Studies on the synthesis of some new substituted benzylamino and phenyl-acrylamido-methyl flavone derivatives

Article abstract of DOI:10.1007/s00044-007-9021-z

The synthesis and biological activity of a new series of 2-{3-[substituted benzylamino-methyl)-phenyl]-4H-benzopyrane-4-one (IVa-e) and N-substituted benzyl-N-[3-(4-oxo-4H-benzopyrane-2-yl)benzyl]-3-phenyl-acrylamide (Va-e) derivatives are reported. The s

Full text of DOI:10.1007/s00044-007-9021-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2007) 16:170–178
DOI 10.1007/s00044-007-9021-z
ORIGINAL RESEARCH
Studies on the synthesis of some new substituted
benzylamino and phenyl-acrylamido-methyl flavone
derivatives
¨
˘
Meltem Ceylan-Unlu¨soy Æ Oya Bozdag-Du¨ndar Æ Nurten Altanlar Æ Rahmiye Ertan
Received: 10 April 2007 / Accepted: 4 June 2007 / Published online: 8 August 2007
¨
ꢀ Birkhauser Boston 2007
Abstract The synthesis and biological activity of a new series of 2-{3-[substituted
benzylamino-methyl)-phenyl]-4H-benzopyrane-4-one (IVa-e) and N-substituted
benzyl-N-[3-(4-oxo-4H-benzopyrane-2-yl)benzyl]-3-phenyl-acrylamide
(Va-e)
derivatives are reported. The synthesized compounds were tested in vitro for anti-
fungal and antibacterial activities. Compound IVa showed the best antifungal
activity compared with miconazole (CAS 22916-47-8). Compound IVc indicated
the best antibacterial activity compared with the control drug ampicillin (CAS 69-
53-4).
Keywords Flavone derivatives ꢀ Antimicrobial activity ꢀ Synthesis
Introduction
Flavonoids are polyphenols that are ubiquitously found in a wide variety of edible
plants, fruits, nuts, seeds, and plant-derived beverages, such as juice and tea
(Seyoum et al., 2006). Additionally, they have been described as health-promoting,
disease-preventing dietary supplements, and have many biological activities as
antibacterial and antiviral agents (Havsteen, 2002). They are extremely safe and
associated with low toxicity, making them excellent candidates for chemopreven-
tive agents (Moon et al., 2006). The cinnamoyl and the benzylamino groups are
¨
˘
M. Ceylan-Unlu¨soy ꢀ O. Bozdag-Du¨ndar ꢀ R. Ertan (&)
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara University, TR-06100
Tandogan, Ankara, Turkey
e-mail: ertan@pharmacy.ankara.edu.tr
N. Altanlar
Faculty of Pharmacy, Department of Microbiology, Ankara University, TR-06100 Tandogan,
Ankara, Turkey

Med Chem Res (2007) 16:170–178
171
´
good pharmacogenic moieties to obtain potent antimicrobial activities (Lopez et al.,
2004; Wang et al., 2006)
The intriguing biological activity and unique structure of these compounds
prompted us to undertake a synthetic study of new flavone derivatives containing
benzylamino and cinnamoyl moieties. Previously, we reported that the synthesis and
antimicrobial evaluation of some new flavone derivatives with cinnamoyl and
benzylamino groups at 40 position showed a comparable activity to that of
ampicillin and miconazole against Escherichia coli and Candida albicans,
˘
respectively (Bozdag-Du¨ndar et al., 2005). As part of our ongoing research, in
this study we explain the synthesis and antimicrobial testing of new flavone
derivatives having N-substituted benzylaminomethyl and N-substituted benzyl-N-
phenyl-acrylamido-methyl at 30 position, with the aim of evaluating the difference
in activity of these isomeric flavonyl compounds.
Materials and methods
Chemistry
Melting points were determined with a Bu¨chi SMP-20 melting-point apparatus
(Bu¨chi, Flawil, Switzerland) and used uncorrected. All the instrumental analyses
were performed by the Instrumental Analysis Laboratory of Scientific and Technical
Research Council of Turkey (Tubitak, Ankara, Turkey), with a Shimadzu IR-470
spectrometer (Jasco, Tokyo, Japan, with IR spectra recorded using potassium
bromide discs), a Bruker DPX 400 nuclear magnetic resonance (NMR) spectrometer
1
[Bruker, Rheinstetten, Germany, with H NMR spectra measured in CDCl3 and all
chemical shifts reported as d(ppm) values], and a VG Platform II Mass spectrometer
(Micromass, Manchester, England). Elementary analyses were performed on a Leco
CHNS 932 analyzer (Leco, St. Joseph, USA) and satisfactory results 0.4% of
calculated values (C, H, and N) were obtained. For the chromatographic analysis
Merck Silica Gel 60 (230-400 mesh ASTM) was used. The chemical reagents used
in the synthesis were purchased from E. Merck (Darmstadt, Germany) and Aldrich
(Milwaukee, MI, USA). 30-Methyl flavone (I) (Cramer and Elsching, 1956), 30-
bromomethyl flavone (II) (Tunc¸bilek and Ertan, 1999) were synthesized according
to the literature.
Chemical synthesis
Synthesis of 30-Bromomethyl flavone (II)
A mixture of N-bromosuccinimide (0.01 mol) and 30-methyl flavone (0.01 mol) (I)
was dissolved in 90 ml carbon tetrachloride, and benzoyl peroxide (0.1 g) was
added. The reaction mixture was refluxed for 7 h and filtered while still hot. The
crude product was crystallized from toluene [II, m.p.: 137ꢁC (Tunc¸bilek and Ertan,
1999)].

