Synthesis and antimicrobial activity of (E) stilbene derivatives

Article abstract of DOI:10.1016/j.bmc.2011.07.015

Plants use multiple defence mechanisms comprising both constitutive and inducible barriers to prevent entering of phytopathogenic micro-organisms. In many plant species one of the most efficient responses to combat attacking microbes is the rapid synthesis of antimicrobial low molecular weight phytoalexins, for example, resveratrol, 3,5,4′-trihydroxystilbene (1). Resveratrol and its natural derivatives, however, display only moderate antimicrobial effects. Nevertheless, resveratrol may be a useful lead structure for the chemical synthesis of antimicrobials. In this study, several series of stilbenes have been synthesized, starting from the aldehydes using Wittig reactions to access the corresponding styrenes that were subjected to Mizoroki-Heck reactions to yield the stilbenes in good yields. The stilbenes were tested in an agar diffusion assay against several bacteria and fungi. For some of these compounds the inhibiting zones for bacteria and fungi were comparable with those of the antibiotics tetracycline, streptomycin, ampicillin, or kanamycin, directed against prokaryotes, and nourseothricin or hygromycin controlling fungi, respectively.

Full text of DOI:10.1016/j.bmc.2011.07.015

Bioorganic & Medicinal Chemistry 19 (2011) 5155–5166
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and antimicrobial activity of (E) stilbene derivatives
Sabrina Albert a, Ralf Horbach b, Holger B. Deising b, Bianka Siewert a, René Csuk a,
⇑
a Bereich Organische Chemie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany
b Interdisziplinäres Zentrum für Nutzpflanzenforschung IZN, Martin-Luther-Universität Halle-Wittenberg, Betty-Heimann-Str. 3, D-06120 Halle (Saale), Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Plants use multiple defence mechanisms comprising both constitutive and inducible barriers to prevent
entering of phytopathogenic micro-organisms. In many plant species one of the most efficient responses
to combat attacking microbes is the rapid synthesis of antimicrobial low molecular weight phytoalexins,
for example, resveratrol, 3,5,40-trihydroxystilbene (1). Resveratrol and its natural derivatives, however,
display only moderate antimicrobial effects. Nevertheless, resveratrol may be a useful lead structure
for the chemical synthesis of antimicrobials. In this study, several series of stilbenes have been synthe-
sized, starting from the aldehydes using Wittig reactions to access the corresponding styrenes that were
subjected to Mizoroki–Heck reactions to yield the stilbenes in good yields. The stilbenes were tested in an
agar diffusion assay against several bacteria and fungi. For some of these compounds the inhibiting zones
for bacteria and fungi were comparable with those of the antibiotics tetracycline, streptomycin, ampicil-
lin, or kanamycin, directed against prokaryotes, and nourseothricin or hygromycin controlling fungi,
respectively.
Received 5 June 2011
Revised 7 July 2011
Accepted 10 July 2011
Available online 19 July 2011
Keywords:
Antimicrobial compounds
Phytoalexins
Stilbenes
Mizoroki–Heck reaction
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Plants in their natural environment are challenged by many
potentially damaging organisms including viruses, nematodes, bac-
teria, fungi and insects. To perceive and combat biotic attack plants
have devised sophisticated constitutive and inducible defence
mechanism. As part of a preformed front-line defence plants pro-
duce cutin, suberin, waxes, lignin, cellulose and cell wall proteins
which form a structural barrier preventing the invasion of microbial
pathogens.1 In addition, preformed compounds like saponins, gluc-
osinolates or cyanogenic glycosides, some of which occur as inac-
tive precursors that are immediately activated in response to
tissue damage or pathogen attack, confer basic resistance.2
As a second line of defence, post-infectional mechanisms are
activated which depend on specific receptors that recognize path-
ogen-associated molecular pattern (PAMPs), and transduce the
information by signal cascades. This results in rapid stress re-
sponses such as forming reactive oxygen species (ROS), the initia-
tion of hypersensitive cell death, and the de novo synthesis of
pathogenesis-related proteins and toxic phytoalexins.3–6
Figure 1. Structure of trans-resveratrol (1).
70 further species.7–9 In wood, however, 1 is produced constitu-
tively and acts as a phytoanticipin.10
Antifungal properties of 1 and its naturally occurring deriva-
tives against various pathogens including Cladosporium cuccumeri-
num, Pyricularia oryzae, Plasmopara viticola, Botrytis cinerea and
Sphaeropsis sapinea have been described. MIC values of up to
200 lg/ml, however, raised the question whether 1 should be con-
sidered as a precursor of compounds displaying higher fungitoxic-
ity, for example of viniferins or pterostilbenes, rather than as a
phytoalexin [11 and reference citations therein].
Fungal pathogens may avoid the inhibitory effect of stilbenes by
oxidative degradation. Resveratrol detoxification by extracellular
laccases has been reported12 and may represent a mechanism that
contributes to fungal virulence. Conceivably, the natural stilbenes
appear to be not suitable for the chemical control of pathogenic
fungi. To overcome this problem, however, substituted resveratrol
analogues that are not prone to oxidative degradation may repre-
sent excellent lead structures to develop agents allowing efficient
control of various plant pathogenic bacteria and fungi.
The stilbene trans-resveratrol (1, Fig. 1) is a phytoalexin being
produced in response to environmental stresses such as wounding
or pathogen attack. It was first isolated from the White hellebore
(Veratrum grandiflorum O. Loes) but can also be found in Japanese
knotweed (Polygonum cuspidatum syn. Fallopia japonica) and about
⇑
Corresponding author. Tel.: +49 345 55 25660; fax: +49 345 55 27030.
E-mail address: rene.csuk@chemie.uni-halle.de (R. Csuk).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.07.015

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S. Albert et al. / Bioorg. Med. Chem. 19 (2011) 5155–5166
Scheme 1. Synthesis of substituted styrenes by Wittig olefination and of the 4-hydroxy substituted stilbenes 16–23 by Mizoroki–Heck reactions. Reagents and conditions: (a)
H3CP(C6H5)3I, tBuOK, THF, 24 h, 25 °C; (b) triethanolamine, Pd(II) acetate, 24 h, 100 °C.
Scheme 2. Synthesis of substituted styrenes by Wittig olefination and of 3-hydroxy substituted stilbenes 24–31 by Mizoroki–Heck reactions. Reagents and conditions: (a)
H3CP(C6H5)3I, tBuOK, THF, 24 h, 25 °C; (b) triethanolamine, Pd(II) acetate, 24 h, 100 °C.

