Structural modifications of salicylates: Inhibitors of human CD81-receptor HCV-E2 interaction

Article abstract of DOI:10.1002/ardp.200700261

Starting point of the present paper was the result of a virtual screening using the open conformation of the large extracellular loop (LEL) of the CD81-receptor (crystal structure: PDB-ID: 1G8Q). After benzyl salicylate had been experimentally validated to be a moderate inhibitor of the CD81-LEL-HCV-E2 interaction, further optimization was performed and heterocyclic-substituted benzyl salicylate derivatives were synthesized. The compounds were tested for their ability to inhibit the interaction of a fluorescence-labeled antibody to CD81-LEL using HUH7.5 cells. No compound showed an increase concerning the inhibition of the protein-protein interaction compared to benzyl salicylate.

Full text of DOI:10.1002/ardp.200700261

478
Arch. Pharm. Chem. Life Sci. 2008, 341, 478–484
Full Paper
Structural Modifications of Salicylates: Inhibitors of Human
CD81-Receptor HCV-E2 Interaction
Marcel Holzer, Sigrid Ziegler, Alexander Neugebauer, Bernd Kronenberger, Christian D. Klein,*
and Rolf W. Hartmann*
Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrꢀcken, Germany
Starting point of the present paper was the result of a virtual screening using the open confor-
mation of the large extracellular loop (LEL) of the CD81-receptor (crystal structure: PDB-ID:
1G8Q). After benzyl salicylate had been experimentally validated to be a moderate inhibitor of
the CD81-LEL–HCV-E2 interaction, further optimization was performed and heterocyclic-substi-
tuted benzyl salicylate derivatives were synthesized. The compounds were tested for their ability
to inhibit the interaction of a fluorescence-labeled antibody to CD81-LEL using HUH7.5 cells. No
compound showed an increase concerning the inhibition of the protein-protein interaction
compared to benzyl salicylate.
Keywords: Benzyl salicylates / CD81-receptor / Hepatitis C Virus / Large extracellular loop / Virtual screening /
Received: December 13, 2007; accepted: April 16, 2008
DOI 10.1002/ardp.200700261
HCV-E2 interaction by binding to CD81-LEL, a virtual
screening using the crystal structure of the latter protein
was performed.
Introduction
Hepatitis C Virus (HCV), a positive-stranded RNA virus,
infects approximately 170 million people worldwide [1].
The majority of those infected fail to clear the virus
under current therapy and in many cases the chronic
infection with HCV leads to cirrhosis or liver cancer [2].
Recently, the large extracellular loop (LEL) of the human
cell surface protein CD81, a member of the tetraspanin
family, was identified as a binding partner for the HCV
envelope glycoprotein E2 (HCV-E2) [3]. Inhibition of this
interaction prevents infection of HCV target cells, mainly
human hepatocytes. This has been demonstrated using
several methods including a small molecule LEL-D-helix
mimetic that binds to HCV-E2 [4]. Following our aim to
synthesize compounds which inhibit the CD81-LEL–
More than 400000 compounds obtained from the
Available Chemicals Directory, the National Cancer Insti-
tute Database, the Maybridge Database, and the inhouse-
substance library of our group were used. Subsequently,
reactive compounds were excluded as well as compounds
which do not follow Lipinski's Rule-of-Five. Approxi-
mately 100000 compounds were then docked into the
CD81-LEL crystal structure (PDB-ID: 1G8Q) by means of
GOLD, DOCK, and FlexX software. The docking site
within the 1G8Q structure was a superficial cleft that is
localized between two alpha-helical parts of the LEL with
pronounced conformational flexibility [5]. There are indi-
cations that this part of the LEL is involved in the virus
binding process [6] and we hypothesized that conforma-
tional changes – which can possibly be blocked by small-
molecular ligands – in that area may be linked to virus
binding and internalization. Moreover, the cleft-like
region in 1G8Q appeared as a more promising binding
site for small-molecular ligands than other, purely super-
ficial regions of LEL. About 200 virtual hits were identi-
fied. Selected compounds (criterions were commercial
availability or easy synthetic route) were tested using the
assay developed by Pileri et al. [7]. The best compound
Correspondence: Prof. Dr. Rolf W. Hartmann, Saarland University,
Pharmaceutical and Medicinal Chemistry, P. O. Box. 151150, 66041
Saarbruecken, Germany.
E-mail: rwh@mx.uni-saarland.de
Fax: +49 681 302 4386
Prof. Dr. C. Klein (new address:) Universitꢁt Heidelberg, Pharmazie und
Molekulare Biotechnologie, Abt. Chemie, Im Neuenheimer Feld 364,
69120 Heidelberg, Germany.
Abbreviations: Hepatitis C Virus (HCV); HCV envelope glycoprotein E2
(HCV-E2); large extracellular loop (LEL)
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Arch. Pharm. Chem. Life Sci. 2008, 341, 478–484
Inhibitors of Human CD81-Receptor HCV-E2 Interaction
479
Figure 1. Benzyl salicylate.
found was benzyl salicylate (Fig. 1), which was capable to
inhibit the CD81-LEL–HCV-E2 interaction by 25% at
50 lM.
Reagents and conditions: (i) 10 mL EtOH
Pd(PPh3)4, O2-free, 908C over night; (ii-1) SOCl2, rt, 2 h; (ii-2) NEt3, dry CH2Cl2, 08C
+ 15 mL 10% Na2CO3-solution,
30 min, rt 2 h (Het = heterocycle, X = -O-, -NH-, Y = -H, -OH, Ar = aromat, n = 0, 1).
Scheme 1. Synthetic pathway and a general structure of the
synthesized benzyl salicylate derivatives.
Structure modification
After experimental validation of benzyl salicylate as a hit
compound, structural optimizations were performed to
increase inhibition of protein-protein interaction. The
aim was to synthesize compounds with a core structure
similar to benzyl salicylate in which the aromatic ring
containing the carboxyl function should be coupled to
variable heterocycles to improve drug-likeness. Further-
more, a few compounds with heterocyclic substitution at
the benzyl alcohol moiety were prepared.
