Synthesis and antimicrobial activity of some novel phenyl and benzimidazole substituted benzyl ethers

Article abstract of DOI:10.1016/j.bmcl.2007.01.061

In this study, a series of novel phenyl- and benzimidazole-substituted benzyl ethers were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Methicillin-resistant S. aureus (MRSA), Escherichia coli, Candid

Full text of DOI:10.1016/j.bmcl.2007.01.061

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2233–2236
Synthesis and antimicrobial activity of some novel phenyl
and benzimidazole substituted benzyl ethers
a,
*
a
b
c
¨
¨
Ozden Ozel G u¨ ven, Taner Erdo g˘ an, Hakan G o¨ ker and Sulhiye Yıldız
a
Department of Chemistry, Zonguldak Karaelmas University, 67100 Zonguldak, Turkey
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100 Tando g˘ an, Ankara, Turkey
b
c
Department of Microbiology, Faculty of Pharmacy, Ankara University, 06100 Tando g˘ an, Ankara, Turkey
Received 12 December 2006; revised 17 January 2007; accepted 19 January 2007
Available online 25 January 2007
Abstract—In this study, a series of novel phenyl- and benzimidazole-substituted benzyl ethers were synthesized and evaluated for
antibacterial and antifungal activities against Staphylococcus aureus, Methicillin-resistant S. aureus (MRSA), Escherichia coli,
Candida albicans, and Candida krusei. Compound 6g exhibited the most potent antibacterial activity with lowest MIC values of
3
.12 and 6.25 lg/mL against S. aureus and MRSA, respectively.
Ó 2007 Elsevier Ltd. All rights reserved.
The synthesis of a new class of antibacterial and anti-
fungal agents against especially Gram-positive drug-re-
sistant bacteria and some fungi is urgent need
nowadays, since these types of microorganisms are
responsible for some infections in the acute and long-
term care units in hospitals. Well-known azole deriva-
tives, having a gem-phenyl-(1H-imidazol-1-ylmethyl)
moiety (Fig. 1) which is thought to be largely responsi-
ble for imparting, antifungal activity, such as clotrima-
zole, miconazole (Fig. 2), econazole, and ketoconazole,
Cl
Cl
N
O
N
Cl
Cl
Figure 2. Structure of miconazole.
1
have been developed for clinical uses. SAR studies
revealed that imidazole and phenyl rings which are also
pharmacophoric portion of all these molecules can be
structure to benzimidazole with the aim of finding new
agents with higher antifungal and/or antibacterial
activity.
2
,3
replaced by the triazole. In the literature, antibacterial
activity of the azole class of compounds has been report-
4
5
ed. Recently highly potent antifungal and antibacteri-
6
7
The synthetic pathways for preparation of the targeted
compounds listed in Table 1 are shown in Scheme 1.
-Phenylethanone 1 was brominated with bromine in
the presence of aluminum chloride in anhydrous ether
to obtain 2-bromo-1-phenylethanone 2. Dehydrohalo-
genation between 2 and 1H-benzimidazole 3 led to
2-(1H-benzimidazol-1-yl)-1-phenylethanone 4. Reduc-
al activities of the benzimidazoles have been reported in
our previous studies. These encouraging results prompt-
ed us to replace imidazole ring of the miconazole-type
1
N
N
tion of 4 with NaBH gave 2-(1H-benzimidazol-1-yl)-
4
1
-phenylethanol 5. Targeted compounds 6a–i were
Figure 1. Structure of gem-phenyl-(1H-imidazol-1-ylmethyl) moiety.
obtained by the etherification of 5 with the appropriate-
ly substituted benzyl halides in the presence of sodium
hydride.
Keywords: Phenyl; 1H-benzimidazole; Benzyl ether; Antibacterial;
Antifungal.