S. Albert et al. / Bioorg. Med. Chem. 19 (2011) 5155–5166
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2. Chemistry
Stilbenes and stilbenoids have long been in the focus of scien-
tific interest, and the number of publications on stilbenes exceeds
32.000.13 Therefore, many synthetic routes to stilbene derivatives
have been elaborated, among them Aldol-type condensations,14
Perkin reactions,15,16 Wittig-type reactions,17,18 the reductive cou-
pling of carbonyl compounds (e.g., by McMurry reactions19), and
more recently precious metal catalysed Negishi–Stille couplings20
and Mizoroki–Heck reactions.21,22
Mizoroki–Heck reactions can be performed under a great
variety of conditions.23–25 The use of triethanolamine acting simul-
taneously as a base, a ligand and as a solvent allows the straightfor-
ward and economic synthesis of substituted stilbenes-mainly of (E)
configuration.26,27
Thus, reaction of substituted benzaldehydes 2–7 with methyl-
t
triphenylphosphonium bromide in the presence of BuOK28 in a
Wittig reaction (Scheme 1) provided the matching styrene deriva-
tives 8–13 and 15; styrene 14 and 15 was prepared according to
literature.28 Their Mizoroki–Heck reactions with substituted iodo
(or bromo) benzenes gave the matching (E) stilbenes in good
yields. Scheme 1 depicts the synthesis of the 4-hydroxy substituted
stilbenes 16–23.
Scheme 4. Synthesis of the 3-hydroxy substituted stilbenes 36–40 by Mizoroki–
Heck reactions. Reagents and conditions: (a) triethanolamine, Pd(II) acetate, 24 h,
100 °C.
3-Hydroxybenzaldehyde (3, Scheme 2) served as a starting
material for the synthesis of 3-hydroxystyrene (9) and was ob-
tained by a Wittig reaction in 68% isolated yield. Compound 9
was used as a starting material for Mizoroki–Heck reactions using
iodo (or bromo) benzenes, and stilbenes 24–31 were obtained.
In a similar manner, from 2-hydroxybenzaldehyde (4, Scheme
3) 2-hydroxystyrene (10) was obtained in 65% yield whose Mizor-
oki–Heck reaction with substituted iodo (or bromo) benzenes
yielded the stilbenes 32–35.
representative of actinobacteria. The activity of the stilbenes was
compared with well-established antibiotics, that is, streptomycin,
tetracycline and the aminoglycoside antibiotic kanamycin as well
as the b-lactame antibiotic ampicillin. As shown in Figure 2 all
the 4-hydroxylated stilbenes 16–23 (except compound 17) show
antibacterial activity against B. brevis. The inhibiting areolae are
comparable with those obtained from treating the bacteria with
tetracycline. Compound 17 acts in a selective manner against M. lu-
teus whereas compound 23 is a selective antibiotic against bacte-
ria. None of these compounds, however, displays activity against
Gram-negative Enterobacter.
For comparison, the 20,50-dihydroxylated stilbenes 36 and 37
(Scheme 4, from 2,5-dihydroxy-iodobenzene and 6-fluoro-3-hy-
droxy-4-methoxystyrene (15) or from 3,4-dihydroxystyrene (13),
respectively), as well as analogs 38–40 were prepared.
The 3-hydroxystilbenes 24–31 are active (Fig. 3) against bacilli
and M. luteus. The highest activity is found for the trifluoro com-
pound 27. The corresponding 2-hydroxystilbenes 32–35, however,
show similar activity against all the strains (Fig. 4).
3. Results and discussion
To compare the antibacterial/antifungal activity of the stilbenes,
the effect of the compounds on the growth of several bacteria and
fungi was evaluated in agar diffusion tests.
Bacillus subtilis and Bacillus brevis were chosen as representa-
tives of Gram-positive bacteria, Enterobacter dissolvens as an exam-
ple for a Gram-negative bacterium, and Micrococcus luteus as
These data suggest that all stilbenes that do not show a mono-
hydroxy-substitution on ring A are only active when the com-
pounds have a 20,50-dihydroxy substitution in ring B. Figure 5
summarizes6 the activity of all 20,50-dihydroxylated stilbenes in
this study (22, 30, 34, 36, 37 and 39). The highest activity is found
for compound 36.
Scheme 3. Synthesis of substituted styrenes by Wittig olefination and of 2-hydroxy substituted stilbenes 32–35 by Mizoroki–Heck reactions. Reagents and conditions: (a)
H3CP(C6H5)3I, tBuOK, THF, 24 h, 25 °C; (b) triethanolamine, Pd(II) acetate, 24 h, 100 °C.

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S. Albert et al. / Bioorg. Med. Chem. 19 (2011) 5155–5166
Figure 2. Inhibition zone [diameter in mm] of 4-hydroxystilbenes 16–23 against bacteria (standards: streptomycin, ampicillin, tetramycin, kanamycin).
Figure 3. Inhibition zone [diameter in mm] of 3-hydroxystilbenes 24–31 against bacteria (standards: streptomycin, ampicillin, tetramycin, kanamycin).
Figure 4. Inhibition zone (diameter in mm) of 2-hydroxystilbenes 32–35 against bacteria (standards: streptomycin, ampicillin, tetramycin, kanamycin).

S. Albert et al. / Bioorg. Med. Chem. 19 (2011) 5155–5166
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Figure 5. Inhibition zone (diameter in mm) of 20,50di-hydroxystilbenes 22, 30, 34, 36, 37 and 39 against bacteria (standards: streptomycin, ampicillin, tetramycin,
kanamycin).
To evaluate antifungal activity, agar diffusion tests using the fol-
lowing fungi were performed: Nematospora coryli (a plant patho-
gen infesting fruit trees, cotton and vegetables (e.g., tomatoe),
Rhizomucor miehei, Penicillium notatum, Colletotrichum graminicola
(a fungus causing anthracnosis of maize) as well as B. cinerea.
Figure 6 shows the results for the 4-hydroxystilbenes 16–23; all
compounds (except 17) show activity comparable to that of well-
established noursethricin and hygromycin. Compound 22 is even
more active than the commercial antifungals. Compound 19 shows
activity against N. coryli, too. None of these compounds, however,
shows significant activity against B. cinerea.
In the series of the 3-hydroxystilbenes, compound 27 (Fig. 7) is
active against Mucor miehei. The activities of the 2-hydroxystilb-
enes are lower (Fig. 8); compound 33, however, exhibits significant
activity against all the strains. Compounds 38–40 are selective
inhibitors; the same seems true for the 20,50-dihydroxylated stilb-
enes 22, 30, 34 and 35 (Fig. 9).
been shown that the activity of a fungal tyrosinase is inhibited by
resveratrol and some of its analogs.29,30 Whereas methoxylated
derivatives exhibited a significant antifungal activity, activity of
these compounds is low against bacteria. Stilbenes containing at
least one hydroxyl group exhibited inhibitory activity against bac-
teria—but this result is not surprising because phenolic com-
pounds are viewed as one of the major classes of natural
antimicrobial agents. The mechanisms thought to be responsible
include enzyme inhibition through reaction with sulfhydryl
groups and through more non-specific interactions with the pro-
teins.31,32 Our results parallel some recent findings observed for
stilbenes and their ability to inhibit methicillin-resistant Staphylo-
coccus aureus strains.33
Addition of fluorine substituents enhanced the antibacterial ef-
fect compared to other compounds; this may be due to the overall
change in the partion coefficient resulting in a higher permeability
of the compounds into the membrane rather than a direct effect of
the substitution.34,35 Direct damage of the bacteria cell membrane,
however, cannot be excluded since several wine phenolics36 were
Little is known about the antimicrobial action of stilbenes on a
molecular level. As far as an antifungal activity is concerned it has
Figure 6. Inhibition zone [diameter in mm] of selected 4-hydroxystilbenes 16, 18, 19, 21, 22 and 23 against fungi (standards: noursethricin and hygromycin).