Biological testing of the synthesized compounds 1–37
was performed by means of a medium-throughput assay
developed in our group [8] which is based on the proce-
dure of Pileri et al. [7]. Briefly, the inhibition of the inter-
action of the fluorescence-labeled CD81 antibody JS81
with HUH7.5 cells caused by our compounds is deter-
mined by FACS. No synthesized compound showed an
increase concerning the inhibition of the CD81-LEL–
HCV-E2 interaction compared to the original hit benzyl
salicylate. The probable point of contact of our com-
pounds should be the cleft-like region of the LEL as
shown in the above mentioned docking studies. How-
ever, it can not be excluded that our compounds in addi-
tion also interact with the E2-mimicking epitope of the
antibody.
Syntheses and biological testing
The desired compounds were obtained by connecting
substituted benzoic acids to alcohols and amines, respec-
tively. The synthetic pathway and a general structure of
the synthesized benzyl salicylate derivatives are shown
in Scheme 1, the compounds prepared are outlined in
Table 1. Formation of the amides and esters was accom-
plished by activating the carboxylic acids with thionyl
chloride followed by addition of the corresponding alco-
hols or amines.
A possible explanation for the low activity of the com-
pounds might be an unfavorable substitution pattern of
the core structure that diminishes binding affinity to the
LEL compared to the original hit. Therefore, we are cur-
rently looking for an appropriate substitution pattern to
solve this problem.
The carboxylic acids needed for the formation of the
target compounds were prepared using commercially
available reagents. Starting from the bromo-substituted
aromatic heterocycle and the corresponding boronic
acid, Suzuki coupling was performed with tetrakis-(tri-
phenylphosphine) palladium(0) as catalyst and the
desired compounds 38–43 obtained in satisfactory yields
(Scheme 1).
We thank the Deutsche Forschungsgemeinschaft (DFG) for the
grants given to M.H., S.Z. and A.N. (KFO129) and the Fonds der
Chemischen Industrie for financial support.
The authors have declared no conflict of interest.
The alcohols and amines used for the formation of the
target compounds were commercially available with the
exception of 44–46 (Table 1). These had to be prepared
starting from the bromo-substituted heterocycle and the
boronic acid of the corresponding alcohol or amine via
Suzuki coupling, performed as mentioned above.
Experimental
General procedure
Solvents and reagents were used as received from commercial
distributors without further purification. Anhydrous reactions
were conducted under a nitrogen atmosphere. Proton and car-
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M. Holzer et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 478–484
Table 1. Synthesized compounds 1–37.
bon NMR spectra were recorded at a Bruker AM 500 (Bruker Bio-
science, Billerica, MA, USA). The proton NMR spectra were
recorded at 500 MHz, the carbon NMR spectra at 125 MHz.
Chemical shifts d are reported in ppm units. Molecular mass was
determined by liquid chromatography – tandem mass spec-
trometry (LC-MS/MS) using a TSQ Quantum from Thermo Finni-
gan equipped with an electro spray interface and connected to a
Surveyor HPLC (Thermo Finnigan, Bremen, Germany). Positive
and negative ion mass spectra were recorded (mass range m/z
150–1500) in normal scan mode. Melting points were deter-
mined using a Stuart Scientific SMP3 melting point apparatus
(Stuart Scientific Stone, Staffordshire, UK). IR measurements
were performed on a Bruker Vector 33 at a frequency range from
4000–250 cm– 1 (Bruker). Wave numbers m are reported in cm– 1
.
Flash chromatography was performed using Merck silica gel 35/
40-63/70 (Merck, Germany).
Biological test system
HUH7.5 cells (16105) were incubated with 100 lL of the poten-
tial inhibitor (50 lM + 1% DMSO) in 96 transwell plates for 10
minutes at room temperature. Next 4 lL of the fluorescence-
labeled CD81 antibody JS81 and 21 lL of PBS were added. After
10 minutes at room temperature 125 lL of PBS were added and
the resulting cell suspension was left to incubate in darkness for
5 hours. After addition of 250 lL of PBS FACS analyses followed.
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Arch. Pharm. Chem. Life Sci. 2008, 341, 478–484
Inhibitors of Human CD81-Receptor HCV-E2 Interaction
481
129.16, 128.17, 127.85, 127.52, 127.32, 125.98, 121.69; LC/MS-
MS: 326.17 [M + H+].
General procedure for the Suzuki coupling
The boronic acid (1 equivalent) and the bromo-substituted het-
erocycle (1 equivalent) were added to a mixture of 10 mL ethanol
and 15 mL sodium carbonate solution (10%). This solution was
freed from oxygen by evacuating and flushing with nitrogen sev-
eral times. After addition of 4 mol% of tetrakis-(triphenylphos-
phine) palladium(0) under nitrogen the mixture was stirred at
908C over night.
Phenyl 4-(pyridin-4-yl)benzoate 4
Yield 39%, m. p. 1468C; IR m cm– 1: 3043, 2928, 1725, 1592, 1486,
1401, 1272, 1185, 1085; 1H-NMR (CDCl3) 8.65 (s, 2H), 8.24 (d, 2H, J
= 8.51), 7.70 (d, 2H, J = 8.51), 7.48 (s, 2H), 7.39–7.36 (m, 2H), 7.23–
7.20 (m, 1H), 7.18–7.16 (m, 2H); 13C-NMR (CDCl3) d: 164.67,
150.89, 150.50, 147.06, 143.18, 130.95, 130.06, 129.55, 127.24,
126.03, 121.75, 121.64; LC/MS-MS: 276.27 [M + H+].
Work-up for the carboxylic acids
The remaining solid was filtered off at that temperature. Subse-
quently, half of the solvent was removed. The product precipi-
tated after acidifying to pH = 2 using formic acid. It was then fil-
tered off and dried under high vacuum.
Phenyl 4-(pyrimidin-5-yl)benzoate 5
Yield 59%, m. p. 1418C; IR m cm– 1: 3064, 2926, 1726, 1610, 1554,
1489, 1414, 1268, 1183, 1077; 1H-NMR (CDCl3) d: 9.28 (s, 1H), 9.03
(s, 2H), 8.35 (d, 2H, J = 8.83), 7.73 (d, 2H, J = 8.51), 7.47–7.43 (m,
2H), 7.31–7.28 (m, 1H), 7.26–7.23 (m, 2H); 13C-NMR (CDCl3) d:
164.52, 158.25, 155.06, 150.85, 139.27, 133.28, 131.23, 130.13,
129.56, 127.17, 126.08, 121.61; LC/MS-MS: 277.25 [M + H+].
