhinovirus B
B14 B42 B70
>148 >148 10 ꢀ 0.2 >148 >148
CC50
median ꢀ Med. Abs. Dev.
A2
A9
A15
A29
A41
A59
A63
A85
A89
B72
B86
11
12
13
14
27
17
18
20
22
23
6
>296 >148
>262 >131
>132 >132
>286 >143
>148
>131
>132
>143
>148
>131
>132
>143
ND
>148
>131
>44
>148
>131
>44
ND
>148
>131
>44
7 ꢀ 4
11 ꢀ 2
75 ꢀ 2
>131 >131 6 ꢀ 0.6
>44
>132 2 ꢀ 0.1
>143 >143 3 ꢀ 0.7
>131 25 ꢀ 0.1 17 ꢀ 2
8 ꢀ 0.2 66 ꢀ 0
>44
>132
1 ꢀ 0.2 1 ꢀ 0.4 10 ꢀ 1
>143
>143
>143 ND
10 ꢀ 1
22 ꢀ 6
9 ꢀ 0.4 72 ꢀ 9
>55
171 ꢀ 44
380 ꢀ 0
>329 108 ꢀ 4 >164
53 ꢀ 2 11 ꢀ 4 26 ꢀ 10 >164 >164 59 ꢀ 3
>164 >164
>144 >144
>152 >152
>131 >131
>156 >156
>152 46 ꢀ 2
>144 66 ꢀ 1
>135 ND
>287 15 ꢀ 1
>152 53 ꢀ 2
>131 >131
>156 >156
>144
>152
>131
>287
>144
>144
>51
>131
ND
6 ꢀ 2
>287
>135
>156
ND
>144 >144 16 ꢀ 3
>152 >152 29 ꢀ 7
>131 >131 28 ꢀ 3
>156 >156 43 ꢀ 1
>152 >152 2 ꢀ 0.6
>144 >144 4 ꢀ 1
>135 >135 2 ꢀ 0.1
>156 >156 60 ꢀ 9
59 ꢀ 16 >144
85 ꢀ 3 >152
>152
>131
ND
9 ꢀ 3
20 ꢀ 3
>135
>156
76 ꢀ 3
33 ꢀ 5
>52
111 ꢀ 2 144 ꢀ 51
>262
>131
>156
>152
>144
>135
>156
10 ꢀ 5
>156
52 ꢀ 13
37 ꢀ 8 >156
135 ꢀ 41
ND
ND
41 ꢀ 9
>152
>144
>135
>156
>152
>287
ND
7 ꢀ 0.5 4 ꢀ 0.8 116 ꢀ 23
42 ꢀ 3
7 ꢀ 0.1 7 ꢀ 1
95 ꢀ 12
51 ꢀ 17
104 ꢀ 11
24
25
>135 >135
>156 >52
8 ꢀ 5
3 ꢀ 1
>52
ND
>156 >156
81 ꢀ 4
4.1.1.21. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(pyridin-3-yl)ethanol
108.0, 75.2, 56.2, 56.0, 45.5, 30.0. HRMS m/z calcd for C18H18N2O5,
360.1554 (M þ Na); found: 360.1555.
(28). Yellow solid. Yield, 33%. Mp 150 ꢂC. 1H NMR (200 MHz, CDCl3)
d
8.60e8.59 (m, 1H), 8.49e8.47 (m, 1H), 7.77e7.73 (m, 1H), 7.62 (s,
1H), 7.31e7.29 (m, 1H), 6.59 (s, 1H), 5.12 (dd, 1H, J ¼ 8.4, 4.2), 3.93 (s,
4.1.1.27. 1-(4,5-Dimethoxy-2-nitrophenyl)-2-(4-nitrophenyl)propan-
2-ol (34). Brown solid. Yield 34%. Mp 116 ꢂC. 1H NMR (200 MHz,
3H), 3.86 (s, 3H), 3.45 (dd, 1H, J ¼ 13.3, 4.2), 3.06 (dd, 1H, J ¼ 13.3,
8.4). 13C NMR (50 MHz, CDCl3)
d 152.8, 148.9, 147.8, 147.6, 141.6,
CDCl3)
d
8.18 (d, 2 H, J ¼ 8.5), 7.61 (d, 2H, J ¼ 8.5), 7.50 (s, 1H), 6.23 (s,
139.3, 133.6, 128.0, 123.4, 114.9, 108.2, 71.9, 56.4, 43.7. Anal
(C15H16N2O5) C, H, N.