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S. Albert et al. / Bioorg. Med. Chem. 19 (2011) 5155–5166
Figure 7. Inhibition zone [diameter in mm] of selected 3-hydroxystilbenes 24, 26, 27, 29–31 against fungi (standards: noursethricin and hygromycin).
Figure 8. Inhibition zone [diameter in mm] of selected 2-hydroxystilbenes 32–35 against fungi (standards: noursethricin and hygromycin).
Figure 9. Inhibition zone [diameter in mm] of selected 20,50di-hydroxystilbenes 22, 30, 36, 37 and 39 against fungi (standards: noursethricin and hygromycin).

S. Albert et al. / Bioorg. Med. Chem. 19 (2011) 5155–5166
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Table 1
5.1.2. General procedure for the Mizoroki–Heck reactions
Biological activity (cytotoxicity, NiH3T3 mouse embryonic fibroblasts, IC50 in
from SRB assay) of compounds 1 and 16–40 (error: 5%)
lm,
A mixture of the styrene (3 mmol), the halogenated benzene
(3 mmol), triethanolamine (3 mmol) and Pd(II) acetate (0.03 g)
was stirred under argon at 100 °C for 24 h. The reaction was cooled
to 25 °C, quenched by the addition of dil. aq. hydrochloric acid (2 N,
10 ml), and extracted with ether (3 ꢀ 100 ml). The organic phases
were dried (Na2SO4), the solvents evaporated, and the crude prod-
uct subjected to chromatography (silica gel, hexane/ethyl acetate
mixtures).
1
>30
16
12.2
17
24.2
18
11.5
19
6.9
20
>30
21
7.4
22
9.6
23
8.2
24
>30
25
>30
26
11.8
27
>30
28
>30
29
25.8
30
10.5
31
19.6
32
14.8
33
>30
34
12.4
35
>30
36
21.1
37
>30
38
0.2
39
>30
40
2.1
5.1.3. 4-Hydroxystyrene (8)
Following the general procedure,
8 was obtained from
shown to damage bacterial cell membranes or to lead to cell
aggregation.
4-hydroxybenzaldehyde (2) as a slightly yellowish solid; yield:
58.0%; mp 63–65 °C (lit.: 73.5 °C,38 71–72.5 °C,39 67–69 °C,40 55–
65 °C41).
The compounds 1 and 16–40 were tested for their cytotoxic
activity (NiH3T3 cells, mouse embryonic fibroblasts) using a sulfo-
rhodamine B assay (SRB).37 The results (IC50 values, three indepen-
dent experiments for each compound) from these tests are
summarized in Table 1. Whereas some of the compounds exhibit
low toxicity (e.g., 20, 24, 25, 27, 28, 33, 35, 37 and 39), other ana-
5.1.4. 3-Hydroxystyrene (9)
Following the general procedure,
3-hydroxybenzaldehyde (3) as a slightly yellowish oil; yield: 67.6%.
9 was obtained from
logs are cytotoxic with IC50 <10 lM (e.g., 21–23, 38 and 40) making
them interesting (lead) structures for the development of stilbene
5.1.5. 2-Hydroxystyrene (10)
Following the general procedure, 10 was obtained from
2-hydroxybenzaldehyde (4) as a colorless oil; yield: 64.8%.
derived antitumor active compounds.
4. Conclusion
5.1.6. 3,4-Dimethoxystyrene (11)
Following the general procedure, 11 was obtained from 3,
4-dimethoxybenzaldehyde (5) as a yellowish oil; yield: 75.2%.
Several series of stilbenes were synthesized starting from the
aldehydes using Wittig reactions to access the corresponding sty-
renes that were subjected to Mizoroki–Heck reactions to yield
the stilbenes in good yields. The stilbenes were tested in an agar
diffusion assay against several bacteria and fungi. For several of
these compounds the inhibiting areolae are comparable with those
obtained from treating the bacteria with tetracycline, streptomy-
cin, ampicillin or kanamycin or noursethricin or hygromycin for
the antifungal assay. As far as the antibacterial activity is con-
cerned, all stilbenes that do not show a monohydroxy-substitution
on ring A are only active when the compounds have a 20,50-dihy-
droxy substitution in ring B.
5.1.7. 3-Methoxystyrene (12)
Following the general procedure, 12 was obtained from 3-
methoxybenzaldehyde (6) as a yellowish oil; yield: 70.1%.
5.1.8. 3,4-Dihydroxystyren (13)
Following the general procedure, 13 was obtained from 3,
4-dihydroxybenzaldehyde (7) as an off-white, highly viscous oil;
yield: 59.9%.
5.1.9. 3-Hydroxy-4-methoxystyrene (14)
Compound 14 was prepared according to 28, and obtained as
5. Experimental
5.1. Chemistry
colorless sold; mp 56–58 °C (lit.: 57–58 °C.40
5.1.10. 6-Fluoro-3-hydroxy-4-methoxystyrene (15)
Following the general procedure, 15 was obtained as an amor-
phous, slightly yellow powder; yield: 72.3%; Rf = 0.44 (silica gel,
Melting points are uncorrected (Leica hot stage microscope),
NMR spectra were recorded using the Varian spectrometers Gem-
ini 200, Gemini 2000 or Unity 500 (d given in ppm, J in Hz, internal
Me4Si or freon-11 for 19F NMR spectra), IR spectra (film or KBr pel-
let) on a Perkin–Elmer FT-IR spectrometer Spectrum 1000, MS
spectra were taken on a Intectra GmbH AMD 402 (electron impact,
70 eV) instrument; for elemental analysis a Foss-Heraeus Vario EL
instrument was used; TLC was performed on silica gel (Merck
5554, detection by UV absorption or by treatment with a solution
of 10% sulfuric acid, ammonium molybdate and cerium(IV) sulfate)
followed by gentle heating. The solvents were dried according to
usual procedures.
hexane/ethyl acetate, 8:2); IR (KBr):
m = 3388br, 3077m, 2985m,
2938m, 2849m, 1809w, 1632s, 1587w, 1508s, 1444s, 1418m,
1361s, 1315m, 1285s, 1206s, 1164s, 1102s, 1049m cmꢁ1; UV–vis
(methanol): kmax (log e
) = 207 (4.37), 254 (4.18), 306 (3.87); 1H
NMR (400 MHz, acetone-d6): d = 7.58 (br s, 1H, OH), 7.01 (d, 1H,
4JH,F = 7.5 Hz, CH (6)), 6.75 (dd, 1H, 3J (trans) = 17.7 Hz, 3J
3
(cis) = 11.2 Hz, CH (7)), 6.74 (d, 1H, JH,F = 11.8 Hz, CH (3)), 5.67
(d, 1H, 3J (trans) = 17.7 Hz, CHa (8)), 5.20 (d, 1H, 3J (cis) = 11.2 Hz,
CHb (8)), 3.85 (s, 3H, OCH3); 13C NMR (100 MHz, acetone-d6):
1
3
d = 153.7 (d, JC,F = 264.3 Hz, C2, Cquart.), 148.1 (d, JC,F = 26.9 Hz,
C4, Cquart.), 142.9 (d, 4JC,F = 2.0 Hz, C5, Cquart.), 128.7 (d, 3JC,F = 3.3 Hz,
2
4
C7, CH), 116.6 (d, JC,F = 13.4 Hz, C1, Cquart.), 113.2 (d, JC,F = 1.0 Hz,
5.1.1. General procedure for the synthesis of styrenes
3
2
C8, CH), 111.4 (d, JC,F = 4.8 Hz, C6, CH)), 99.7 (d, JC,F = 28.8 Hz,
To a solution methyltriphenylphosphonium iodide (37 mmol)
C3, CH), 55.7 (OCH3); 19F NMR (188 MHz, acetone-d6): d = ꢁ129.6
t
in dry THF (60 ml), BuOK (40 mmol) was added in several por-
3
4
(dd, JF,H = 11.8 Hz, JF,H = 7.5 Hz
, –F); MS (e.i., 70 eV): m/z
tions, and stirring under argon was continued for 1 h. The aldehyde
(14 mmol) was added, and stirring was continued for another 24 h.