Work-up for the alcohol and amines
After extracting the aqueous phase two times with ethyl acetate,
the organic layer was dried and the solvent removed. Flash col-
umn chromatography (ethyl acetate / n-hexane mixture) led to
the purified product.
Benzyl 4-(thiophen-3-yl)benzoate 6
Yield 58%, m. p. 1388C; IR m cm– 1: 1705, 1607, 1267, 1105; H-
1
General procedure for the formation of the amides
and esters
NMR (CDCl3) d: 8.11 (d, 2H, J = 8.51), 7.66 (d, 2H, J = 8.51), 7.57–
7.56 (m, 1H), 7.48–7.47 (m, 2H), 7.43–7.36 (m, 5H), 5.39 (s, 2H);
13C-NMR (CDCl3) d: 164.50, 139.47, 138.47, 134.42, 128.64,
126.89, 126.53, 126.45, 124.98, 124.51, 124.47, 120.22, 64.96; LC/
MS-MS: 294.18 [M + H+].
The carboxylic acid (1 equivalent) was stirred with an excess of
thionyl chloride for 2 hours at room temperature. The resulting
clear solution was freed from remaining thionyl chloride under
reduced pressure. The acid chloride was dissolved in dry
dichloromethane and added drop wise at 08C to a solution con-
sisting of the corresponding alcohol or amine (1 equivalent) and
an equimolar amount of triethylamine in dry dichloromethane.
After stirring for 30 minutes at 08C the mixture was warmed to
room temperature and stirred for 2 hours. The precipitated solid
was filtered off. The solvent was removed and the raw product
was purified by column flash chromatography using an ethyl
acetate / n-hexane mixture.
Benzyl 4-(pyridin-3-yl)benzoate 7
Yield 44%, m. p. 988C; IR m cm– 1: 2925, 1708, 1455, 1379, 1272,
1
1097; H-NMR (CDCl3) d: 8.88 (s, 1H), 8.65 (s, 1H), 8.18 (d, 2H, J =
8.51), 7.90 (dt, 1H, J = 7.88), 7.65 (d, 2H, J = 8.83), 7.48–7.46 (m,
2H), 7.42–7.34 (m, 4H), 4.67 (s, 2H); 13C-NMR (CDCl3) d: 166.03,
149.29, 148.37, 142.37, 135.97, 134.45, 130.48, 129.76, 128.63,
128.19, 127.10, 123.64, 66.85; LC/MS-MS: 290.19 [M + H+].
Benzyl 4-(quinolin-3-yl)benzoate 8
Phenyl 4-(thiophen-3-yl)benzoate 1
Yield 15%, m. p. 1258C; IR m cm– 1: 3034, 2963, 1707, 1610, 1454,
1266, 1100;1H-NMR (CDCl3) d: 9.19 (s, 1H), 8.35 (s, 1H), 8.22 (d, 2H,
J = 8.51), 8.15 (d, 1H, J = 8.51), 7.91–7.90 (m, 1H), 7.80–7.74 (m,
3H), 7.62–7.59 (m, 1H), 7.49–7.48 (m, 2H), 7.43–7.35 (m, 3H),
5.42 (s, 2H); 13C-NMR (CDCl3) d: 166.08, 149.49, 147.71, 142.43,
135.99, 133.78, 132.70, 130.58, 129.91, 129.74, 129.31, 128.65,
128.32, 128.20, 128.13, 127.85, 127.64, 127.36, 127.27, 126.98,
66.88; LC/MS-MS: 340.31 [M + H+].
Yield 43%, m. p. 1558C; IR m cm– 1: 1719, 1605, 1487, 1278, 1195,
1160, 1079;1H-NMR (CDCl3) d: 8.23 (d, 2H, J = 8.51), 7.73 (d, 2H, J =
8.83), 7.62–7.61 (m, 1H), 7.48–7.43 (m, 4H), 7.30–7.28 (m, 1H),
7.26–7.24 (m, 2H);13C-NMR (CDCl3) d: 164.95, 151.02, 141.08,
140.70, 130.83, 129.49, 128.01, 127.50, 126.81, 126.37, 126.19,
125.86, 122.15, 121.74; LC/MS-MS:280.96 [M + H+].
Phenyl 4-(pyridin-3-yl)benzoate 2
Yield 45%, m. p 1108C; IR m cm– 1: 2925, 2360, 1730, 1266, 1190,
1073; 1H-NMR (CDCl3) d: 8.69 (s, 1H), 8.57 (dd, 1H, J = 4.73), 8.23 (d,
2H, J = 8.51), 7.84 (dt, 1H, J = 7.88), 7.63 (d, 2H, J = 8.51), 7.37–7.30
(m, 3H), 7.21–7.16 (m, 3H);13C-NMR (CDCl3) d: 164.77, 150.93,
149.43, 148.39, 42.90, 135.41, 134.50, 130.94, 129.52, 129.19,
127.27, 125.97, 123.68, 121.67; LC/MS-MS: 276.20 [M + H+].
Benzyl 4-(pyridin-4-yl)benzoate 9
Yield 20%; IR m cm– 1: 3035, 2926, 1716, 1595, 1401, 1268, 1101;
1H-NMR (CDCl3) d: 8.61 (d, 2H, J = 5.68), 8.10 (d, 2H, J = 8.51), 7.60
(d, 2H, J = 8.51), 7.42 (d, 2H, J = 5.99), 7.39 (m, 2H), 7.33–7.26 (m,
3H), 5.31 (s, 2H); 13C-NMR (CDCl3) d: 164.87, 149.42, 146.12,
134.87, 129.46, 127.62, 127.20, 126.84, 126.02, 124.77, 120.66,
65.90; LC/MS-MS: 290.19 [M + H+].