172
Med Chem Res (2007) 16:170–178
O
O
O
NBS
Benzoylperoxide
CH2Br
CH3
II
O
I
H2N CH2
X
X2
X1
IIIa-e
'
6
'
5
O
'
4
2'' 3''
B
A
'
2
CH2
N
H
CH2
X
O
X2
X2=H, Cl
X=H, F, Cl, Br, NO2
X1
IVa-e
X1=H, Cl
CH CH COCl
O
O
O
C
CH CH
CH2
N
CH2
X
X2
X1
Va-e
Scheme 1 General synthesis of compounds IVa-e and Va-e
Synthesis of compounds IVa-e
30-Bromomethyl flavone (II) (0.01 mol) and substituted benzylamine derivatives
(IIIa-e) (0.01 mol) were stirred in 5 ml dimethyl formamide (DMF) and NaH (0.01
mol) under a nitrogen atmosphere at room temperature for two days (Scheme 1).
The mixture was diluted with water and filtered. The filtrate was purified by column
chromatography using silica gel 60 (230–400 mesh ASTM) as the adsorbent and
CHCl3 as the eluent.
2-[3-(benzylamino-methyl)-phenyl]-4H-benzopyrane-4-one (IVa)
Yield (%): 45.6, m.p.: 188ꢁC. Spectroscopic analysis: IR (KBr) tmax/cmꢁ1: 1644 (c
pyrone CO); 1H-NMR (CDCl3, 400 MHz, d, ppm): 3.89 (s, 2H, A), 3.95 (s, 2H, B),
6.88 (s, 1H, 3-H), 7.29ꢁ7.42 (m, 5H, Ar-H), 7.45 (ddd, 1H, 6-H), 7.48–7.58 (m, 2H,
40, 50-H), 7.62 (d, 1H, j8,7 = 7.94 Hz, 8-H), 7.74 (ddd, 1H, 7-H), 7.85 (dd, 1H, 60-H),