The reaction mixture was diluted with dichloromethane (150 ml),
washed with water and brine (2 ꢀ 10 ml each), dried (Na2SO4),
and the solvents were evaporated under diminished pressure.
The crude product was purified by chromatography (silica gel, hex-
ane/ethyl acetate mixtures).
(%) = 168 (92), 153 (100), 125 (39), 97 (11), 77 (16); Anal. Calcd
for C8H7O3 (170.14): C, 56.48; H, 4.15. Found: C, 56.31; H, 4.36.
5.1.11. (E) 30,50-Dimethoxy-4-hydroxystilbene (16)
From 8 and 3,5-dimethoxyiodobenzene; yield: 55.0%; white so-
lid; mp 83–84 °C (lit.: 88 °C,41 86–88 °C,42 55–64 °C.43

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S. Albert et al. / Bioorg. Med. Chem. 19 (2011) 5155–5166
5.1.12. (E) 30,4,50-Trihydroxystilbene (17)
5.1.16. (E) 20,50-Dimethoxy-4-hydroxystilbene (21)
From 8 and 3,5-dihydroxyiodobenzene; yield: 41.4%; white so-
From 8 and 2,5-dimethoxyiodobenzene; yield: 52.2%; off-white
solid; mp 81–82 °C; Rf = 0.27 (silica gel, hexane/ethyl acetate/acetic
lid; mp >260 °C (lit.: 275–276 °C,35 260 °C,44 256–258 °C45).
acid, 8:2:0.01); IR (KBr):
m = 3341br, 2867m, 1605m, 1515m,
5.1.13. (E) 30,50-Dimethoxy-40-fluoro-4-hydroxystilbene (18)
1497m, 1460m, 1436m, 1416w, 1359w, 1316w, 1299w, 1271w,
1215m, 1172m, 1099w, 1039m, 1009w cmꢁ1; UV–vis (methanol):
From
47.6%; off-white solid; mp 123–125 °C; Rf = 0.49 (silica gel, hex-
ane/ethyl acetate, 3:1); IR (KBr): = 3419br, 2940w, 1606m,
1585w, 1519m, 1455w, 1420w, 1330w, 1265w, 1249w, 1219w,
8 and 3,5-dimethoxy-4-fluoro-bromobenzene; yield:
kmax (log e
) = 208 (4.41), 284 (4.34), 341 (4.30) nm; 1H NMR
(400 MHz, CDCl3): d = 7.40 (d, 2H, 3J = 8.5 Hz, CH (2) + CH (6)),
7.28 (d, 1H, 3J (trans) = 16.4 Hz, CH@ (1)), 7.11 (d, 1H, 4J = 2.9 Hz,
CH (60)), 7.00 (d, 1H, 3J (trans) = 16.4 Hz, CH@ (2)), 6.81 (d, 1H,
3J = 9.0 Hz, CH (30)), 6.79 (d, 2H, 3J = 8.5 Hz, CH (3) + CH (5)), 6.76
m
1171w, 1124m cmꢁ1
; UV–vis (methanol): kmax (log e) = 209
(4.49), 306 (4.53) nm; 1H NMR (400 MHz, CDCl3): d = 7.37 (d, 2H,
3J = 8.5 Hz, CH (2) + CH (6)), 6.92 (d, 1H, 3J (trans) = 16.2 Hz, CH@
(1)), 6.84 (d, 1H, 3J (trans) = 16.2 Hz, CH@ (2)), 6.81 (d, 2H,
4
(dd, 1H, 3J = 9.0 Hz, J = 2.9 Hz, CH (40)), 4.92 (br s, 1H, OH), 3.82
(s, 3H, OCH3), 3.80 (s, 3H, OCH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 155.1 (C4, Cquart.), 153.8 (C50, Cquart.), 151.3 (C20, Cquart.), 130.8
(C1, Cquart.), 128.9 (CH@), 128.0 (C2 + C6, CH), 127.6 (C10, Cquart.),
121.2 (CH@), 115.5 (C3 + C5, CH), 113.3 (C40, CH), 112.4 (C30, CH),
111.5 (C60, CH), 56.3 (OCH3), 55.8 (OCH3) ppm; MS (i.e., 70 eV):
m/z (%) = 256 (100), 241 (16), 213(56), 198 (11), 181 (16),
169(9); Anal. Calcd for C16H16O3 (256.30): C, 74.98; H, 6.29. Found:
C, 74.85; H, 6.51.
3J = 8.5 Hz, CH (3) + CH (5)), 6.70 (d, 2H, JH,F = 7.1 Hz, CH (20) + CH
4
(60)), 3.91 (s, 6H, OCH3) ppm; 13C NMR (100 MHz, CDCl3):
2
d = 155.3 (C4, Cquart.), 148.4 (d, JC,F = 8.8 Hz, C30 + C50, Cquart.),
1
4
142.1 (d, JC,F = 245.8 Hz, C40, Cquart.), 133.0 (d, JC,F = 5.0 Hz, C10,
Cquart.) 130.0 (C1, Cquart.), 128.1 (CH@), 127.8 (C2 + C6, CH), 126.1
(CH@), 115.6 (C3 + C5, CH), 103.9 (C20 + C60, CH), 56.5 (OCH3) ppm;
19F NMR (188 MHz, CDCl3): d = ꢁ159.1 (t, JF,H = 7.1 Hz, –F) ppm;
4
MS (ESI, MeOH): m/z = 273.6 (100% [MꢁH]ꢁ), 319.2 (10%
[M+HCO2]ꢁ), 547.0 (17% [2MꢁH]ꢁ); Anal. Calcd for C16H15FO3
(274.28): C, 70.06; H, 5.51. Found: C, 69.85; H, 5.62.
5.1.17. (E)-20,4,50-Trihydroxystilbene (22)
From 8 and 2,5-dihydroxybenzene; yield: 48.7%; off-white so-
lid; mp 198–200 °C.
5.1.14. (E) 4-Hydroxy-30,40,50-trifluorostilbene (19)
From 8 and 3,4,5-trifluorobromobenzene; yield: 56.9%; white
solid; mp 149–151 °C; Rf = 0.30 (silica gel, hexane/ethyl acetate,
5.1.18. (E) 20,40-Dimethoxy-4-hydroxystilbene (23)
From 8 and 2,5-dimethoxyiodobenzene; yield: 52.2%; off-white
solid; mp 118–121 °C.