Phenyl 4-(quinolin-3-yl)benzoate 3
Yield 43%, m. p. 1378C; IR m cm– 1: 3057, 2924, 1728, 1608, 1492,
1269, 1197, 1082; 1H-NMR (CDCl3) d: 9.15 (s, 1H), 8.31 (s, 1H), 8.27
(d, 2H, J = 8.51), 8.01 (d, 1H, J = 8.51), 7.85 (d, 1H, J = 6.94), 7.78 (d,
2H, J = 8.51), 7.71–7.68 (m, 1H), 7.56–7.52 (m, 1H), 7.39–7.36 (m,
2H), 7.23–7.17 (m, 3H); 13C-NMR (CDCl3) d: 164.83, 150.96,
149.47, 147.82, 142.99, 133.86, 131.04, 130.00, 129.53, 129.36,
Benzyl 4-(pyrimidin-5-yl)benzoate 10
Yield 36%, m. p. 788C; IR m cm– 1: 2924, 2855, 1716, 1611, 1554,
1418, 1375, 1268; 1H-NMR (CDCl3) d: 9.25 (s, 1H), 8.98 (s, 1H), 8.21
(d, 2H, J = 8.51), 7.65 (d, 2H, J = 8.83), 7.48–7.46 (m, 2H), 7.42–
7.34 (m, 2H), 5.40 (s, 2H); 13C-NMR (CDCl3) d: 165.73, 158.11,
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Arch. Pharm. Chem. Life Sci. 2008, 341, 478–484
154.98, 138.69, 135.78, 133.35, 130.75, 128.63, 128.37, 128.23,
126.97, 67.00; LC/MS-MS: 291.24 [M + H+].
(s, 2H), 8.31 (s, 1H), 8.24 (d, 2H, J = 8.22), 8.13 (d, 1H, J = 8.53), 7.88
(d, 1H, J = 7.92), 7.76–7.72 (m, 3H), 7.67 (d, 2H, J = 7.92), 7.62 (d,
2H, J = 8.22), 7.60–7.57 (m, 1H), 5.48 (s, 2H); 13C-NMR (CDCl3) d:
165.78, 158.15, 155.02, 149.74, 147.42, 138.82, 138.04, 135.78,
133.30, 133.24, 130.81, 130.52, 129.58, 129.25, 129.13, 128.02,
127.96, 127.72, 127.05, 66.63; LC/MS-MS: 418.27 [M + H+].
Benzyl 2-hydroxy-5-(pyridin-3-yl)benzoate 11
Yield 46%; IR m cm– 1: 3033, 2926, 2855, 1675, 1594, 1472, 1387,
1203; 1H-NMR (CDCl3) d: 10.87 (s, 1H), 8.82 (s, 1H), 8.59 (s, 1H),
8.10 (s, 1H), 7.83–7.81 (m, 1H), 7.68 (dd, 1H, J = 8.51), 7.50–7.46
(m, 2H), 7.44–7.34 (m, 4H), 7.11 (d, 1H, J = 8.83), 5.44 (s, 2H); 13C-
NMR (CDCl3) d: 169.71, 161.81, 148.26, 147.90, 135.11, 134.41,
133.91, 129.09, 128.79, 128.70, 128.44, 128.39, 127.88, 125.81,
123.59, 123.56, 118.60, 112.92, 67.32; LC/MS-MS: 306.15 [M + H+].
N-phenyl-4-(thiophen-3-yl)benzamide 18
Yield 19%, m. p. 1658C; IR m cm– 1: 3341, 2926, 1637, 1600, 1413;
1H-NMR (CDCl3) d: 8.51–8.46 (m, 2 H), 8.24–8.18 (m, 4H), 7.95 (s,
1H), 7.89–7.86 (m, 2H), 7.73 (d, 1H, J = 5.68), 7.67–7.61 (m, 2H);
LC/MS-MS: 280.19 [M + H+].
4-Methoxyphenyl 4-(pyridin-4-yl)benzoate 12
Yield 48%, m. p. 1718C; IR m cm– 1: 2964, 1724, 1592, 1504, 1460,
1277, 1177, 1081; 1H-NMR (CDCl3) d: 8.85 (d, 2H, J = 6.67), 8.43 (d,
2H, J = 8.39), 8.15 (d, 2H, J = 6.65), 7.89 (d, 2H, J = 8.38), 7.16 (d, 2H,
J = 9.04), 6.97 (d, 2H, J = 9.08), 3.84 (s, 3H); 13C-NMR (CDCl3) d:
167.07, 157.07, 148.78, 138.18, 136.10, 130.09, 129.00, 127.91,
126.16, 121.50, 55.54; LC/MS-MS: 306.01 [M + H+].
N-phenyl-4-(pyridin-3-yl)benzamide 19
Yield 29%, m. p. 2228C; IR m cm– 1: 3240, 2924, 1674, 1597, 1533,
1
1438, 1317; H-NMR (d6-DMSO) d: 10.31 (s, 1H), 8.99 (s, 1H), 8.62
(dd, 1H, J = 4.73), 8.19 (dt, 1H, J = 7.88), 8.10 (d, 2H, J = 8.20), 7.91
(d, 2H, J = 8.20), 7.81 (d, 2H, J = 7.57), 7.55-7.52 (m, 1H), 7.36 (t, 2H,
J = 7.25), 7.11 (t, 1H, J = 7.25); 13C-NMR (d6-DMSO) d: 164.96,
149.04, 147.78, 139.97, 139.09, 134.55, 134.33, 128.56, 128.43,
126.77, 123.91, 123.67, 120.36; LC/MS-MS: 275.15 [M + H+].
4-Methoxyphenyl 4-(pyrimidin-5-yl)benzoate 13
Yield 29%, m. p. 1568C; IR m cm– 1: 2934, 1725, 1607, 1555, 1504,
1420, 1339, 1248, 1180, 1069; 1H-NMR (CDCl3) d: 9.27 (s, 1H), 9.02
(s, 2H), 8.34 (d, 2H, J = 8.49), 7.73 (d, 2H, J = 8.49), 7.16 (d, 2H, J =
9.03), 6.96 (d, 2H, J = 9.04), 3.84 (s, 3H); 13C-NMR (CDCl3) d: 164.85,
161.28, 157.14, 154.29, 146.36, 134.52, 130.89, 130.42, 124.78,
123.56, 114.29, 55.49; LC/MS-MS: 307.97 [M + H+].
N-phenyl-4-(pyridin-4-yl)benzamide 20
Yield 23%, m. p. 2258C; IR m cm– 1: 3305, 2925, 2443, 1632, 1595,
1494, 1412, 1316; 1H-NMR (CDCl3) d: 8.12 (d, 2H, J = 5.99), 7.57 (d,
2H, J = 8.20), 7.36 (d, 2H, J = 8.51), 7.25–7.23 (m, 2H), 7.19 (d, 2H, J
= 7.57), 6.87 (m, 2H), 7.67-6.64 (m, 1H); 13C-NMR (CDCl3) d: 166.22,
148.91, 147.71, 140.20, 137.79, 135.16, 128.03, 127.77, 126.45,
123.97, 121.47, 120.57; LC/MS-MS: 272.91 [M – H+].