*
Corresponding author. Tel.: +90 372 2574010; fax: +90 372
574181; e-mail: ozdenozel_guven@yahoo.com
All described benzyl ethers 6a–i were tested in vitro for
8
antibacterial and antifungal activity. According to the
2
0
960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.01.061

¨ ¨
O. Ozel G u¨ ven et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2233–2236
2234
Table 1. Formulas and in vitro antibacterial activities as MIC (lg/mL) for 6a–i
Ar
O
N
N
Compound
Ar
S. aureus
MRSA
ATCC43300
C. albicans
C. krusei
E. coli
ATCC25923
ATCC10231
ATCC6258
ATCC25922
6a
6b
6c
6d
6e
6f
25
25
25
25
25
25
25
25
25
NT
NT
NT
NT
NT
NT
F
12.5
3.12
3.12
6.25
3.12
25
25
Cl
Br
12.5
12.5
12.5
12.5
25
25
CF3
Cl
12.5
25
Cl
Cl
6
6
6
g
h
i
3.12
NT
6.25
NT
12.5
NT
12.5
NT
NT
NT
Cl
Cl
Cl
Cl
Cl
3.12
0.78
—
25
25
—
—
—
12.5
—
25
NT
—
Ampicillin
—
Fluconazole
Miconazole
Ciprofloxacin
0.78
0.19
—
25
—
—
0.78
—
—
—
0.39
NT, not tested, since no clear visible inhibition zone at the disc diffusion method.
obtained results, unexpectedly, the antifungal activity
has been found less than the antibacterial activity of
the synthesized compound 6a–i. Surprisingly, all of the
synthesized compounds 6a–i exhibited good to moderate
activity against Gram-positive bacteria. The best activi-
ties were obtained with the compound 6g which is hav-
ing two chlorine atoms at the ortho positions of the
phenyl ring. Compound 6a without halogen substitution
showed the least activity. Compound 6h was not tested
because of its oily structure. It appears that halogenated
benzyl-substitution enhances the activity and also the
position of halogen substitutions should be effective to
modulate the activity. None of the compounds were
active against Escherichia coli.
Imidazole-substituted benzyl ether derivatives which
have similar structures to those of reported above have
antimycotic as well as antibacterial activity were reported
4
in the literature. We have discovered that introduction
of the benzimidazole moiety instead of imidazole moiety
to the miconazole-type structure allowed us to obtain
the desired good profile of Gram-positive antibacterial

¨
O. Ozel G u¨ ven et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2233–2236
¨
2235
N
N
CH Br
H
CH3
O
2
Br2
3
O
1
2
Ar
OH
O
O
N
N
N
NaBH4
NaH
N
N
N
ArCH X
2
4
5
6a—i
Scheme 1. Synthetic pathway of the targeted compounds 6a–i.
activity against Staphylococcus aureus and MRSA. In
vivo and cytotoxicity studies of the best active com-
pound 6g, are necessary to fully evaluate the potential
of this compound.
reaction mixture was warmed to ambient temperature and
stirred for an additional 18 h then diluted with 20 mL of
water and extracted with chloroform. Organic extract was
dried over anhydrous sodium sulfate, concentrated under
reduced pressure, and chromatographed on neutral silica
gel using (200:1) chloroform–methanol as the eluent. The
ketone (4) (2.85 g) was obtained as yellowish solid and
recrystallized from ethyl acetate–hexane; yield: 60%, mp
Acknowledgments
1
0
À1
1
54–156 °C, lit.
mp 151 °C. IR (KBr): 1673 cm
1
This work was supported by Zonguldak Karaelmas
University Research Fund (Project No.: 2004-13-02-
(C@O); H NMR (400 MHz, CDCl ): d 5.54 (2H, s),
3
7.18–7.32 (3H, m), 7.50–7.58 (2H, t, J = 7.6 Hz), 7.64 (1H,
t, J = 7.6 Hz), 7.84 (1H, d, J = 7.2 Hz), 7.91 (1H, s), 8.05
1
6). Central Laboratory of Pharmacy, Faculty of Ankara
1
3
(
2H, d, J = 7.6 Hz). C NMR (100 MHz, CDCl ): d
University, provided support for acquisition of the
NMR, mass spectrometer, and elemental analyzer used
in this work.
3
5
1
0.59, 109.49, 120.77, 122.57, 123.50, 128.28, 129.40,
34.45, 134.70, 143.78, 144.00, 191.49. ESI (+) m/e 237
(
M+1, 100). Anal. found: C, 75.74; H, 5.08; N, 11.78.
Calcd for C H N OÆ 0.1HOH: C, 75.68; H, 5.17; N,
1
5
12
2
11.77.
2-(1H-Benzimidazol-1-yl)-1-phenylethanol (5) was pre-
References and notes
1
pared according to the literature. Yield: 88%, mp 104–
1
1
1
. Bennett, G. A.; Mullen, G. B.; Mitchell, J. T.; Jones, W.