9:1); IR (KBr):
m = 3266br, 2361w, 1889w, 1638w, 1594s, 1529s,
1508s, 1442s, 1360m, 1321m, 1269m, 1231s, 1174m, 1131w,
5.1.19. (E) 30,50-Dimethoxy-3-hydroxystilbene (24)
1106w, 1043s cmꢁ1; UV–vis (methanol): kmax (log
e) = 230 (4.19),
From 9 and 3,5-dimethoxyiodobenzene; yield: 54.2%; white so-
321 (4.50) nm; 1H NMR (400 MHz, CDCl3): d = 7.36 (d, 2H,
3J = 8.5 Hz, CH (2) + CH (6)), 7.03 (dt, 1H, 3JH,F = 9.2 Hz, 4JH,F = 6.6 Hz,
CH (20) + CH (60)), 6.92 (d, 1H, 3J (trans) = 16.2 Hz, CH@ (1)), 6.81 (d,
2H, 3J = 8.5 Hz, CH (3) + CH (5)), 6.75 (d, 1H, 3J (trans) = 16.2 Hz,
CH@ (2)) ppm; 13C NMR (100 MHz, CDCl3): d = 155.8 (C4, Cquart.),
lid (lit.: oil46); mp 58–60 °C; Rf = 0.44 (silica gel, hexane/ethyl ace-
tate, 3:1); IR (KBr):
m
= 3252br, 3936m, 2361w, 1596s, 1455m,
1425m, 1317m, 1251w, 1193s, 1155s, 1060m cmꢁ1; UV–vis (meth-
anol): kmax (log
e
) = 218 (4.31), 301 (4.29) nm; 1H NMR (400 MHz,
CDCl3): d = 7.21 (t, 1H, 3J = 7.7 Hz, CH (5)), 7.05 (d, 1H, 3J = 7.7 Hz,
CH (6)), 7.00 (d, 1H, 3J (trans) = 16.7 Hz, CH@ (1)), 6.98 (d, 1H, 3J
(trans) = 16.7 Hz, CH@ (2)), 6.96 (d, 1H, 4J = 2.3 Hz, CH (2)), 6.74
(dd, 1H, 3J = 7.7 Hz, 4J = 2.3 Hz, CH (4)), 6.64 (d, 2H, 4J = 2.2 Hz, CH
1
2
3
151.4 (ddd, JC,F = 252.3 Hz, JC,F = 10.1 Hz, JC,F = 4.3 Hz, C30 + C50,
1
Cquart.), 138.7 (m, JC,F = 250.7 Hz, C40, Cquart.), 133.9 (dd,
3JC,F = 12.2 Hz, JC,F = 7.7 Hz, C10, Cquart.), 130.4 (d, JC,F = 2.4 Hz,
4
5
CH@), 129.2 (C1, Cquart.), 128.2 (C2 + C6, CH), 123.6 (d, 4JC,F = 2.8 Hz,
3
(20) + CH (60)), 6.39 (t, 1H, J = 2.2 Hz, CH (40)), 3.81 (s, 6H,
2
3
CH@), 115.7 (C3 + C5, CH), 109.8 (dd, JC,F = 16.8 Hz, JC,F = 4.9 Hz,
C20 + C60, CH) ppm; 19F NMR (188 MHz, CDCl3): d = ꢁ135.2 (dd,
OCH3) ppm; 13C NMR (100 MHz, CDCl3): d = 160.9 (C30 + C50,
Cquart.), 155.8 (C3, Cquart.), 139.2 (C1, Cquart.), 138.8 (C10, Cquart.),
129.8 (C5, CH), 129.1 (CH@), 128.8 (CH@), 119.5 (C6, CH), 114.7
(C4, CH), 113.0 (C2, CH), 104.7 (C20 + C60, CH), 100.1 (C40, CH),
55.4 (OCH3) ppm; MS (ESI, MeOH): m/z = 255.4 (100% [MꢁH]ꢁ),
301.0 (29% [MꢁHCO2]ꢁ), 510.9 (82% [2MꢁH]ꢁ); Anal. Calcd for
3JF,F = 19.7 Hz, 3JF,H = 9.2 Hz,
F
(30) + F (50)), ꢁ161.7 (tt,
3JF,F = 19.7 Hz, JF,H = 6.6 Hz, F (40)) ppm; MS (ESI, MeOH): m/
4
z = 249.6 (55% [MꢁH]ꢁ), 498.9 (100% [2MꢁH]ꢁ); Anal. Calcd for
C
14H9F3O (250.22): C, 67.20; H, 3.63. Found: C, 66.98; H, 3.83.
C16H16O3 (256.30): C, 74.98; H, 6.29. Found: C, 74.74; H, 6.31.
5.1.15. (E) 40-Fluoro-30,4,50-trihydroxystilbene (20)
From and 3,5-dihydroxy-4-fluoro-bromobenzene; yield:
39.8%; white solid; mp >250 °C; Rf = 0.52 (silica gel, hexane/ethyl
acetate, 1:1); IR (KBr): = 3346br, 1604w, 1554w, 1521w,
1442w, 1369w, 1255w, 1192w, 1175w, 1104w, 1048w cmꢁ1
5.1.20. (E) 3,30,50-Trihydroxystilbene (25)
8
From 9 and 3,5-dihydroxyiodobenzene; yield: 47.1%; white so-
lid; mp 208–210 °C (lit.: 228–231 °C47); Rf = 0.43 (silica gel, hex-
m
;
ane/ethyl acetate, 1:1); IR (KBr):
m = 3263m, 2363w, 1596s,
UV–vis (methanol): kmax (log e
) = 217 (4.30), 305 (4.39) nm; 1H
1491w, 1457m, 1382w, 1325m, 1282w, 1248m, 1159s, 1008w
NMR (400 MHz, methanol-d4): d = 7.30 (d, 2H, 3J = 8.3 Hz, CH
(2) + CH (6)), 6.84 (d, 1H, 3J (trans) = 16.4 Hz, CH@ (1)), 6.73 (d,
2H, 3J = 8.3 Hz, CH (3) + CH (5)), 6.72 (d, 1H, 3J (trans) = 16.4 Hz,
cmꢁ1
;
UV–vis (methanol): kmax (log e) = 219 (4.42), 307
(4.43) nm; 1H NMR (400 MHz, methanol-d4): d = 7.13 (t, 1H,
3J = 7.8 Hz, CH (5)), 6.96 (d, 1H, 3J = 7.8 Hz, CH (6)), 6.94 (d, 1H, 3J
(trans) = 16.3 Hz, CH@ (1)), 6.93 (d, 1H, 4J = 2.0 Hz, CH (2)), 6.91
(d, 1H, 3J (trans) = 16.3 Hz, CH@ (2)), 6.67 (dd, 1H, 3J = 7.7 Hz,
4
CH@ (2)), 6.52 (d, 2H, JH,F = 7.1 Hz, CH (20) + CH (60)) ppm; 13C
NMR (100 MHz, methanol-d4): d = 156.8 (C4, Cquart.), 145.5 (d,
2JC,F = 7.9 Hz, C30 + C50, Cquart.), 140.5 (d, 1JC,F = 248.7 Hz, C40, Cquart.),
4J = 2.0 Hz, CH (4)), 6.47 (d, 2H, J = 2.2 Hz, CH (20) + CH (60)), 6.19
4
4
133.5 (d, JC,F = 5.0 Hz, C10, Cquart.) 128.9 (C1, Cquart.), 127.6 (CH@),
(t, 1H, J = 2.2 Hz, CH (40)) ppm; 13C NMR (100 MHz, methanol-
3
d4): d = 159.7 (C30 + C50, Cquart.), 158.7 (C3, Cquart.), 140.7 (C1, Cquart.),
140.1 (C10, Cquart.), 133.0 (C5, CH), 129.8 (CH@), 129.5 (CH@), 119.2
(C6, CH), 115.7 (C4, CH), 113.8 (C2, CH), 106.1 (C20 + C60, CH), 103.2
(C40, CH) ppm; MS (ESI, MeOH): m/z = 227.5 (37% [MꢁH]ꢁ), 273.3
(44% [M+HCO2]ꢁ), 455.0 (100% [2MꢁH]ꢁ); Anal. Calcd for
127.2 (C2 + C6, CH), 124.9 (CH@), 115.0 (C3 + C5, CH), 105.7
(C20 + C60, CH) ppm; 19F NMR (188 MHz, methanol-d4): d = ꢁ165.3
4
(t, JF,H = 7.1 Hz, –F) ppm; MS (ESI, MeOH): m/z = 245.4 (98%
[MꢁH]ꢁ), 291.0 (23% [M+HCO2]ꢁ), 490.9 (100% [2MꢁH]ꢁ); Anal.