Med Chem Res (2007) 16:170–178
173
7.97 (s, 1H, 20-H), 8.27 (dd, 1H, j5,6 = 7.94 Hz, j5,7 = 1.59 Hz, 5-H). MS (70 eV) m/
z: 341.7 (M+), 250, 235, 221, 121, 120, 106, 105, 102, 101, 92, 64, 63, 57, 43.3
(100%); anal. calcd. for C23H19NO2•0.3H2O C:79.68, H:5.66, N:4.04%; found:
C:79.74, H:5.41, N:3.92%.
2-{3-[(4-fluoro-benzylamino-methyl)-phenyl]-4H-benzopyrane-4-one (IVb)
Yield (%): 25.9, m.p.:86–88ꢁC. Spectroscopic analysis: IR (KBr) tmax/cmꢁ1: 1640
(c pyrone CO); 1H-NMR (CDCl3, 400 MHz, d, ppm): 3.82 (s, 2H, A), 3.89 (s, 2H,
B), 6.84 (s, 1H, 3-H), 7.00ꢁ7.05 (m, 2H, 2@,6@-H), 7.32–7.35 (m, 2H, 3@,5@-H), 7.42
(ddd, 1H, 6-H), 7.46ꢁ7.54 (m, 2H, 40, 50-H), 7.58 (d, 1H, j8,7 = 8.40 Hz, 8-H), 7.71
(ddd, 1H, 7-H), 7.82 (dd, 1H, 60-H), 7.92 (s, 1H, 20-H), 8.23 (dd, 1H, j5,6 = 8.00 Hz,
j
5,7 = 1.60 Hz, 5-H). MS (70 eV) m/z: 358.6 (M+), 250.1, 221.9, 123.0, 120.0, 109.1,
94.8, 92.0, 62.7 (100%); anal. calcd. for C22H18FNO2•0.3H2O C:75.65, H:5.09,
N:3.84%; found: C:75.65, H:4.69, N:3.84%.
2-{3-[(4-chloro-benzylamino-methyl)-phenyl]-4H-benzopyrane-4-one (IVc)
Yield (%): 65.6, m.p.: 88ꢁC. Spectroscopic analysis: IR (KBr) tmax/cmꢁ1: 1635 (c
pyrone CO) 1H-NMR (CDCl3, 400 MHz, d, ppm): 3.87 (d, 2H, A), 3.93 (d, 2H, B),
6.85 (s, 1H, 3-H), 7.21ꢁ7.62 (m, 6H, 2@, 6@, 6, 40, 50, 8-H), 7.73 (ddd, 1H, 7-H), 7.88
(dd, 1H, 60-H), 7.92 (d, 2H, 3@,5@-H), 8.02 (s, 1H, 20-H), 8.25 (dd, 1H, 5-H). MS (70
eV) m/z: 375 (M+), 376 (M+1), 377 (M+2), 250.1, 221.9, 123.0, 120.0, 109.1, 94.8,
92.0, 62.7 (100%); anal. calcd. for C22H18ClNO2•0.1H2O C:73.25, H:4.83,
N:3.72%; found: C:72.99, H:4.75, N:3.64%.
2-{3-[2,4-dichloro-benzylamino-methyl)-phenyl]-4H-benzopyrane-4-one (IVd)
Yield (%): 53.1, m.p.: 119ꢁC. Spectroscopic analysis: IR (KBr) tmax/cmꢁ1: 1633 (c
pyrone CO) 1H-NMR (CDCl3, 400 MHz, d, ppm): 3.95 (s, 2H, A), 3.97 (s, 2H, B),
6.86 (s, 1H, 3-H), 7.27 (dd, 1H, 3@-H), 7.41–7.58 (m, 5H, 2@, 5@, 6, 40, 50-H), 7.61 (d,
1H, j8,7 = 8.28 Hz, 8-H), 7.73 (ddd, 1H, 7-H), 7.85 (dd, 1H, 60-H), 8.00 (s, 1H, 20-H),
8.25 (dd, 1H, j5,6 = 7.95 Hz, j5,7 = 1.54 Hz, 5-H); MS (70 eV) m/z: 409.9 (M+),
410.9 (M+1), 412 (M+2), 236.1 (100%), 220.9, 161.1, 159.1, 121.2, 120.1, 92.2, 63.2;
anal. calcd. for C22H17Cl2NO2 C:67.32, H:4.18, N:3.41%; found: C66.92, H:4.59,
N:3.32%.
2-{3-[3,4-dichloro-benzylamino-methyl)-phenyl]-4H-benzopyrane-4-one (IVe)
Yield (%): 48.0, m.p.: 117ꢁC. Spectroscopic analysis: IR (KBr) tmax/cmꢁ1: 1633 (c
pyrone CO); 1H-NMR (CDCl3, 400 MHz, d, ppm): 3.88 (s, 2H, A), 3.95 (s, 2H, B),
6.89 (s, 1H, 3-H), 7.42ꢁ7.57 (m, 6H, 2@, 3@, 6@, 6, 40, 50-H), 7.61 (d, 1H, j8,7 = 8.43