1H), 3.92 (s, 3H), 3.75 (d, 1H, J ¼ 13.8), 3.65 (s, 3H), 3.26 (d, 1H,
J ¼ 13.8), 2.89 (s, 1H), 1.7 (s, 3H). 13C NMR (50 MHz, CDCl3)
d 154.5,
152.2, 147.7, 146.8, 142.9, 126.3, 125.9, 123.3, 114.5, 108.2, 75.2, 56.3,
56.1, 45.6, 30.2. Anal (C17H18N2O7) C, H, N.
4.1.1.22. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(pyridin-2-yl)ethanol
(29). Brown solid. Yield, 70%. Mp 196 ꢂC. 1H NMR (200 MHz, CDCl3)
d
8.57e8.84 (m, 1H), 7.74e7.63 (m, 1H), 7.61 (s, 1H), 7.42e7.38 (m,
4.1.1.28. (E)-1,2-Dimethoxy-4-nitro-5-(4-nitrostyryl)benzene
(38).
8.25
Yellow solid, Yield, 65%. Mp 186 ꢂC. 1H NMR (200 MHz, CDCl3)
d
1H), 7.24e7.20 (m,1H), 6.76 (s,1H), 5.08 (dd,1H, J ¼ 8.3, 3.2), 3.92 (s,
3H), 3.89 (s, 3H), 3.45 (dd, 1H, J ¼ 13.3, 3.2), 3.06 (dd, 1H, J ¼ 13.3,
(d, 2H, J ¼ 8.7), 7.93 (d, 1H, J ¼ 16.1), 7.67 (d, 2H, J ¼ 8.7), 7.66 (s, 1H),
8.3), 2.78 (s, 1H). 13C NMR (50 MHz, CDCl3)
d 160.9, 152.7, 148.1,
7.08 (s, 1H), 6.98 (d, 1H, J ¼ 16.1), 4.05 (s, 3H), 3.99 (s, 3H). 13C NMR
147.6, 141.4, 136.9, 129.0, 122.7, 121.0, 115.1, 108.1, 72.6, 56.3, 43.3.
Anal (C15H16N2O5) C, H, N.
(50 MHz, CDCl3) d 153.3, 149.1, 147.3, 143.1, 140.7, 129.8, 129.5, 127.4,
127.2, 124.2, 109.5, 108.0, 56.5. HRMS m/z calcd for C16H14N2O6,
331.025 (M þ H); found: 331.0924.
4 .1.1. 2 3 . E t h y l 3 - ( 4 , 5 - d i m e t h o x y - 2 - n i t r o p h e n y l ) - 2 -
hydroxypropanoate (30). Yellow solid. Yield, 85%. Mp 102 ꢂC. 1H
4.1.1.29. trans-2-(4-Bromophenyl)-3-(4,5-dimethoxy-2-nitrophenyl)
oxirane (44). Yellow solid. Yield, 52%. Mp 153 ꢂC. 1H NMR
NMR (200 MHz, CDCl3)
d 7.60 (s, 1H), 6.83 (s, 1H), 4.51 (dd, 1H,
J ¼ 9.1, 4.5), 4.23 (q, 2H, J ¼ 7.4), 3.96 (s, 3H), 3.94 (s, 3H), 3.60 (dd,
(200 MHz, CDCl3)
d
7.75 (s, 1H), 7.54 (d, 2H, J ¼ 8.2), 7.31 (d, 2H,
1H, J ¼ 13.6, 4.5), 3.15 (dd, 1H, J ¼ 13.6, 9.1), 1.30 (t, 3H, J ¼ 7.4). 13
C
J ¼ 8.2), 7.14 (s, 1H), 4.50 (d, 1H, J ¼ 1.7), 4.02 (s, 3H), 3.98 (s, 3H),
3.74 (d, 1H, J ¼ 1.7). 13C NMR (50 MHz, CDCl3)
d
154.3, 148.4, 135.3,
NMR (50 MHz, CDCl3)
d 174.2, 152.7, 147.8, 141.7, 126.9, 114.6, 108.2,
70.3, 62.1, 56.3, 37.9, 14.1. Anal (C13H17NO7) C, H, N.
131.8, 129.3, 128.7, 127.5, 122.6, 108.0, 107.8, 61.5, 60.5, 56.6, 56.5.
Anal (C16H14BrNO5) C, H, N.