Calcd for C14H11FO3 (246.23): C, 68.29; H, 4.50. Found: C, 67.98;
H, 4.67.
C14H12O3 (228.24): C, 73.67; H, 5.30. Found: C, 73.54; H, 5.51.

S. Albert et al. / Bioorg. Med. Chem. 19 (2011) 5155–5166
5163
5.1.21. (E) 30,50-Dimethoxy-40-fluoro-3-hydroxystilbene (26)
From and 3,5-dimethoxy-4-fluoro-bromobenzene; yield:
53.5%; off-white solid; mp 108–111 °C; Rf = 0.59 (silica gel, hex-
ane/ethyl acetate, 3:1); IR (KBr): = 3241br, 2944w, 1743w,
5.1.24. (E) 20,50-Dimethoxy-3-hydroxystilbene (29)
From 9 and 2,5-dimethoxyiodobenzene; yield: 51.1%; off-white
solid; mp 66–68 °C; RF = 0.26 (silica gel, hexane/ethyl acetate, 8:2);
9
m
IR (KBr): m = 3415br, 2955m, 1633w, 1609m, 1581m, 1496s,
1601m, 1518m, 1457m, 1420m, 1336m, 1279w, 1247m, 1225m,
1462m, 1414m, 1384m, 1313m, 1277m, 1250m, 1216s, 1179m,
1184w, 1159m, 1149m, 1131s cmꢁ1; UV–vis (methanol): kmax
1157m, 1102w, 1039s, 1008m cmꢁ1; UV–vis (methanol): kmax
(log
e
) = 214 (4.41), 319 (4.44) nm; 1H NMR (400 MHz, CDCl3):
(log e
) = 291 (4.44), 338 (4.35) nm; 1H NMR (400 MHz, CDCl3):
d = 7.21 (t, 1H, 3J = 7.7 Hz, CH (5)), 7.05 (d, 1H, 3J = 7.7 Hz, CH
(6)), 6.97 (d, 1H, 4J = 2.3 Hz, CH (2)), 6.96 (d, 1H, 3J
(trans) = 16.2 Hz, CH@ (1)), 6.90 (d, 1H, 3J (trans) = 16.2 Hz, CH@
(2)), 6.74 (dd, 1H, 3J = 7.7 Hz, 4J = 2.3 Hz, CH (4)), 6.72 (d, 2H,
4JH,F = 7.1 Hz, CH (20) + CH (60)), 3.91 (s, 6H, OCH3) ppm; 13C
NMR (100 MHz, CDCl3): d = 155.8 (C3, Cquart.), 148.4 (d,
d = 7.40 (d, 1H, 3J (trans) = 16.4 Hz, CH@ (1)), 7.19 (t, 1H,
4
3J = 7.9 Hz, CH (5)), 7.12 (d, 1H, J = 3.0 Hz, CH (60)), 7.07 (d, 1H,
3J = 7.9 Hz, CH (6)), 7.00 (d, 1H, 4J = 1.7 Hz, CH (2)), 6.99 (d, 1H, 3J
3
(trans) = 16.4 Hz, CH@ (2)), 6.82 (d, 1H, J = 8.9 Hz, CH (30)), 6.78
4
(dd, 1H, 3J = 8.9 Hz, J = 3.0 Hz, CH (40)), 6.71 (dd, 1H, 3J = 7.9 Hz,
4J = 1.7 Hz, CH (4)), 3.82 (s, 3H, OCH3), 3.80 (s, 3H, OCH3) ppm;
13C NMR (100 MHz, CDCl3): d = 155.8 (C3, Cquart.), 153.7 (C50,
Cquart.), 151.5 (C20, Cquart.), 139.5 (C1, Cquart.), 129.8 (C5, CH), 128.9
(CH@), 127.1 (C10, Cquart.), 123.7 (CH@), 119.6 (C6, CH), 114.5 (C4,
CH), 113.9 (C40, CH), 112.9 (C2, CH), 112.4 (C30, CH), 111.7 (C60,
CH), 56.3 (OCH3), 55.8 (OCH3) ppm; MS (ESI, MeOH): m/z = 255.4
(100% [MꢁH]ꢁ), 301.1 (19% [M+HCO2]ꢁ), 510.9 (50% [2MꢁH]ꢁ);
Anal. Calcd for C16H16O3 (256.30): C, 74.98; H, 6.29. Found: C,
74.86; H, 6.41.
2JC,F = 8.6 Hz, C30 + C50, Cquart.), 142.1 (d, JC,F = 243.1 Hz, C40,
1
4
Cquart.), 138.8 (C1, Cquart.), 132.7 (d, JC,F = 5.0 Hz, C10, Cquart.),
129.9 (C5, CH), 128.6 (CH@), 128.3 (CH@), 119.4 (C6, CH), 114.8
(C4, CH), 112.9 (C2, CH), 104.4 (C20 + C60, CH), 56.7 (OCH3) ppm;
4
19F NMR (188 MHz, CDCl3): d = ꢁ158.3 (t, JF,H = 7.1 Hz, –F) ppm;
MS (e.i., 70 eV): m/z (%) = 274 (100), 242(10), 228 (10), 199 (15),
170 (9); Anal. Calcd for C16H15FO3 (274.28): C, 70.06; H, 5.51.
Found: C, 69.84; H, 5.73.