4-Methoxybenzyl 4-(pyridin-4-yl)benzoate 14
Yield 13%, m. p. 1628C; IR m cm– 1: 2925, 1629, 1548, 1512, 1417,
1297, 1255, 1178, 1024; 1H-NMR (CDCl3) d: 8.62 (d, 2H, J = 6.03),
8.10 (d, 2H, J = 8.52), 7.61 (d, 2H, J = 8.53), 7.45 (d, 2H, J = 6.15),
7.34 (d, 2H, J = 8.68), 6.86 (d, 2H, J = 8.70), 5.26 (s, 2H), 3.75 (s, 3H);
13C-NMR (CDCl3) d: 167.16, 160.45, 149.89, 148.65, 138.14,
131.19, 130.82, 130.34, 129.08, 126.08, 121.46, 113.75, 67.15,
55.39; LC/MS-MS: 320.14 [M + H+].
N-phenyl-4-(pyrimidin-5-yl)benzamide 21
Yield 49%, m. p. 2208C; IR m cm– 1: 3316, 2361, 1677, 1599, 1538,
1400, 1326;1H-NMR (CDCl3) d: 9.19 (s, 1H), 8.96 (s, 2H), 8.02 (d, 2H,
J = 8.20), 7.68–7.64 (m, 4H), 7.34 (m, 2H), 7.15–7.11 (m, 1H), 7.89
(dt, 1H, J = 7.92), 7.72–7.68 (m, 3H), 7.47 (t, 1H, J = 7.92), 7.37–
7.34 (m, 2H); 13C-NMR (CDCl3) d: 165.36, 157.66, 154.94, 137.84,
137.18, 135.53, 133.51, 129.01, 128.40, 127.14, 124.75, 120.52;
LC/MS-MS: 273.96 [M – H+].
4-Methoxybenzyl 4-(pyrimidin-5-yl)benzoate 15
Yield 50%, m. p. 1658C; IR m cm-1: 1709, 1610, 1513, 1414, 1276,
1241, 1184, 1097, 1028; 1H-NMR (CDCl3) d: 9.61 (s, 1H), 8.89 (s,
2H), 8.53 (d, 2H, J = 8.53), 7.56 (d, 2H, J = 8.54), 7.32 (d, 2H, J =
8.69), 6.84 (d, 2H, J = 8.70), 5.25 (s, 2H), 3.74 (s, 3H); 13C-NMR
(CDCl3) d: 167.07, 161.32, 160.65, 154.31, 133.61, 131.19, 130.88,
130.28, 129.02, 126.25, 123.35, 113.65, 67.16, 55.48; LC/MS-MS:
321.00 [M + H+].
N-benzyl-4-(thiophen-3-yl)benzamide 22
Yield 62%, m. p. 1808C; IR m cm– 1: 3346, 2928, 1635, 1521, 1278;
1H-NMR (CDCl3) d: 7.82 (d, 2H, J = 8.83), 7.65 (d, 2H, J = 8.51), 7.53
(t, 1H, J = 2.21), 7.42 (d, 2H, J = 2.21), 7.38–7.37 (m, 4H), 7.33–7.29
(m, 1H), 4.67 (d, 2H, J = 5.68); 13C-NMR (CDCl3) d: 166.89, 141.17,
138.88, 138.20, 132.75, 128.81, 127.95, 127.65, 127.57, 127.64,
126.64, 126.15, 121.53, 44.18; LC/MS-MS: 294.11 [M + H+].
4-(Quinolin-3-yl)benzyl 4-(quinolin-3-yl)benzoate 16
Yield 20%, m. p. 1908C; IR m cm– 1: 2925, 1718, 1608, 1494, 1273,
1116; 1H-NMR (CDCl3) d: 9.21–9.19 (m, 2H), 8.36 (s, 1H), 8.32 (s,
1H), 8.25 (d, 2H, J = 8.22), 8.17–8.14 (m, 2H), 7.90 (t, 2H, J = 7.61),
7.81 (d, 2H, J = 8.22), 7.78–7.72 (m, 4H), 7.66–7.56 (m, 4H), 5.50
(s, 2H); 13C-NMR (CDCl3) d: 166.09, 149.50, 147.74, 147.45, 142.56,
137.98, 135.98, 133.53, 133.30, 132.64, 130.61, 129.95, 129.53,
129.33, 128.14, 128.03, 127.84, 127.71, 127.41, 127.29, 66.48; LC/
MS-MS: 467.40 [M + H+].
N-benzyl-4-(pyridin-3-yl)benzamide 23
Yield 50%, m. p. 1088C; IR m cm– 1: 3324, 2925, 2359, 1636, 1541,
1313, 1260, 1027; 1H-NMR (CDCl3) d: 8.69 (s, 1H), 8.48 (dd, 1H, J =
5.04), 7.82 (d, 2H, J = 8.20), 7.77 (dt, 1H, J = 7.88), 7.50 (d, 2H, J =
8.83), 7.29–7.23 (m, 4H), 7.21–7.18 (m, 1H), 6.94–6.92 (m, 1H),
4.57 (d, 2H, J = 5.68); 13C-NMR (CDCl3) d: 165.89, 148.03, 147.20,
139.78, 137.23, 134.52, 133.38, 127.74, 126.87, 126.56, 126.17,
122.63, 43.12; LC/MS-MS: 289.22 [M + H+].
4-(Quinolin-3-yl)benzyl 4-(pyrimidin-5-yl)benzoate 17
Yield 29%, m. p. 1668C; IR m cm– 1: 3031, 1713, 1611, 1555, 1417,
1265, 1185, 1094; 1H-NMR (CDCl3) d: 9.25 (s, 1H), 9.18 (s, 1H), 8.99
N-benzyl-4-(quinolin-3-yl)benzamide 24
Yield 51%, m. p. 1908C; IR m cm– 1: 3280, 3306, 2926, 2430, 1625,
1551, 1437, 1303; 1H-NMR (CDCl3) d: 8.63 (s, 1H), 8.47 (s, 1H), 8.07
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(s, 1H), 7.57–7.50 (m, 4H), 7.37 (d, 2H, J = 8.51), 7.15–7.08 (m,
3H), 7.03–7.00 (m, 2H), 6.87–6.85 (m, 2H), 4.10 (s, 2H); LC/MS-MS:
339.26 [M + H+].