4.1.1. 24. Diethyl 2-(4, 5-dimethoxy-2-nitrobenzyl)-2-
hydroxymalonate (31). Yellow solid. Yield, 72%. Mp 102 ꢂC. 1H
4.1.1.30. trans-4-(3-(4,5-Dimethoxy-2-nitrophenyl)oxiran-2-yl)ben-
zonitrile (45). Yellow solid. Yield, 40%. Mp 188 ꢂC. 1H NMR
NMR (200 MHz, CDCl3)
d 7.44 (s, 1H), 6.96 (s, 1H), 4.22 (q, 4H,
J ¼ 7.2), 3.92 (s, 3H), 3.91 (s, 3H), 3.83 (m, 3H),1.27 (t, 6H, J ¼ 7.2). 13
C
(200 MHz, CDCl3)
d
7.76 (s, 1H), 7.71 (d, 2H, J ¼ 8.2), 7.52 (d, 2H,
NMR (50 MHz, CDCl3) d 169.7, 151.9, 147.8, 143.3, 123.7, 114.8, 108.0,
J ¼ 8.2), 7.14 (s, 1H), 4.47 (d, 1H, J ¼ 1.6), 4.02 (s, 3H), 3.98 (s, 3H),
3.84 (d, 1H, J ¼ 1.7). 13C NMR (50 MHz, CDCl3)
d
154.3, 148.6, 141.7,
78.7, 63.0, 56.3, 56.2, 35.5, 13.9. Anal (C16H21NO9) C, H, N.
139.9, 132.5, 128.1, 126.4, 118.6, 112.3, 108.0, 107.8, 61.1, 61.0, 56.6,
56.5. Anal (C17H14N2O5) C, H, N.
4.1.1.25. Ethyl 3-(4,5-dimethoxy-2-nitrophenyl)-2-hydroxy-2-
methylpropanoate (32). Brown semi-solid. Yield, 59%. 1H
NMR (200 MHz, CDCl3)
d
7.46 (s, 1H), 6.87 (s, 1H), 4.15 (q, 2H,
4.1.1.31. trans-2-(4,5-Dimethoxy-2-nitrophenyl)-3-(4-nitrophenyl)
oxirane (46). Yellow solid. Yield, 58%. Mp 202 ꢂC. 1H NMR
J ¼ 6.9), 3.93 (s, 3H), 3.91 (s, 3H), 3.57 (d, 1H, J ¼ 13.9), 3.38 (d, 1H,
J ¼ 13.9), 1.46 (s, 3H), 1.27 (t, 3H, J ¼ 6.9). 13C NMR (50 MHz, CDCl3)
(200 MHz, CDCl3)
d
8.28 (d, 2H, J ¼ 8.2), 7.77 (s, 1H), 7.58 (d, 2H,
d
176.0, 151.9, 147.6, 142.9, 125.2, 114.6, 108.0, 74.8, 62.3, 56.2, 40.7,
J ¼ 8.2), 7.15 (s, 1H), 4.49 (d, 1H, J ¼ 1.6), 4.03 (s, 3H), 3.99 (s, 3H),
3.88 (d, 1H, J ¼ 1.6). 13C NMR (50 MHz, CDCl3)
d 154.4, 148.7, 148.1,
26.1, 14.0. Anal (C14H19NO7) C, H, N.
143.6, 139.9, 128.0, 126.6, 123.9, 108.9, 107.8, 61.1, 60.8, 56.6, 56.5.
Anal (C16H14N2O7) C, H, N.
4.1.1.26. 4-(1-(4,5-Dimethoxy-2-nitrophenyl)-2-hydroxypropan-2-
yl)benzonitrile (33). Brown solid. Yield, 78%. Mp 136 ꢂC. 1H NMR
(200 MHz, CDCl3)
d
7.60 (d, 2H, J ¼ 8.6), 7.52 (d, 2H, J ¼ 8.6), 7.46 (s,
4.1.1.32. trans-2-(4-Chlorophenyl)-3-(4,5-dimethoxy-2-nitrophenyl)
1H), 6.18 (s, 1H), 3.89 (s, 3H), 3.72 (d, 1H, J ¼ 13.8), 3.64 (s, 3H), 3.20
oxirane (47). Yellow solid. Yield, 40%. Mp 146 ꢂC. 1H NMR
(d, 1H, J ¼ 13.8), 2.71 (s, 1H), 1.65 (s, 3H). 13C NMR (50 MHz, CDCl3)
(200 MHz, CDCl3) d 7.75 (s, 1H), 7.37 (m, 4H), 7.14 (s, 1H), 4.50 (d, 1H,
d
152.5, 152.0, 147.6, 142.9, 131.9, 126.1, 125.9, 118.6, 114.5, 110.6,
J ¼ 1.8), 4.02 (s, 3H), 3.98 (s, 3H), 3.75 (d, 1H, J ¼ 1.8). 13C NMR

M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
457
(50 MHz, CDCl3)
107.8, 61.4, 60.5, 56.6, 56.5. Anal (C16H14ClO5) C, H, N.