5.1.22. (E)-3-Hydroxy-30,40,50-trifluorostilbene (27)
5.1.25. (E) 20,3,50-Trihydroxystilbene (30)48,49
From 9 and 3,4,5-trifluorobromobenzene; yield: 58.4%; white
solid; mp 132–134 °C; Rf = 0.30 (silica gel, hexane/ethyl acetate,
From 9 and 2,5-dihydroxyiodobenzene; yield: 47.9%; off-white
solid; mp 208–210 °C; RF = 0.13 (silica gel, hexane/ethyl acetate,
9:1); IR (KBr):
m
= 3285m, 1638w, 1594w, 1529m, 1508w, 1442w,
3:1); IR (KBr):
m = 3300br, 1613w, 1582w, 1505w, 1457m,
1360w, 1331w, 1269w, 1231m, 1174w, 1106w, 1043m cmꢁ1
;
1377w, 1305w, 1254w, 1199w, 1156w, 1095w cmꢁ1; UV–vis
UV–vis (methanol): kmax (log
e
) = 230 (4.15), 320 (4.47) nm; 1H
(methanol): kmax (log e) = 211 (4.57) , 291 (4.42), 345 (4.31) nm;
NMR (400 MHz, CDCl3): d = 7.23 (t, 1H, 3J = 7.7 Hz, CH (5)), 7.08–
7.02 (m, 3H, CH (20) + CH (6) + CH (60)), 6.95 (d, 1H, 4J = 2.1 Hz, CH
(2)), 6.94 (d, 1H, 3J (trans) = 16.0 Hz, CH@ (1)), 6.86 (d, 1H, 3J
(trans) = 16.0 Hz, CH@ (2)), 6.81(dd, 2H, 3J = 7.7 Hz, 4J = 2.1 Hz, CH
(4)) ppm; 13C NMR (100 MHz, CDCl3): d = 155.8 (C3, Cquart.), 151.4
1H NMR (400 MHz, DMSO-d6): d = 9.44 (br s, 1H, OH), 9.07 (br s,
1H, OH), 8.81 (br s, 1H, OH), 7.27 (d, 1H, 3J (trans) = 16.4 Hz, CH@
(1)), 7.13 (t, 1H, 3J = 7.8 Hz, CH (5)), 6.96 (d, 1H, 3J (trans) = 16.4 Hz,
CH@ (2)), 6.94–6.92 (m, 3H, CH (2) + CH (6) + CH (60)), 6.66 (d, 1H,
3J = 8.5 Hz, CH (30)), 6.64 (d, 1H, 3J = 7.8 Hz, CH (4)), 6.53 (dd, 1H,
1
2
3
4
(ddd, JC,F = 251.6 Hz, JC,F = 11.3 Hz, JC,F = 5.0 Hz, C30 + C50, Cquart.),
3J = 8.5 Hz, J = 2.9 Hz, CH (40)) ppm; 13C NMR (100 MHz, DMSO-
1
139.1 (m, JC,F = 250.7 Hz, C40, Cquart.), 137.4 (C1, Cquart.), 133.4
d6): d = 157.7 (C3, Cquart.), 150.2 (C50, Cquart.), 148.0 (C20, Cquart.),
139.2 (C1, Cquart.), 129.9 (C5, CH), 127.7 (CH@), 124.3 (C10, Cquart.),
123.7 (CH@), 117.8 (C6, CH), 116.8 (C30, CH), 116.1 (C40, CH),
114.8 (C4, CH), 112.7 (C60, CH), 112.0 (C2, CH) ppm; MS (ESI,
MeOH): m/z = 227.4 (25% [MꢁH]ꢁ), 273.1 (100% [M+HCO2]ꢁ),
454.9 (27% [2MꢁH]ꢁ); Anal. Calcd for C14H12O3 (228.24): C,
73.67; H, 5.30. Found: C, 73.49; H, 5.35.
3
4
(dd, JC,F = 12.2 Hz, JC,F = 7.7 Hz, C10, Cquart.), 130.5 (d, 5JC,F = 2.4 Hz,
4
CH@ (1)), 130.0 (C5, CH), 126.1 (d, JC,F = 3.0 Hz, CH@), 119.7 (C6,
2
CH), 115.5 (C4, CH), 113.2 (C2, CH), 110.1 (dd, JC,F = 17.1 Hz,
3JC,F = 5.0 Hz, C20 + C60, CH) ppm; 19F NMR (188 MHz, CDCl3):
d = ꢁ134.9 (dd, JF,F = 19.5 Hz, 3J F,H = 9.0 Hz, F (30) + F (50)), ꢁ161.7
3
3
4
(tt, JF,F = 19.5 Hz, JF,H = 6.0 Hz, F (40)) ppm; MS (ESI, MeOH): m/
z = 249.5 (24% [MꢁH]ꢁ), 295.3 (25% [M+HCO2]ꢁ), 499.1 (100%
[2MꢁH]ꢁ), 545.1 (12% [2M+HCO2]ꢁ); Anal. Calcd for C14H9F3O
(250.22): C, 67.20; H, 3.63. Found: C, 66.96; H, 3.83.
5.1.26. (E) 20,40-Dimethoxy-3-hydroxystilbene (31)
From 9 and 2,4-dimethoxyiodobenzene; yield: 53.7%; off-white
solid; mp 106–108 °C; RF = 0.30 (silica gel, dichloromethane/hex-
5.1.23. (E) 40-Fluoro-3,30,50-trihydroxystilbene (28)
ane, 3:1); IR (KBr):
m = 3397br, 2945m, 1603m, 1577m, 1505m,
From
46.8%; off-white solid; mp >250 °C; RF = 0.57 (silica gel, hexane/
ethyl acetate, 1:1); IR (KBr): = 3340br, 2605w, 2465m,
1606m, 1581m, 1518s, 1455m, 1368m, 1278m, 1213w, 1159m,
9 and 3,5-dihydroxy-4-fluoro-bromobenzene; yield:
1468m, 1434w, 1419w, 1296m, 1277m, 1200m, 1152m, 1107w,
1023 cmꢁ1
; UV–vis (methanol): kmax (log e) = 213 (4.34), 326
m
(4.36) nm; 1H NMR (400 MHz, CDCl3): d = 7.47 (d, 1H, 3J = 8.5 Hz,
CH (60)), 7.35 (d, 1H, 3J (trans) = 16.4 Hz, CH@ (1)), 7.18 (t, 1H,
3J = 7.9 Hz, CH (5)), 7.05 (d, 1H, 3J = 7.9 Hz, CH (6)), 6.97 (d, 1H,
4J = 1.7 Hz, CH (2)), 6.92 (d, 1H, 3J (trans) = 16.4 Hz, CH@ (2)),
6.68 (dd, 1H, 3J = 7.9 Hz, 4J = 1.7 Hz, CH (4)), 6.50 (dd, 1H,
1069m cmꢁ1; UV–vis (methanol): kmax (log
e) = 219 (4.47), 300
(4.50) nm; 1H NMR (400 MHz, methanol-d4): d = 7.50 (t, 1H,
3J = 7.9 Hz, CH (5)), 7.32 (d, 1H, 3J = 7.9 Hz, CH (6)), 7.28 (d, 1H,
4J = 1.9 Hz, CH (2)), 7.26 (d, 1H, 3J (trans) = 16.6 Hz, CH@ (1)),
7.22 (d, 1H, 3J (trans) = 16.6 Hz, CH@ (2)), 7.03 (dd, 1H,
4
4
3J = 8.5 Hz, J = 2.3 Hz, CH (50)), 6.46 (d, 1H, J = 2.3 Hz, CH (30)),
3.85 (s, 3H, OCH3), 3.82 (s, 3H, OCH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 160.7 (C40, Cquart.), 158.1 (C20, Cquart.), 155.7 (C3, Cquart.),