174
Med Chem Res (2007) 16:170–178
Hz, 8-H), 7.75 (ddd, 1H, 7-H), 7.85 (dd, 1H, 60-H), 8.00 (s, 1H, 20-H), 8.25 (dd, 1H,
5,6 = 7.97 Hz, j5,7 = 1.51 Hz, 5-H).MS (70 eV) m/z: 409.9 (M+), 412.1 (M+2), 413.5
j
(M+3), 250.2 (100%), 235.7 (100%), 220.9, 161.1, 159.1, 121.2, 120.1, 92.2, 63.2
anal. calcd. for C22H17Cl2NO2•0.4H2O C:66.16, H:4.27, N3.36%; found: C:65.97,
H:4.36, N:3.37%.
Synthesis of compounds Va-e
IVa-e (0.01 mol) and cinnamoyl chloride (0.01 mol) were stirred in 5 ml of dioxane/
N(C2H5)3 (0.01 mol) at room temperature for 24 h (Scheme 1). The mixture was
diluted with water and filtered. The filtrate was purified by column chromatography
using silica gel 60 (230ꢁ400 mesh ASTM) as the adsorbent and CH2Cl2:n-hexane
(2:1) as the eluent.
N-benzyl-N-[3-(4-oxo-4H-benzopyrane-2-yl)benzyl]-3-phenyl-acrylamide (Va)
Yield (%): 60.0, m.p.: 95ꢁC. Spectroscopic analysis: IR (KBr) tmax/cmꢁ1: 1646 (c
pyrone CO); 1H-NMR (CDCl3, 400 MHz, d, ppm): 4.70 (d, 2H, A), 4.79 (d, 2H, B),
6.81 (s, 1H, 3-H), 6.95 (d, 1H, =CH-Ar), 7.34–7.50 (m, 13H, 6,40,50,60,10-Ar-H),
7.57 (d, 1H, j8,7 = 8.40 Hz, 8-H), 7.70 (ddd, 1H, 7-H), 7.78 (d, 1H, =CH-CO), 7.87
(dd, 1H, 60-H), 7.92 (s, 1H, 20-H),8.23 (dd, 1H, j5,6 = 8.40 Hz, j5,7 = 1.60 Hz, 5-H);
MS (70 eV) m/z: 471.4 (M+), 472.3 (M+1), 235.9, 223.9, 131.0, 121.2, 91 (100%),
76.8, 63.0; anal. calcd. for C32H25NO3•0.3H2O C:80.50, H:5.36, N:2.93%; found:
C:80.17, H:5.70, N:2.63%.
N-(4-fluoro-benzyl)-N-[3-(4-oxo-4H-benzopyrane-2-yl)benzyl]-3-phenyl-
acrylamide (Vb)
Yield (%): 37.2, m.p.: 126–128ꢁC. Spectroscopic analysis: IR (KBr) tmax/cmꢁ1
:
1642 (c pyrone CO); 1H-NMR (CDCl3, 400 MHz, d, ppm): 4.72 (t, 4H, A, B), 6.82
(s, 1H, 3-H), 6.91 (dd, 1H, =CH-Ar), 7.03ꢁ7.12 (m, 2H, 2@, 6@-H), 7.22 (ddd, 1H, 6-
H), 7.27ꢁ7.55 (m, 9H, 40,50,3@, 5@, 5-Ar-H), 7.58 (d, 1H, j8,7 = 8.00 Hz, 8-H), 7.70
(ddd, 1H, 7-H), 7.78 (d, 1H, =CH-CO), 7.86–7.92 (m, 2H, 20,60-H), 8.24 (dd, 1H,
j
5,6 = 7.60 Hz, j5,7 = 1.60 Hz, 5-H); MS (70 eV) m/z: 490.3 (M+1) (100%), 301.4,
278.4, 235.4, 131.3, 109.1; anal. calcd. for C32H24FNO3•1.4H2O C:74.68, H:5.21,
N:2.72%; found: C:74.76, H:5.43, N:2.49%.
N-(4-chloro-benzyl)-N-[3-(4-oxo-4H-benzopyrane-2-yl)benzyl]-3-phenyl-
acrylamide (Vc)
Yield (%): 47.0, m.p.: 129ꢁC. Spectroscopic analysis: IR (KBr) tmax/cmꢁ1: 1631
(c pyrone CO); 1H-NMR (CDCl3, 400 MHz, d, ppm): 4.72 (t, 4H, A, B), 6.81