d
154.3,148.4,134.8,134.4,128.9,128.7,127.2,108.1,
(dichloromethane) clearly showed that the diarylethanol was
totally consumed. Solvent evaporation led to a brown product. The
residue was solubilized with dichloromethane (10 mL) and washed
with saturated NaCl (20 mL) and dried with MgSO4. Purification by
flash column chromatography using CH2Cl2 gave 100 mg of corre-
sponding azido derivative 54 (37%) or 55 (30%).
4.1.1.33. trans-2-(4,5-Dimethoxy-2-nitrophenyl)-3-(3-nitrophenyl)
oxirane (48). Brown solid. Yield, 40%. Mp 175 ꢂC. 1H NMR (200 MHz,
CDCl3)
d 8.28e8.21 (m, 2H), 7.77 (s, 1H), 7.63e7.55 (m, 2H), 7.15 (s,
1H), 4.53 (d, 1H, J ¼ 1.8), 4.03 (s, 3H), 3.99 (s, 3H), 3.88 (d, 1H,
J ¼ 1.8). 13C NMR (50 MHz, CDCl3)
d 154.4, 148.6, 140.0, 138.7, 131.8,
4.1.3.1. 1-[Azido-2-(4-nitrophenyl)ethyl]-4,5-dimethoxy-2-
nitrobenzene (54). Yellow semi-solid. Yield, 37%. 1H NMR
129.7, 128.1, 123.5, 120.8, 108.1, 107.8, 61.0, 60.7, 56.6, 56.5. Anal
(C16H14N2O7) C, H, N.
(200 MHz, CDCl3)
d
8.25 (d, 2H, J ¼ 8.7), 7.70 (s, 1H), 7.68 (d, 2H,
J ¼ 8.7), 6.70 (s, 1H), 5.35 (dd, 1H, J ¼ 9.4, 4.3), 3.96 (s, 3H), 3.92 (s,
3H), 3.77 (dd, 1H, J ¼ 13.8, 4.3), 3.04 (dd, 1H, J ¼ 13.8, 9.4). 13C NMR
4.1.1.34. trans-2-(2-Bromophenyl)-3-(4,5-dimethoxy-2-nitrophenyl)
oxirane (49). Yellow solid. Yield, 38%. Mp 162 ꢂC. 1H NMR
(50 MHz, CDCl3) d 153.1, 148.2, 148.0, 146.8, 141.1, 127.6, 127.1, 124.0,
(200 MHz, CDCl3)
2H), 7.23 (s, 1H), 7.18 (s, 1H), 4.52 (m, 1H), 4.07 (m, 1H), 4.03 (s, 3H),
3.98 (s, 3H). 13C NMR (50 MHz, CDCl3)
154.2, 148.4, 140.2, 135.6,
d 7.77 (s, 1H), 7.61e7.57 (m, 1H), 7.41e7.37 (m,
115.0, 108.4, 65.5, 56.4, 41.9. HRMS m/z calcd for C16H15N5O6,
391.1361 (M þ Na); found: 391.1361.
d
132.6, 129.7, 128.4, 127.7, 126.1, 123.1, 108.1, 108.0, 61.7, 60.2, 56.6,
56.5. Anal (C16H14BrNO5) C, H, N.
4.1.3.2. 4-[1-Azido-2-(4,5-dimethoxy-2-nitrophenyl)ethyl]benzoni-
trile (55). Yellow solid. Yield, 30%. 99 ꢂC (dec). 1H NMR (200 MHz,
CDCl3)
d
7.68 (d, 2H, J ¼ 8.3), 7.66 (s, 1H), 7.50 (d, 2H, J ¼ 8.3), 6.60 (s,
4.1.2. Procedure for chlorination of linker hydroxyl group
To a solution of products 13, 23, 6 or 27 in dichloromethane
(10 mL), 3 equiv of thionyl chloride was added slowly at 0 ꢂC. The
mixture was stirred at 50 ꢂC for 4 h. After this time TLC analysis
(dichloromethane) clearly showed that the diarylethanol was
totally consumed. Solution was neutralized with Na2CO3 solution
and the organic phase, after washing with brine was dried with
MgSO4. Purification by silica gel led to corresponding chloride
products.