E.; Allen, S. D.; Kinsolving, C. R.; Georgiev, V. Eur.
J. Med. Chem. 1989, 28, 579.
. Rossello, A.; Bertini, S.; Lapucci, A.; Macchia, M.;
Martinelli, A.; Rapposelli, S.; Herreros, E.; Macchia, B.
J. Med. Chem. 2002, 45, 4903.
. Wahbi, Y.; Caujolle, R.; Tournaire, C.; Payard, M.; Linas,
M. D.; Seguela, J. P. Eur. J. Med. Chem. 1995, 30, 955.
. Godefroi, E. F.; Heeres, J.; Cutsem, J. V.; Janssen, P. A. J.
J. Med. Chem. 1969, 12, 784.
. G o¨ ker, H.; Kus, C.; Boykin, D. W.; Yildiz, S.; Altanlar,
N. Bioorg. Med. Chem. 2002, 10, 2589.
106 °C, H NMR (400 MHz, CDCl ): d 4.22 (1H, dd,
3
J = 14.4, 8.4 Hz), 4.29 (1H, dd, J = 14.0, 3.6 Hz), 5.07 (1H,
dd, J = 8.0, 3.6 Hz), 6.16 (1H, s), 7.10 (1H, t, J = 8.0 Hz),
7.2 (1H, t, J = 7.6 Hz), 7.29–7.43 (7H, m), 7.69 (1H, s).
1
3
2
C
NMR (100 MHz, CDCl ): d 53.25, 72.11, 110.00, 119.60,
3
122.60, 123.29, 126.15, 128.40, 128.97, 133.68, 141.47,
142.30, 143.72. ESI (+) m/e 239 (M+1, 100). Anal. found:
C, 74.57; H, 5.71; N, 11.66. Calcd for C H N OÆ0.15-
3
4
5
6
7
1
5
14
2
HOH: C, 74.76; H, 5.98; N, 11.62.
General procedure for the preparation of benzyl ethers (6a–
i). To a solution of alcohol (5) (0.530 mmol) in 1.2 mL
DMF was added NaH (0.663 mmol) in small fractions.
The appropriate benzyl halide (0.530 mmol) in 0.6 mL
DMF was then added dropwise. The mixture was stirred
at room temperature for 2 h and the excess hydride was
decomposed with a small amount of methyl alcohol. After
evaporation to dryness under reduced pressure, the crude
residue was suspended with water and extracted with
methylene chloride. The organic layer was dried over
anhydrous sodium sulfate and then evaporated to dryness.
The crude residue was purified by chromatography on a
silica-gel column using (50:1) chloroform–methanol as the
eluent to obtain benzyl ethers (6a–i).
¨
. Ozden, S.; Karataßs, H.; Yildiz, S.; G o¨ ker, H. Arch. Pharm.
2
004, 337, 556.
. Experimental. Melting points were recorded on Stuart
Scientific SMP 1 instrument. IR spectra were recorded on
Jasco FT-IR spectrometer, NMR spectra were recorded
on Varian Mercury 400 MHz FT-NMR spectrometer
(
Varian Inc., Palo Alto, CA, USA). The mass spectra
were taken on a Waters ZQ micromass LC-MS spectrom-
eter (Waters Corporation, Milford, MA, USA) by using
ESI (+) method. Elemental analysis was performed on
LECO 932 CHNS (Leco-932, St. Joseph, MI, USA)
instrument and was within ± 0.4% of the theoretical
values.
1-(2-(Benzyloxy)-2-phenylethyl)-1H-benzimidazole (6a).
1
Yield: 69%, mp 60–64 °C. H NMR (400 MHz, CDCl ):
3
2
the literature.