(d, 2H, J = 8.53), 7.56 (d, 2H, J = 8.54), 7.32 (d, 2H, J = 8.69), 6.84 (d,
2H, J = 8.70), 3.74 (s, 3H); 13C-NMR (CDCl3) d: 167.35, 156.56,
153.45, 150.07, 135.30, 134.71, 131.58, 130.62, 129.47, 123.17,
121.48, 114.35, 55.44; LC/MS-MS: 306.01 [M + H+].
N-benzyl-4-(pyrimidin-5-yl)benzamide 25
Yield 90%, m. p. 1718C; IR m cm– 1: 3314, 3056, 2229, 1641, 1533,
1418, 1313; H-NMR (CDCl3) d: 9.23 (s, 1H), 8.96 (s, 2H), 7.94 (d,
2H, J = 8.51), 7.64 (d, 2H, J = 8.51), 7.38–7.30 (m, 5H), 6.55 (s, 1H),
4.67 (d, 2H, J = 5.68); 13C-NMR (CDCl3) d: 166.46, 158.03, 154.94,
137.96, 137.35, 134.85, 133.34, 128.87, 128.13, 127.97, 127.78,
127.18, 44.30; LC/MS-MS: 290.19 [M + H+].
N-(4-methoxyphenyl)-4-(pyrimidin-5-yl)benzamide 32
Yield 22%; IR m cm– 1: 3046, 1645, 1514, 1410, 1325, 1246, 1175,
1118; H-NMR (CDCl3) d: 9.26 (s, 1H), 9.00 (s, 2H), 8.03 (d, 2H, J =
8.06), 7.76 (s, 1H), 7.71 (d, 2H, J = 8.17), 7.57 (d, 2H, J = 8.48), 6.94
(d, 2H, J = 8.86), 3.83 (s, 3H); 13C-NMR (CDCl3) d: 167.35, 161.21,
156.48, 155.84, 137.86, 135.35, 134.54, 131.71, 130.69, 128.05,
121.25, 114.37, 55.43; LC/MS-MS: 306.27 [M + H+].
1
1
N-benzyl-2-hydroxy-5-(pyridin-3-yl)benzamide 26
Yield 11%; IR m cm– 1: 3349, 2926, 1732, 1642, 1543, 1474, 1290,
1230; 1H-NMR (CDCl3) d: 8.81 (s, 1H), 8.51 (s, 1H), 7.84 (s, 1H), 7.66
(s, 1H), 7.55 (d, 1H, J = 8.51), 7.37–7.29 (m, 7H), 7.08 (d, 2H, J =
8.51), 4.66 (d, 2H, J = 5.68); LC/MS-MS: 303.19 [M – H+].
N-(4-methoxybenzyl)-4-(pyridin-4-yl)benzamide 33
Yield 19%, m. p. 1748C; IR m cm– 1: 3298, 1635, 1594, 1556, 1511,
1414, 1316, 1242, 1174, 1033; 1H-NMR (CDCl3) d: 8.75 (d, 2H, J =
5.67), 7.89 (d, 2H, J = 8.13), 7.91 (d, 2H, J = 5.63), 7.76 (d, 2H, J =
7.63), 7.29 (d, 2H, J = 8.33), 6.88 (d, 2H, J = 8.53), 6.43 (s, 1H), 4.60
(d, 2H, J = 5.55), 3.79 (s, 3H); 13C-NMR (CDCl3) d: 166.58, 160.28,
153.34, 150.11, 135.41, 132.57, 130.18, 129.86, 128.68, 123.07,
113.88, 55.14, 44.20; LC/MS-MS: 319.58 [M + H+].
N-(furan-2-ylmethyl)-4-(pyridin-3-yl)benzamide 27
Yield 23%, m. p. 1378C; IR m cm– 1: 3313, 2934, 1630, 1544, 1310,
1190, 1154; 1H-NMR (CDCl3) d: 8.84 (s, 1H), 8.61 (s, 1H), 7.91–7.86
(m, 3H), 7.63 (d, 2H, J = 8.51), 7.40–7.37 (m, 2H), 6.61 (s, 1H),
6.36–6.31 (m, 2H), 4.66 (d, 2H, J = 5.36); 13C-NMR (CDCl3) d:
166.31, 151.10, 149.12, 148.28, 142.36, 141.01, 135.54, 134.42,
133.75, 127.85, 127.27, 123.64, 110.56, 107.80, 37.09; LC/MS-MS:
279.21 [M + H+].
N-(3-(thiophen-3-yl)phenyl)-4-(pyridin-3-yl)benzamide 34
Yield 24%, m. p. 1758C; IR m cm– 1: 3270, 2924, 1650, 1601, 1480,
1
1304; H-NMR (CDCl3) d: 8.81 (s, 1H), 8.58 (s, 1H), 7.95-7.93 (m,
3H), 7.90 (s, 1H), 7.85 (dt, 1H, J = 7.88), 7.63 (d, 2H, J = 8.51), 7.53–
7.50 (m, 1H), 7.43–7.42 (m, 1H), 7.34–7.31 (m, 3H), 7.19 (s, 1H);
13C-NMR (CDCl3) d: 165.17, 149.24, 148.30, 141.79, 141.31,
138.35, 136.89, 134.46, 129.55, 127.88, 127.50, 126.33, 126.28,
123.70, 122.81, 120.80, 118.90, 118.27; LC/MS-MS: 357.24 [M +
H+].
N-(furan-2-ylmethyl)-4-(quinolin-3-yl)benzamide 28
Yield 76%, m. p. 1768C; IR m cm– 1: 2962, 1728, 1649, 1546, 1495,
1377, 1272, 1122, 1073; 1H-NMR (CDCl3) d: 9.10 (s, 1H), 8.25 (s,
1H), 8.07 (d, 1H, J = 8.20), 7.87 (d, 2H, J = 8.51), 7.81 (d, 1H, J =
8.20), 7.71–7.64 (m, 3H), 7.54–7.51 (m, 1H), 7.32 (s, 1H), 6.53 (s,
1H), 6.29–6.26 (m, 2H), 4.61 (d, 2H, J = 5.36); 13C-NMR (CDCl3) d:
166.24, 151.10, 149.49, 147.66, 142.38, 141.10, 133.68, 133.61,
129.83, 129.30, 128.84, 128.09, 127.87, 127.93, 127.53, 127.24,
110.57, 107.81, 37.11; LC/MS-MS: 329.04 [M + H+].