1H), 5.12 (dd, 1H, J ¼ 9.1, 4.4), 3.93 (s, 3H), 3.89 (s, 3H), 3.40 (dd, 1H,
J ¼ 13.3, 4.4), 3.05 (dd, 1H, J ¼ 13.3, 9.2). 13C NMR (50 MHz, CDCl3)
d
153.0, 148.2, 144.8, 141.1, 132.6, 127.3, 127.0, 118.3, 115.0, 112.1,
108.3, 65.7, 56.4, 56.3, 41.9. HRMS m/z calcd for C17H15N5O4,
371.1462 (M þ NH4); 371.1466.
4.1.4. Synthesis of amino derivative 56
One equivalent of PPh3 was added to a solution of azido deriv-
ative 54 in THF (10 mL). Then distillate water (2 mL) was added. The
reaction mixture was stirred at 70 ꢂC over 24 h. After this time, TLC
analysis (dichloromethane) clearly showed that the formation of
amino derivative. The concentrate was treated with saturated NaCl
solution (20 mL) and was extracted with dichloromethane
(3 ꢃ 10 mL). The aqueous layer basified with 2 M NaOH (2 mL), and
extracted with EtOAc (10 mL) and was dried with MgSO4. Solvent
was removed in vacuo, providing 120 mg of 56 (20%) as yellow oil.
4.1.2.1. 1-(2-Chloro-2-(4-nitrophenyl)ethyl)-4,5-dimethoxy-2-
nitrobenzene (50). Brown solid. Yield, 95%. Mp 144 ꢂC. 1H NMR
(200 MHz, CDCl3)
d
8.24 (d, 2H, J ¼ 8.7), 7.68 (s, 1H), 7.66 (d, 2H,
J ¼ 8.7), 6.70 (s, 1H), 5.34 (dd, 1H, J ¼ 9.4, 4.3), 3.95 (s, 3H), 3.90 (s,
3H), 3.77 (dd, 1H, J ¼ 13.8, 4.3), 3.04 (dd, 1H, J ¼ 13.8, 9.4). 13C NMR
(50 MHz, CDCl3) d 153.0, 148.3, 148.1, 147.7, 141.1, 127.9, 126.9, 123.9,
115.4, 108.3, 58.3, 56.4, 56.3, 44.8. Anal (C16H15ClN2O6) C, H, N.
4.1.4.1. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(4-nitrophenyl)ethan-
4.1.2.2. 4-(1-Chloro-2-(4,5-dimethoxy-2-nitrophenyl)ethyl)biphenyl
amine (56). Yellow solid. Yield, 20%. 190 ꢂC (dec). 1H NMR
(51). Brown solid. Yield, 87%. Mp 112 ꢂC. 1H NMR (200 MHz, CDCl3)
(200 MHz, CDCl3)
d
8.17 (d, 2H, J ¼ 8.7), 7.65 (s, 1H), 7.55 (d, 2H,
d
7.67 (s, 1H), 7.61e7.36 (m, 9H), 6.58 (s, 1H), 5.30 (dd, 1H, J ¼ 5.6,
J ¼ 8.7), 6.47 (s, 1H), 4.49e4.43 (m, 1H), 3.93 (s, 3H), 3.81 (s, 3H),
3.35 (dd, 1H, J ¼ 13.1, 5.5), 3.04 (dd, 1H, J ¼ 13.1, 7.94), 1.93 (bs, 2H).
8.3), 3.94 (s, 3H), 3.82 (s, 3H), 3.72 (dd, 1H, J ¼ 13.6, 5.6), 3.55 (dd,
1H, J ¼ 13.6, 8.3). 13C NMR (50 MHz, CDCl3)
d 152.7, 147.0, 141.5,
13C NMR (50 MHz, CDCl3)
d 152.8, 152.6, 147.8, 147.2, 141.3, 131.9,
141.4, 140.5, 140.2, 128.9, 127.8, 127.5, 127.4, 127.1, 115.4, 108.2, 62.6,
56.3, 44.9. Anal (C22H20ClNO4) C, H, N.
128.4, 127.4, 123.7, 114.5, 108.5, 56.3, 55.8, 44.3. HRMS m/z calcd for
16H17N3O6, 348.1190 (M þ H); found: 348.1189.