2
1
8
-Bromo-1-phenylethanone (2) was prepared according to
d 4.17 (1H, d, J = 11.6 Hz), 4.48 (1 H, d, J = 11.6 Hz), 4.35
(1H, dd, J = 14.4, 4.0 Hz), 4.43 (1H, dd, J = 14.4, 8.0 Hz),
4.68 (1H, dd, J = 8.0, 4.0 Hz), 6.95–7.05 (2H, m), 7.17–
7.22 (2H, m), 7.24–7.42 (9H, m), 7.82–7.86 (1H, m), 8.06
9
-(1H-Benzimidazol-1-yl)-1-phenylethanone (4). 2-Bromo-
-phenylethanone (2) (4 g, 20.10 mmol) was dissolved in
mL of dioxane–ether (4:1). This solution was added to
1
3
(1H, s). C NMR (100 MHz, CDCl ): d 51.73, 71.05,
3
an ice-cold solution of (3) (11.87 g, 100.5 mmol) in 20 mL
of methanol over 60 min under argon atmosphere. The
79.41, 110.00, 120.27, 122.52, 123.25, 126.94, 127.87,
127.99, 128.61, 129.04, 129.26, 134.03, 137.48, 138.41,

¨ ¨
O. Ozel G u¨ ven et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2233–2236
2236
1
43.00, 143.98. ESI (+) m/e 329 (M+1, 100). Anal. found:
12). Anal. found: C, 66.17; H, 4.63; N, 7.18. Calcd for
22 2 2
C H18Cl N O: C, 66.51; H, 4.57; N, 7.05.
C, 79.51; H, 6.16; N, 8.53. Calcd for C22
C, 79.58; H, 6.19; N, 8.43.
1
azole (6b). Yield: 83%, mp 92–96 °C. H NMR (400 MHz,
CDCl ): d 4.12 (1H, d, J = 11.6 Hz), 4.42 (1H, d,
H
20
2
N OÆ0.2HOH:
1-(2-(2,6-Dichlorobenzyloxy)-2-phenylethyl)-1H-benzimid-
1
-(2-(4-Fluorobenzyloxy)-2-phenylethyl)-1H-benzimid-
azole (6g). Yield: 76%, mp 96–98 °C. H NMR (400 MHz,
1
3
CDCl ): d 4.27 (1H, dd, J = 14.4, 4.0 Hz), 4.35 (1H, dd,
3
J = 14.8, 8.0 Hz), 4.45 (1H, d, J = 10.8 Hz), 4.72 (1H, d,
J = 10.8 Hz), 4.78 (1H, dd, J = 8.0, 4.0 Hz), 7.04–7.10 (1H,
m), 7.15–7.29 (5H, m), 7.33–7.42 (5H, m), 7.75–7.79 (1H, m),
J = 11.6 Hz), 4.36 (1H, dd, J = 14.4, 4.0 Hz), 4.42 (1H,
dd, J = 14.4, 8.0 Hz), 4.67 (1H, dd, J = 8.0, 4.0 Hz), 6.82–
1
3
6
7
5
1
1
3
.88 (2H, m), 6.91–6.97 (2H, m), 7.25–7.44 (8H, m), 7.83–
3
7.90 (1H, s). C NMR (100 MHz, CDCl ): d 51.80, 66.14,
1
3
.88 (1H, m), 8.15 (1H, s). C NMR (100 MHz, CDCl ): d
80.54, 109.79, 120.17, 122.36, 123.08, 126.88, 128.49, 129.01,
129.09, 130.23, 132.97, 133.84, 136.87, 138.39, 142.93,
143.89. ESI (+) m/e 398 (M+1, 100), 399 (M+2+1, 68), 401
(M+4+1, 13). Anal. found: C, 66.63; H, 4.46; N, 7.35. Calcd
for C H Cl N O: C, 66.51; H, 4.57; N, 7.05.
3
1.60, 70.10, 78.97, 109.96, 115.11, 115.32, 119.71, 122.75,
23.36, 126.69, 128.92, 129.09, 129.38, 129.46, 132.92,
33.52, 137.89, 141.69, 143.42, 161.09, 163.54. ESI (+) m/e
47 (M+1, 100). Anal. found: C, 76.26; H, 5.45; N, 8.25.
2
2
18
2
2
Calcd for C22
H
19FN
2
O: C, 76.28; H, 5.53; N, 8.09.