N-(3-(pyridin-3-yl)phenyl)-4-(pyridin-3-yl)benzamide 35
Yield 3%, m. p. 708C; IR m cm– 1: 2963, 1655, 1594, 1545, 1425,
1260; 1H-NMR (CDCl3) d: 8.90–8.88 (m, 2H), 8.67–8.65 (m, 1H),
8.62–8.61 (m, 1H), 8.05–7.99 (m, 4H), 7.94–7.92 (m, 2H), 7.72 (d,
2H, J = 8.51), 7.69–7.67 (m, 1H), 7.51 (t, 1H, J = 7.88), 7.43–7.38
(m, 3H); LC/MS-MS: 350.91 [M – H+].
N-(furan-2-ylmethyl)-4-(pyridin-4-yl)benzamide 29
Yield 77%, m. p. 1588C; IR m cm– 1: 3254, 1635, 1596, 1554, 1486,
1
1414, 1315, 1189, 1070; H-NMR (CDCl3) d: 8.66–8.65 (m, 2H),
7.90 (d, 2H, J = 8.51), 7.56 (d, 2H, J = 8.83), 7.50–7.48 (m, 2H),
7.37–7.36 (m, 1H), 6.82 (s, 1H), 6.34–6.33 (m, 1H), 6.30–6.29 (m,
1H), 4.65 (d, 2H, J = 5.36); 13C-NMR (CDCl3) d: 166.55, 151.11,
150.34, 147.21, 142.32, 141.18, 134.66, 132.10, 128.55, 128.46,
127.91, 127.17, 121.63, 110.54, 107.78, 37.08; LC/MS-MS: 279.21
[M + H+].
N-(3-(pyridin-3-yl)phenyl)-4-(pyridin-4-yl) benzamide 36
Yield 6%; IR m cm– 1: 3265, 3039, 1665, 1595, 1547, 1471, 1401,
1295, 1259; H-NMR (CDCl3) d: 8.88 (s, 1H), 8.72–8.71 (m, 2H),
8.61–8.60 (m, 1H), 8.24 (s, 1H), 8.04 (d, 2H, J = 8.51), 8.00 (s, 1H),
7.94–7.92 (m, 1H), 7.76 (d, 2H, J = 8.83), 7.70 (s, 1H), 7.55–7.54
(m, 2H), 7.50 (t, 1H, J = 7.88), 7.40–7.37 (m, 2H); LC/MS-MS: 349.98
[M – H+].
1
N-(furan-2-ylmethyl)-4-(pyrimidin-5-yl)benzamide 30
Yield 73%, m. p. 1658C; IR m cm– 1: 3343, 1634, 1544, 1415, 1307,
1190; 1H-NMR (CDCl3) d: 9.14 (s, 1H), 8.87 (s, 2H), 7.87 (d, 2H, d, J =
8.51), 7.55 (d, 2H, J = 8.51), 7.30–7.29 (m, 1H), 6.72 (s, 1H), 6.28–
6.27 (m, 1H), 6.26–6.24 (m, 1H), 4.59 (d, 2H, J = 5.36); 13C-NMR
(CDCl3) d: 166.37, 157.99, 154.91, 151.02, 142.36, 137.34, 134.68,
133.32, 128.20, 127.11, 110.57, 107.84, 37.11; LC/MS-MS: 280.12
[M + H+].
N-(3-(pyridin-3-yl)phenyl)-4-(pyrimidin-5-yl) benzamide
37
Yield 24%, m. p. 1558C; IR m cm– 1: 3287, 3045, 1677, 1597, 1554,
1
1399, 1294; H-NMR (CDCl3) d: 9.24 (s, 1H), 8.96 (s, 2H), 8.84 (s,
1H), 8.57–8.53 (m, 2H), 8.07 (d, 2H, J = 8.53), 7.97 (s, 1H), 7.89 (dt,
1H, J = 7.92), 7.72–7.68 (m, 3H), 7.47 (t, 1H, J = 7.92), 7.37–7.34
(m, 2H); 13C-NMR (CDCl3) d: 165.20, 158.09, 154.95, 148.63,
148.16, 138.78, 138.69, 137.69, 136.21, 135.24, 134.57, 129.87,
128.36, 127.31, 123.65, 123.46, 120.04, 119.11; LC/MS-MS: 353.25
[M + H+].
N-(4-methoxyphenyl)-4-(pyridin-4-yl)benzamide 31
Yield 26%; IR m cm– 1: 2987, 1715, 1598, 1515, 1453, 1402, 1365,
1249, 1182, 1026; 1H-NMR (CDCl3) d: 9.16 (s, 1H), 8.89 (s, 2H), 8.12
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13C-NMR (CDCl3) d: 148.33, 134.28, 132.11, 132.03, 131.93,
129.98, 128.46, 123.44, 117.30, 114.78, 113.57.
4-(Thiophen-3-yl)benzoic acid 38
Yield 94%, m. p. 2808C (Lit.: 281–2828C) [9]; 1H-NMR (d6-DMSO) d:
8.05–8.04 (m, 1H), 7.96 (d, 2H, J = 8.51), 7.85 (d, 2H, J = 8.20),
7.63–7.68 (m, 1H), 7.64–7.63 (m, 1H); 13C-NMR (d6-DMSO) d:
167.02, 140.31, 139.09, 129.92, 129.07, 127.46, 126.14, 125.99,
122.79.
4-(Chinolin-3-yl)benzyl alcohol 46
Yield 48%;1H-NMR (CDCl3) d: 9.06 (s, 1H), 8.28 (s, 1H), 8.12 (d, 1H, J
= 8.53), 7.87–7.85 (m, 1H), 7.73–7.67 (m, 3H), 7.58–7.55 (m, 1H),
7.50 (d, 2H, J = 8.53), 7.24 (s, 1H), 4.77 (s, 2H); (Lit.: d6-DMSO: 8.88
(d, 1H, J = 2.00), 8.56 (dd, 1H, J = 5, 20), 8.07 (dt, 1H, J = 8, 20), 7.68
(d, 2H, J = 8.00), 7.48 (dd, 1H, J = 8, 50), 7.44 (d, 2H, J = 8.00), 5.25 (t,
1H, J = 6.00), 4.55 (d, 2H, J = 6.00)) [17]; 13C-NMR (CDCl3) d: 149.82,
147.27, 142.30, 141.03, 140.36, 140.31, 137.16, 133.52, 133.19,
129.46, 129.16, 127.99, 127.81, 127.56, 127.05, 64.31.