Med Chem Res (2007) 16:170–178
175
(s, 1H, 3-H), 6.89 (d, 1H, =CH-Ar), 7.2 (d, 2H, 2@, 6@-H), 7.24–7.57 (m, 11H,
40,50,6,8, 3@, 5@, 5-Ar-H), 7.68 (ddd, 1H, 7-H), 7.77 (d, 1H, = CH-CO), 7.88 (dd,
1H, 60-H), 7.92 (s, 1H, 20-H), 8.22 (d, 1H, j5,6 = 7.60 Hz, 5-H); MS (70 eV) m/z:
505 (M+), 506.3 (M+1) (100%), 507 (M+2), 301.4, 235.4, 149.4, 147.5, 125.3,
86.0, 69.0; anal. calcd. for C32H24ClNO3 0.3 Hexane C:76.30, H:5.31, N:2.64%;
found: C:76.30, H:5.60, N:2.68%.
N-(2,4-dichloro-benzyl)-N-[3-(4-oxo-4H-benzopyrane-2-yl)benzyl]-3-phenyl-
acrylamide (Vd)
Yield (%): 60.7, m.p.: 98ꢁC. Spectroscopic analysis: IR (KBr) tmax/cmꢁ1: 1636 (c
pyrone CO); 1H-NMR (CDCl3, 400 MHz, d, ppm): 4.75 (d, 2H, A), 4.83 (d, 2H, B),
6.75 (d, 1H, =CH-Ar), 6.82 (s, 1H, 3-H), 6.92ꢁ7.51 (m, 11H, 6,40,50,2@,3@,5@,5-Ar-
H), 7.58 (d, 1H, j8,7 = 8.40 Hz, 8-H), 7.71 (ddd, 1H, 7-H),7.80 (d, 1H, =CH-CO),
7.86–7.92 (m, 2H, 20,60-H), 8.24 (d, 1H, j5,6 = 7.60 Hz, 5-H); MS (70 eV) m/z: 540.2
(M+1) (100%), 541 (M+2), 542.3 (M+3), 301.4, 235.4, 197.3, 161.4, 131.3, 121.2,
102.1, 69.0; anal. calcd. for C32H23Cl2NO3•0.6 Hexane C:72.21, H:5.31, N:2.36%;
found: C:72.32, H:5.66, N:2.08%.
N-(3,4-dichloro-benzyl)-N-[3-(4-oxo-4H-benzopyrane-2-yl)benzyl]-3-phenyl-
acrylamide (Ve)
Yield (%): 50.6, m.p.: 148ꢁC. Spectroscopic analysis: IR (KBr) tmax/cmꢁ1: 1635 (c
pyrone CO); 1H-NMR (CDCl3, 400 MHz, d, ppm): 4.72 (d, 2H, A), 4.82 (d, 2H, B),
6.87 (s, 1H, 3-H), 6.97 (d, 1H, =CH-Ar), 7.13 (d, 1H, ja,b=8.80 Hz, 2@-H), 7.22 (d,
1H, jb,a=7.6 Hz, 3@-H), 7.32–7.64 (m, 10H, 40,50,6,8,6@,5-Ar-H), 7.75 (ddd, 1H, 7-
H), 7.83 (d, 1H, =CH-CO), 7.90ꢁ7.95 (m, 1H, 60-H), 7.99 (s, 1H, 20-H), 8.29 (d, 1H,
j
5,6 = 8.00 Hz, 5-H); MS (70 eV) m/z: 540.3 (M+1), 541 (M+2), 542.3 (M+3), 301.4,
261.3, 197.3, 175.3, 99.1 (100%); anal. calcd. for C32H23Cl2NO3 C:71.12, H:4.29,
N:2.59%; found: C:71.37, H:4.17, N:2.54%.
Antimicrobial activity
The disk diffusion method was used for assessing antibacterial activity against
Staphylococcus aureus ATCC 250 (American Type Culture Collection, Manas-
sas, VA, USA), Escherichia coli RSKK 313 (Refik Saydam Ku¨ltu¨r Kolleksiyon,
Ankara, Turkey) and antifungal activity against Candida albicans RSKK 628
(Refik Saydam Ku¨ltu¨r Kolleksiyon, Ankara, Turkey). Cultures of each bacteria
and yeast strain, kept in Mueller-Hinton broth (Difco, Detroit, MI, USA), at
37ꢁC for 18ꢁ24 h and diluted with the same broth to 105 cfu/ml, were pipetted
into the Mueller-Hinton agar (Difco) plates prepared according to the procedure.
Paper disks (8 mm in diameter) embedded into 3000 lg.mlꢁ1 compound solution
were put onto the surface of the inoculated plates, placed in an incubator at