1-(2-(2,5-Dichlorobenzyloxy)-2-phenylethyl)-1H-benzimid-
azole (6h). Yield: 64%, oily. H NMR (400 MHz, CDCl ): d
3
1
1
-(2-(4-Chlorobenzyloxy)-2-phenylethyl)-1H-benzimid-
1
azole (6c). Yield: 73%, mp 114–116 °C. H NMR
4.29 (1H, d, J = 12.8 Hz), 4.44 (1H, d, J = 12.8 Hz), 4.37–
4.52 (2H, m), 4.78 (1 H, dd, J = 8.0, 4.4 Hz), 7.09–7.23 (3H,
(
(
(
400 MHz, CDCl ): d 4.11 (1H, d, J = 11.6 Hz), 4.41
1H, d, J = 11.6 Hz), 4.31 (1H, dd, J = 14.8, 4.0 Hz), 4.39
1H, dd, J = 14.8, 8.4 Hz), 4.63 (1H, dd, J = 8.4,4.0 Hz),
3
1
3
C
m), 7.25–7.44 (8H, m), 7.78–7.85 (1H, m), 8.02 (1H, s).
NMR (100 MHz, CDCl ): d 51.64, 67.93, 80.85, 110.02,
3
6
7
.88 (1H, d, J = 8.4 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.24–
.34 (5H, m), 7.36–7.42 (3H, m), 7.81–7.85 (1H, m), 7.95
120.24, 122.77, 123.51, 126.80, 128.85, 128.93, 129.26,
129.34, 130.47, 130.94, 133.01, 133.94, 137.14, 137.78,
142.54, 143.64. ESI (+) m/e 397 (M+1, 100), 399 (M+2+1,
68), 401 (M+4+1, 13). Anal. found: C, 64.85; H, 4.62; N,
6.72. Calcd for C H Cl N OÆ0.55HOH: C, 64.89; H, 4.72;
13
(
1H, s). C NMR (100 MHz, CDCl
3
): d 51.64, 70.21,
9.40, 109.93, 120.39, 122.53, 123.24, 126.90, 128.71,
7
1
1
29.13, 129.32, 133.73, 133.98, 135.92, 138.16, 143.23,
44.01. ESI (+) m/e 363 (M+1, 100), 365 (M+2+1, 33).
2
2
18
2
2
N, 6.87.
1-(2-(3,4-Dichlorobenzyloxy)-2-phenylethyl)-1H-benzimid-
Anal. found: C, 73.26; H, 5.21; N, 7.84. Calcd for
19ClN O: C, 72.82; H, 5.28; N, 7.72.
-(2-(4-Bromobenzyloxy)-2-phenylethyl)-1H-benzimid-
1
C
1
22
H
2
azole (6i). Yield: 46%, mp 82–86 °C. H NMR (400 MHz,
CDCl ): d 4.10 (1H, d, J = 12.4 Hz), 4.38 (1H, d,
3
1
azole (6d). Yield: 64%, mp 112–116 °C. H NMR
J = 12.8 Hz), 4.34 (1H, dd, J = 14.8, 3.6 Hz), 4.42 (1H, dd,
J = 14.8, 8.0 Hz), 4.65 (1H, dd, J = 8.0, 4.0 Hz), 6.75 (1H, dd,
J = 8.4, 1.6 Hz), 7.11 (1H, d, J = 2.0 Hz), 7.19 (1H, d,
J = 8.4 Hz), 7.24–7.35 (5H, m), 7.37–7.44 (3H, m), 7.81–7.85
(
(
(
3
400 MHz, CDCl ): d 4.09 (1H, d, J = 11.6 Hz), 4.39
1H, d, J = 11.6 Hz), 4.34 (1H, dd, J = 14.8, 4.0 Hz), 4.41
1H, dd, J = 14.8, 8.4 Hz), 4.64 (1H, dd, J = 8.4, 4.0 Hz),
13
6.83 (2H, d, J = 8.8 Hz), 7.22–7.43 (10H, m), 7.84 (1H, d,
J = 8.4 Hz), 8.05 (1H, s). C NMR (100 MHz, CDCl
5
1
1
3
(1H, m), 7.96 (1H, s). C NMR (100 MHz, CDCl ): d 51.58,
1
3
3
): d
69.60, 79.87, 109.93, 120.43, 122.60, 123.33, 126.86, 129.25,
129.37, 129.51, 130.57, 131.86, 132.57, 133.95, 137.75, 137.87,
143.17, 143.90. ESI (+)m/e 397 (M+1, 100), 399 (M+2+1, 71),
401 (M+4+1, 12). Anal. found: C, 66.18; H, 4.48; N, 7.24.
1.71, 70.25, 79.38, 110.05, 120.20, 121.90, 122.76, 123.41,
26.89, 129.16, 129.32, 129.45, 131.66, 133.88, 136.40,
38.07, 142.67, 143.83. ESI (+) m/e 408 (M+1, 100), 410
(
Calcd for C H BrN O: C, 64.87; H, 4.70; N, 6.88.