C
4.1.2.3. 4-(1-Chloro-2-(4,5-dimethoxy-2-nitrophenyl)ethyl)benzoni-
trile (52). Brown solid. Yield, 90%. Mp 140 ꢂC. 1H NMR (200 MHz,
4.1.5. Synthesis of fluoro compound 57
To a solution of 1.5 equiv of N(Et)2SF3 in dichloromethane
(10 mL) under nitrogen atmosphere, 1 equiv of product 23 was
added slowly at 0 ꢂC using a syringe. The mixture was stirred at rt
for 15 min. After this time, TLC analysis (dichloromethane) clearly
showed that the diarylethanol was totally consumed. Solution was
neutralized with Na2CO3 solution and the organic phase, after
washing with brine was dried with MgSO4. Purification by flash
silica gel using CH2Cl2 gave 90 mg of corresponding fluorinate de-
rivative 57 (90%).
CDCl3)
d
7.65 (d, 2H, J ¼ 8.2), 7.65 (s, 1H), 7.57 (d, 2H, J ¼ 8.2), 6.63 (s,
1H), 5.31e5.24 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.70 (dd, 1H,
J ¼ 14.0, 5.0), 3.35 (dd, 1H, J ¼ 14.0, 9.0). 13C NMR (50 MHz, CDCl3)
d
153.0, 148.3, 146.2, 141.1, 132.5, 127.8, 127.0, 118.4, 115.4, 112.2,
108.3, 61.7, 56.4, 44.8. Anal (C17H15ClN2O4) C, H, N.
4.1.2.4. 4-(1-Chloro-2-(4,5-dimethoxy-2-nitrophenyl)ethyl)pyridine
(53). Brown semi-solid. Yield, 85%. 1H NMR (200 MHz, CDCl3)
d
8.60 (d, 2H, J ¼ 6.0), 7.66 (s, 1H), 7.39 (d, 2H, J ¼ 6.0), 6.60 (s, 1H),
5.21 (dd, 1H, J ¼ 9.0, 4.6), 3.92 (s, 3H), 3.86 (s, 3H), 3.7 (dd, 1H,
J ¼ 13.6, 4.6), 3.32 (dd, 1H, J ¼ 13.6, 9.0). 13C NMR (50 MHz, CDCl3)
4.1.5.1. 4-[2-(4,5-Dimethoxy-2-nitrophenyl)-1-fluoroethyl]benzoni-
trile (57). Yellow solid. Yield, 90%. Mp 152 ꢂC. 1H NMR (200 MHz,
d
162.4, 152.8, 150.0, 148.2, 141.1, 126.8, 121.7, 115.3, 108.2, 60.8, 56.3,
44.6. Anal (C15H15ClN2O4) C, H, N.
CDCl3)
d
7.72e7.64 (m, 3H), 7.56 (d, 2H, J ¼ 8.5), 6.73 (s, 1H), 5.12
(dd,1H, J ¼ 9.2, 2.5), 3.96 (s, 6H), 3.65 (dd,1H, J ¼ 14.2, 2.5), 3.05 (dd,
4.1.3. Procedure of azide derivative formation
1H, J ¼ 14.2, 9.2). 13C NMR (50 MHz, CDCl3)
d 153.1, 148.2, 145.2,
Ten equivalents of natrium azide were added to a solution of
chloride derivative 50 or 52 in ethanol (20 mL). The mixture was
heated to 60 ꢂC and was stirred for 24 h. After this time, TLC analysis
144.7, 141.2, 129.9 (d, CH, J ¼ 296.4), 129.5 (d, CH, J ¼ 81.2), 132.4,
126.7, 125.6 (d, CH, J ¼ 8.0), 115.3 (d, C, J ¼ 313.9), 111.6 (d, CH,
J ¼ 336.6), 108.8 (d, CH, J ¼ 73.9), 92.9 (d, CH, J ¼ 176.0), 56.4, 42.4

458
M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
(d, CH2, J ¼ 23.1). HRMS m/z calcd for (C17H15FN2O4), 353.0908
(M þ Na); found: 353.0910.