176
Med Chem Res (2007) 16:170–178
37ꢁC for 18ꢁ24 h, and then examined. Most of the compounds were found to be
effective against the tested microorganisms by measuring the diameter of the
growth inhibition zone according to Bauer et al. (1966).
Results and discussion
The general Baker-Venkataraman method (Cramer and Elsching, 1956) was used to
prepare 30-methyl flavone (I). The methyl group of the flavone was converted to
bromomethyl with N-bromosuccinimide and a catalytic amount of benzoyl
peroxide. The derivatives IVa-e were synthesized starting with bromomethylflavone
(II) and treating with the appropriate substituted benzylamine derivatives (IIIa-e) in
the presence of NaH/DMF under a nitrogen atmosphere. Compounds Va-e were
obtained reacting with cinnamoyl chloride and IVa-e in dioxane/N(C2H5)3
(Scheme 1). The structure of N-substituted benzylaminomethyl (IVa-e) and N-
substituted benzylcinnamamidomethyl flavone derivatives (Va-e) was elucidated by
1
elementary analysis, H-NMR, mass spectral data, and infrared (IR) findings. All
spectral data were in accordance with assumed structures. IR spectra of the
compounds showed c-pyrone C=O stretching bonds at 1631ꢁ1646 cmꢁ1. In the 1H-
NMR spectra, characteristic flavone protons were observed between 6.81 and 8.29
ppm. Benzylic CH2 protons for IVa-e and Va-e, A and B were observed at 3.82–
3.95 and 3.89–3.97 ppm as a singlet except IVc (observed as a doublet), 4.70–4.75
and 4.79–4.83 ppm as a doublet except Vb-c (observed as a triplet A+B),
respectively. In the mass spectra, N-substituted benzylaminomethyl (IVa-e) flavone
derivatives have molecular (M+) ion peaks. The compounds IVc, IVd, Va-e have
M+1, the compounds IVc-e, Vc-e have M+2, and the compounds IVe, Vd-e have M+3
ion peaks.
All of the new compounds were tested for their antimicrobial activity by the agar
diffusion method (Bauer et al., 1966), using Candida albicans, Staphylococcus
aureus, and Escherichia coli, comparing their activities with those of miconazole
and ampicillin (Table 1). The resulting inhibition zones against Candida albicans,
Staphylococcus aureus, and Escherichia coli were 10–25 mm, 10–25 mm, and 10–
12 mm, respectively. Compounds IVa, IVe, and Vc exhibited activity against
Escherichia coli (inhibition zones: 10, 12, and 12 mm, respectively). Compound
IVc showed high activity against Staphylococcus aureus (inhibition zone: 25 mm).
Compounds IVa-e and Va were active against S. aureus (inhibition zones: 16, 15,
25, 10, 16, and 10 mm, respectively), while Vb-e was inactive. Beside, the
benzylaminomethyl flavone derivatives IVa-e were found to be more active than
cinnamoyl flavone derivatives Vb-e against S. aureus.
Compound IVa showed high activity against Candida albicans (inhibition zone:
25 mm). Compounds IVd-Va-b were inactive against Candida albicans. However,
surveying the values for C. albicans it should be pointed out that flavonyl
compounds showed more activity than the tested bacteria except compounds IVa-e,
Va against S. aureus.

Med Chem Res (2007) 16:170–178
177
Table 1 Antimicrobialactivities(quotedasgrowthinhibitiondiameterinmm)ofcompoundsIVa-eandVa-e
O
R
CH2
N
O
CH2 Ar
Compound
IVa
Ar
R
C. albicans
S. aureus
E. coli
-H
25
16
10
IVb
IVc
IVd
IVe
Va
-H
-H
-H
-H
20
15
*
15
25
10
16
10
*
*
F
*
Cl
Cl
*
Cl
10
*
12
*
Cl
Cl
O
C
CH CH
CH CH
Vb
*
*
O
C
F
Vc
Vd
13
15
*
*
12
*
O
C
Cl
Cl
CH CH
CH CH
O
C
Cl
Ve
15
*
*
O
C
CH CH
Cl
Miconazole
Ampicillin
35
–
–
–
Cl
30
20
*No activity. -: Not tested

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Med Chem Res (2007) 16:170–178
Acknowledgements This work was supported by Scientific and Technical Research Council of Turkey
(TUBITAK, Ankara, Turkey, project no. SBAG-AYD-360)
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