M+2+1, 100). Anal. found: C, 64.86; H, 4.63; N, 7.06.
2 2
Calcd for C22H18Cl N O: C, 66.51; H, 4.57; N, 7.05.
8. Antimicrobial assay. All described benzyl ethers 6a–i were
tested in vitro for antibacterial activity against Gram-
positive Staphylococcus aureus, Methicillin-resistant
S. aureus (MRSA), Gram-negative Escherichia coli bacteria,
and for anti-fungal activity against Candida albicans and
22
19
2
1
-(2-(4-(Trifluoromethyl)benzyloxy)-2-phenylethyl)-1H-
1
benzimidazole (6e). Yield: 59%, mp 74–76 °C. H NMR
(
400 MHz, CDCl ): d 4.21 (1H, d, J = 12.4 Hz), 4.50 (1H,
3
d, J = 12.4 Hz), 4.36 (1H, dd, J = 14.6, 4.0 Hz), 4.44 (1H,
dd, J = 14.8, 8.4 Hz), 4.66 (1H, dd, J = 8.4, 4.0 Hz), 7.07
5
,6
Candida krusei by the diffusion method. The compounds
giving some growth inhibition zone in this method were
(
m), 8.05 (1H, d, J = 6.4 Hz). C NMR (100 MHz,
2H, d, J = 8.0 Hz), 7.24–7.45 (10H, m), 7.83–7.87 (1H,
1
3
12
further tested by the macro-broth dilution assay to
CDCl ): d 51.68, 70.18, 79.67, 109.99, 120.26, 120.31,
determine their MIC values, which are listed in Table 1.
Since none of the compounds gave any inhibition zone
against the E. coli by the diffusion method, their MIC
values were not determined. The synthesized compounds
3
1
1
1
6
22.71, 122.76, 123.37, 123.41, 125.45, 125.49, 126.89,
27.75, 129.26, 129.38, 133.89, 137.93, 141.49, 142.94,
43.95. ESI (+) m/e 397 (M+1, 100). Anal. found: C,
9.59; H, 4.98; N, 7.09. Calcd for C23
H
19
F
3
2
N O: C, 69.69;
2
and reference drugs were dissolved in DMSO–H O (50%),
H, 4.83; N, 7.07.
-(2-(2,4-Dichlorobenzyloxy)-2-phenylethyl)-1H-benz-
at a concentration of 400 lg/mL. The concentration was
adjusted to 100 lg/mL by fourfold dilution with culture
medium and bacterial solution at the first tube. Data were
not taken for the initial solution because of the high
DMSO concentration (12.5%).
1
1
imidazole (6f). Yield: 54%, mp 84–88 °C. H NMR
(
(
(
3
400 MHz, CDCl ): d 4.20 (1H, d, J = 12.8 Hz), 4.37
1H, d, J = 12.8 Hz), 4.28 (1H, dd, J = 14.8, 4.0 Hz), 4.35
1H, dd, J = 14.8, 8.0 Hz), 4.65 (1H, dd, J = 8.0, 4.0 Hz),
9. Cowper, R. M.; Davidson, L. H. Org. Synth. 1943, 2, 480.
10. Herrling, S.; Keller, H.; Muckter, H. DE Patent 1021850
19580102, 1958.
11. Pellicciari, R.; Curini, M.; Spagnoli, N. Arch. Pharm.
1984, 317, 38.
¨
12. G o¨ ker, H.; Ozden, S.; Yildiz, S.; Boykin, D. W. Eur.
J. Med. Chem. 2005, 40, 1062.
6
7
.92 (1H, d, J = 8.4 Hz), 6.96 (1H, d, J = 8.8, 2.0 Hz),
1
3
.15–7.36 (9H, m), 7.73–7.77 (1H, m), 7.9 (1H, s).
): d 51.67, 67.69, 80.21, 109.93,
20.34, 122.63, 123.33, 126.85, 127.31, 129.23, 129.33,
30.08, 133.74, 133.90, 134.19, 137.95, 142.99, 143.90. ESI
C
NMR (100 MHz, CDCl
1
1
3
(
+) m/e 398 (M+1, 100), 399 (M+2+1, 77), 401 (M+4+1,