4.1.8.2. 4-[2-(3,4-Dimethoxyphenyl)-1-hydroxyethyl]benzonitrile
(60). Yellow solid. Yield, 15%. Mp 100 ꢂC. 1H NMR (200 MHz, CDCl3)
d
7.62 (d, 2H, J ¼ 8.4), 7.44 (d, 2H, J ¼ 8.4), 6.82 (d, 1H, J ¼ 8.2), 6.70
4.1.6. Synthesis of sulfonyl compound 58
(dd, 1H, J ¼ 8.2, 1.8), 6.60 (d, 2H, J ¼ 1.8), 4.92 (dd, 1H, J ¼ 8.2, 5.0),
3.86 (s, 3H), 3.82 (s, 3H), 2.98 (dd, 1H, J ¼ 13.7, 5.0), 2.84 (dd, 1H,
Two equivalents of methane sulfonyl chloride and 1 equiv of
pyridine was added to a solution of diarylethanol derivative 23 in
chloroform (20 mL). The mixture was heated to 60 ꢂC and was
stirred for 48 h. After this time, TLC analysis (dichloromethane)
clearly showed the formation of sulfonyl derivative. Solvent evap-
oration led to a brown product. The concentrate was washed with
saturated NaCl solution (20 mL) and was extracted with dichloro-
methane (3 ꢃ 10 mL). Solvent was removed in vacuo, purification by
flash column chromatography using CH2Cl2 gave 90 mg of corre-
sponding sulfonyl derivative 58 (25%).
J ¼ 13.7, 8.2). 13C NMR (50 MHz, CDCl3)
d 149.0, 148.0, 132.1, 129.1,
126.6,121.5,118.8,112.5,111.3,111.1, 74.4, 55.8, 45.6. HRMS m/z calcd
for (C16H17NO5), 301.1547 (M þ Na); found: 301.1547.
4.2. Biology
4.2.1. Cells and virus
HeLa Rh cells were grown in MEM Rega3 (Gibco) supplemented
with 10% heat-inactivated fetal bovine serum (FBS, Integro), 2 mM
L
-glutamine (Gibco) and 0.075% NaHCO3 (Gibco). Cells were grown
4.1.6.1. 1-(4-Cyanophenyl)-2-(4,5-dimethoxy-2-nitrophenyl)ethyl
at 37 ꢂC in a 5% CO2 incubator at 95e99% relative humidity. Human
Rhinoviruses (HRV 2, HRV 9, HRV 15, HRV 29, HRV 41, HRV 59, HRV
63, HRV 85 and HRVA89 from HRV clade A; HRV 14, HRV 42, HRV
70, HRV 72 and HRV 86 from HRV clade B), kindly provided by K.
Andries (Janssen Pharmaceutica, Beerse, Belgium), were cultivated
in HeLa Rh cells in the presence of 30 mM MgCl2.
methanesulfonate (58). Yellow solid. Yield, 25%. Mp 134 ꢂC. 1H NMR
(200 MHz, CDCl3)
d
7.70 (d, 2H, J ¼ 8.3), 7.66 (s, 1H), 7.60 (d, 2H,
J ¼ 8.3), 6.65 (s, 1H), 5.34e5.27 (m, 1H), 3.95 (s, 3H), 3.91 (s, 3H),
3.74 (dd,1H, J ¼ 13.7, 4.4), 3.05 (dd,1H, J ¼ 13.7, 9.2), 3.00 (s, 3H). 13
C
NMR (50 MHz, CDCl3) d 152.9, 148.3, 146.2, 141.2, 132.6, 127.8, 127.0,
118.4, 115.4, 112.3, 108.4, 66.2, 56.4, 56.3, 44.8, 37.5. HRMS m/z calcd
for (C18H18N2O7S), 429.0726 (M þ Na); found: 429.0727.
4.2.2. Virus-cell-based antiviral assay
4.1.7. Synthesis of carbonyl derivative 40
The antiviral activity of the synthesized compounds was
evaluated in an MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-
carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium]-based
live virus-cell-based assay. In this assay, the (residual) metabolic
activity of treated, infected cells is quantified which is represen-
tative for cell survival or reduction of virus-induced cytopathic ef-
fects (CPE), and thus the antiviral effect of a compound. Rhinovirus
assays were performed in 96-well plate format, using MEM Rega3
A solution of CrO3 (3 equiv) in H2SO4 (10 equiv) was added
slowly to a solution of diarylethanol derivative 23 (1 equiv) in
acetone (20 mL). The mixture was stirred for 0.5 h at rt. After this
time, TLC analysis (dichloromethane) clearly showed that the dia-
rylethanol was totally consumed. The solution was extracted with
dichloromethane (3 ꢃ 10 mL) and was washed with saturated NaCl
solution (20 mL). The organic phase was dried with MgSO4. Solvent
was removed in vacuo, purification by flash column chromatog-
raphy using CH2Cl2 gave 150 mg of corresponding 40 (80%).