4-(Pyridin-3-yl)benzoic acid 39
Yield 62%, m. p. 2158C (Lit.: 2158C) [10]; H-NMR (D2O / TFA) d:
7.80 (s, 1H), 7.61–7.56 (m, 2H), 7.00 (d, 2H, J = 8.51), 6.96–6.93
(m, 1H), 6.56 (d, 2H, J = 8.51).
1
4-(Chinolin-3-yl)benzoic acid 40
Yield 92%; 1H-NMR (d6-DMSO / TFA : 1 / 0.1) d: 9.66 (s, 1H), 9.51 (s,
1H), 7.80–7.78 (m, 1H), 8.38 (d, 1H, J = 7.88), 8.27 (d, 1H, J = 8.51),
8.15–8.08 (m, 5H), 7.98–7.95 (m, 1H); (Lit.: 250 MHz, d6-DMSO:
13.09 (br s, 1H), 9.32 (d, 1H), 8.76 (d, 1H), 8.07 (m, 5H), 7.83 (m,
2H), 7.67 (m, 1H)) [11];13C-NMR (d6-DMSO + TFA) d: 166.79, 144.39,
132.64, 131.15, 130.18, 127.61, 129.76, 129.47, 118.44, 116.15,
113.85, 111.56.
References
[1] J. M. Pawlotsky, Trends Microbiol. 2004, 12, 96–102.
[2] F. V. Chisari, Nature 2005, 436, 930–932.
[3] K. Kitadokoro, M. Ponassi, G. Galli, R. Petracca, et al., Biol.
Chem. 2002, 383, 1447–1452.
[4] S. E. VanCompernolle, A. V. Wiznycia, J. R. Rush, M. Dhana-
5-(Pyridin-3-yl)salicylic acid 41
sekaran, et al., Virology 2003, 314, 371–380.
Yield 46%, m. p. 2608C (Lit.: 2638C) [12]; 1H-NMR (D2O / TFA : 1 / 1)
d: 7.61 (s, 1H), 7.42–7.40 (m, 1H), 7.36–7.35 (m, 1H), 6.93 (d, 1H, J
= 2.52), 6.78–6.75 (m, 1H), 6.49 (dd, 1H, J = 8.51), 5.84 (d, 1H, J =
8.83);13C-NMR had no expressiveness because of the TFA.
[5] A. Neugebauer, C. D. Klein, R. W. Hartmann, Bioorg. Med.
Chem. Lett. 2004, 14, 1765–1769.
[6] H. E. Drummer, K. A. Wilson, P. Poumbourios, J. Virol.
2002, 76, 11143–11147.
[7] P. Pileri, Y. Uematsu, S. Campagnoli, G. Galli, Science 1998,
282, 938–941.
4-(Pyrimidin-5-yl)benzoic acid 42
Yield 60%, m. p. 2188C (Lit. 2208C) [13]; 1H-NMR (d6-DMSO) d: 9.17
(s, 1H), 9.15 (s, 2H), 8.01 (d, 2H, J = 8.20), 7.74 (d, 2H, J = 8.20); 13C-
NMR (d6-DMSO) d: 169.60, 157.11, 154.60, 140.35, 133.92, 133.18,
131.47, 131.39, 129.85, 128.75, 125.81.
[8] S. Ziegler, B. Kronenberger, S. Zeuzem, R. W. Hartmann, C.
D. Klein, unpublished results, manuscript in preparation.
[9] F. Francesco, M. Gianlorenzo, T. Aldo, J. Chem. Soc. 1970, 8,
1595–1598.
4-(Pyridin-4-yl)benzoic acid 43
[10] J. W. Guiles, S. G. Johnson, W. V. Murray, J. Org. Chem.
1996, 61, 5169–5171.
Yield 98%, m. p. 2088C (Lit.: 2108C) [14]; due to the insolubility of
the compound, it was impossible to measure NMR. Further reac-
tions showed it to be the desired product.
[11] L. M. Gaster, H. K. Rami, P. A. Wyman (Smithkline Bee-
cham PLC, UK), WO 9850358. 1998.
[12] L. H. Sarett, W. C. Ruyle (Merck & Co, Inc), DE 1801303.
3-(Thiophen-3-yl)aniline 44
1967.
Yield 82%, m. p. 858C (Lit.: 86–888C) [15];1H-NMR (CDCl3) d: 7.44–
7.43 (m, 1H), 7.40–7.39 (m, 2H), 7.22 (t, 1H, J = 7.88), 7.07–7.05
(m, 1H), 6.94–6.93 (m, 1H), 6.66–6.64 (m, 1H); 13C-NMR (CDCl3) d:
146.89, 142.58, 136.96, 129.81, 126.51, 126.04, 120.28, 117.04,
114.12, 113.21.
[13] Y. Gong, H. W. Pauls, Syn. Lett. 2000, 6, 829831.
[14] (Ciba Ltd), NL 6414307. 1965.
[15] W. J. Coates, A. D. Rawlings (Smithkline Beecham PLC, UK)
WO 9429277. 1994.
[16] P. M. Carabateas, P. R. Brundage, K. O. Gelotte, M. D.
Gruett, R. R. Lorenz, J. Heterocycl. Chem. 1984, 21, 1849–
1856.
3-(Pyridin-3-yl)-aniline 45
Yield 54%, m. p. 758C (Lit.: 72–748C) [16]; 1H-NMR (CDCl3) d: 8.80
(s, 1H), 8.54 (s, 1H), 7.80–7.78 (m, 1H), 7.30–7.28 (m, 1H), 7.23–
7.22 (m, 1H), 6.93–6.91 (m, 1H), 6.83 (s, 1H), 6.69–6.67 (m, 1H);
[17] I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley, G. K.
Tranmer, Chem. Eur. J. 2006, 12, 4407–4416.
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com