supplemented with 2% FBS, 2 mM L-glutamine, 0.075% NaHCO3 and
30 mM MgCl2. Briefly, a serial dilution of the compound was added
to cells grown to confluence in 96-well microtiter plates, followed
by infection with a virus inoculum containing as few infectious
virus particles as possible that still causes 100% cytopathic effect
after the desired incubation time (this was determined in advance
by titration of the available virus stock). The cultures were incu-
bated for 3 days at 35 ꢂC until complete CPE was observed in the
untreated, infected virus control condition (VC). After removal of
4.1.7.1. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(4-nitrophenyl)ethanone
(40). Yellow solid. Yield, 10%. Mp 190 ꢂC. 1H NMR (200 MHz, CDCl3)
d
8.12 (d, 2H, J ¼ 8.2), 7.81 (d, 2H, J ¼ 8.2), 7.78 (s, 1H), 6.73 (s, 1H),
4.65 (s, 2H), 3.93 (s, 6H). 13C NMR (50 MHz, CDCl3)
d
194.7, 153.5,
148.4, 140.8, 139.7, 132.6, 128.6, 124.8, 117.9, 116.6, 114.9, 108.6, 56.4,
44.7. HRMS m/z calcd for (C17H14N2O5), 327.0975 (M þ H); found:
327.76.
the medium from each well, 100 mL of a 5% MTS-phenazine solution
in phenol red-free MEM was added. Following incubation for at
least 1 h, a time at which the optical density at 498 nm reaches
values between 0.6 and 0.8, raw OD values were collected using a
microtiter plate reader (Safire2, Tecan). Values were converted to
4.1.8. Formation of products 59 and 60
Thirty five equivalents of iron were added to a solution of dia-
rylethanol derivative 23 (1.52 mol) in acetic acid (20 mL). The
mixture was heated to 115 ꢂC and was stirred for 0.5 h. Solvent
evaporation led a brown product. This product was dissolved in
1.5 mL of H3PO2 at 100 ꢂC, then, 1 equiv of NaNO2 was added
at ꢁ15 ꢂC. The mixture was stirred at 0 ꢂC for 0.75 h. The solution
was extracted with dichloromethane (3 ꢃ 10 mL) and was washed
with saturated NaCl solution (20 mL). The organic phase was dried
with MgSO4. Solvent was removed in vacuo, purification by flash
column chromatography using CH2Cl2 gave 65 mg of derivative 59
(15%) and 52 mg of corresponding amido derivative 60 (10%).
percentage of controls and the 50% effective concentration (EC50
,
defined as the concentration of compound that should offer 50%
protection against virus-induced CPE), was calculated from the
doseeresponse curve using logarithmic interpolation. In addition,
the assays were inspected by light microscope and the adverse
effect of the compound on the cells was quantified by scoring of
the cells from which the CC50 (concentration at which 50%
cytotoxic effect is observed) was calculated using logarithmic
interpolation.
4.1.8.1. N-[2-(2-(4-Cyanophenyl)-2-hydroxyethyl)-4,5-
dimethoxyphenyl]acetamide (59). Brown solid. Yield, 10%. Mp 76 ꢂC.
Acknowledgements
1H NMR (200 MHz, CDCl3)
d
8.83 (s, 1H), 7.54 (d, 2H, J ¼ 8.1), 7.33 (d,
2H, J ¼ 8.1), 7.14 (s, 1H), 6.27 (s,1H), 4.93 (dd,1H, J ¼ 7.4, 3.5), 3.74 (s,
This work was supported by the Centre National de la Recherche
Scientifique. We express our thanks to Vincent Remusat for 1H and
13C NMR spectra recording. The antiviral work, performed by Céline
Lacroix, was funded by a Ph.D. grant from the Agency for Innovation
by Science and Technology (IWT, Belgium). We also would like to
acknowledge Stijn Delmotte for his excellent assistance.
3H), 3.65 (s, 3H), 2.85 (dd, 1H, J ¼ 14.4, 3.5), 2.73 (dd, 1H, J ¼ 14.4,
7.4), 2.06 (s, 3H). 13C NMR (50 MHz, CDCl3)
d 169.3, 149.3, 147.6,
146.2, 132.0, 129.8, 129.5, 126.3, 126.1, 122.2, 118.6, 113.3, 110.9,
108.5, 75.1, 56.0, 41.0, 23.9. HRMS for
C19H20N2O4
[M þ H]þ ¼ 341.1496. Found: [M þ H]þ ¼ 341.1497.

M. Roche et al. / European Journal of Medicinal Chemistry 76 (2014) 445e459
459
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Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.01.034.
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