140.0 (C1, Cquart.), 129.7 (C5, CH), 127.3 (C60, CH), 126.5 (CH@),
123.8 (CH@), 119.4 (C10, Cquart.), 119.3 (C6, CH), 114.0 (C4, CH),
112.6 (C2, CH), 105.6 (C50, CH), 98.5 (C30, CH), 55.5 (OCH3), 55.4
(OCH3) ppm; MS (ESI, MeOH): m/z = 255.3 (100% [MꢁH]ꢁ), 510.8
(21% [2MꢁH]ꢁ); Anal. Calcd for C16H16O3 (256.30): C, 74.98; H,
6.29. Found: C, 74.69; H, 6.42.
4
3J = 7.7 Hz, 4J = 1.9 Hz, CH (4)), 6.94 (d, 2H, JH,F = 7.3 Hz, CH
(20) + CH (60)) ppm; 13C NMR (100 MHz, methanol-d4): d = 158.7
2
(C3, Cquart.), 147.0 (d, JC,F = 8.6 Hz, C30 + C50, Cquart.), 142.3 (d,
1JC,F = 237.6 Hz, C40, Cquart.), 140.1 (C1, Cquart.), 134.5 (d,
4JC,F = 4.3 Hz, C10, Cquart.), 130.6 (C5, CH), 129.2 (CH@), 129.1
(CH@), 119.2 (C6, CH), 115.6 (C4, CH), 113.8 (C2, CH), 107.5
(C20 + C60, CH) ppm; 19F NMR (188 MHz, CDCl3): d = ꢁ164.5 (t,
4
JF,H = 7.3 Hz, F) ppm; MS (ESI, MeOH): m/z = 245.4 (68% [MꢁH]
ꢁ), 291.0 (40% [M+HCO2]ꢁ), 490.9 (100% [2MꢁH]ꢁ); Anal. Calcd
for C14H11FO3 (246.23): C, 68.29; H, 4.50. Found: C, 68.00; H,
4.63.
5.1.27. (E) 30,50-Dimethoxy-40-fluoro-2-hydroxystilbene (32)
From 10 and 3,5-dimethoxy-4-fluoro-bromobenzene; yield:
51.1%; white solid; mp 63–65 °C; RF = 0.16 (silica gel, hexane/

5164
S. Albert et al. / Bioorg. Med. Chem. 19 (2011) 5155–5166
ethyl acetate, 8:2); IR (KBr):
m
= 3418br, 2940m, 2842w, 1704m,
1518m, 1457s, 1425m, 1381m, 1235m, 1198w, 1176m, 1140m,
1605s, 1519s, 1455s, 1421s, 1349s, 1243s, 1128s, 1042m cmꢁ1
;
1120s cmꢁ1; UV–vis (methanol): kmax (log
e) = 214 (4.42), 319
UV–vis (methanol): kmax (log
e
) = 290 (4.12), 326 (4.18) nm; 1H
(4.45) nm; 1H NMR (400 MHz, CDCl3): d = 7.51 (d, 1H, 3J = 8.5 Hz,
CH (60)), 7.49 (d, 1H, 3J = 7.4 Hz, CH (6)), 7.34 (d, 1H, 3J
(trans) = 16.4 Hz, CH@ (1)), 7.23 (d, 1H, 3J (trans) = 16.4 Hz, CH@
(2)), 7.09 (t, 1H, 3J = 7.4 Hz, CH (4)), 6.91 (t, 1H, 3J = 7.4 Hz, CH
(5)), 6.79 (d, 1H, 3J = 7.4 Hz, CH (3)), 6.50 (dd, 1H, 3J = 8.5 Hz,
NMR (400 MHz, CDCl3): d = 7.48 (d, 1H, 3J = 7.7 Hz, CH (6)), 7.28
(d, 1H, 3J (trans) = 16.4 Hz, CH@ (1)), 7.11 (t, 1H, 3J = 7.7 Hz, CH
(4)), 7.01 (d, 1H, 3J (trans) = 16.4 Hz, CH@ (2)), 6.92 (t, 1H,
3J = 7.7 Hz, CH (5)), 6.80 (d, 1H, 3J = 7.7 Hz, CH (3)), 6.74 (d, 2H,
4JH,F = 7.0 Hz, CH (20) + CH (60)) 3.88 (s, 6H, OCH3) ppm; 13C NMR
4
4J = 2.3 Hz, CH (50)), 6.46 (d, 1H, J = 2.3 Hz, CH (30)), 5.28 (br s,
2
(100 MHz, CDCl3): d = 153.3 (C2, Cquart.), 148.3 (d, JC,F = 8.7 Hz,
1H, OH), 3.85 (s, 3H, OCH3), 3.82 (s, 3H, OCH3) ppm; 13C NMR
(125 MHz, CDCl3): d = 160.6 (C40, Cquart.), 158.0 (C20, Cquart.), 152.8
(C2, Cquart.), 128.0 (C4, CH), 127.1 (C60, CH), 126.7 (C6, CH), 125.6
(C1, Cquart.), 124.8 (CH@), 121.1 (CH@), 120.9 (C5, CH), 119.7 (C10,
Cquart.), 115.8 (C3, CH), 105.0 (C50, CH), 98.5 (C30, CH), 55.5
(OCH3), 55.4 (OCH3) ppm; MS (ESI, MeOH): m/z = 255.3 (100%
[MꢁH]ꢁ), 300.9 (8% [M+HCO2]ꢁ), 510.9 (11% [2MꢁH]ꢁ); Anal.
Calcd for C16H16O3 (256.30): C, 74.98; H, 6.29. Found: C, 74.84;
H, 6.42.
1
C30 + C50, Cquart.), 142.2 (d, JC,F = 245.7 Hz, C40, Cquart.), 133.3 (d,
4JC,F = 4.8 Hz, C10, Cquart.) 129.1 (CH@), 128.8 (C4, CH), 127.0 (C6,
CH), 124.4 (C1, Cquart.), 123.3 (CH@), 121.0 (C5, CH), 116.0 (C3,
CH), 104.3 (C20 + C60, CH), 56.5 (OCH3) ppm; 19F NMR (188 MHz,
4
CD3CN): d = ꢁ158.8 (t, JF,H = 7.0 Hz, F) ppm; MS (ESI, MeOH): m/
z = 273.3 (100% [MꢁH]ꢁ); 319.0 (16.3% [M+HCO2]ꢁ); 546.8 (52%
[2MꢁH]ꢁ); Anal. Calcd for C16H15FO3 (274.28): C, 70.06; H, 5.51.
Found: C, 69.89; H, 5.71.
5.1.28. (E) 2-Hydroxy-30,40,50-trifluorostilbene (33)
From 10 and 3,4,5-trifluoro-bromobenzene; yield: 52%; white
solid; mp 98–100 °C; RF = 0.52 (silica gel, hexane/ethyl acetate,
5.1.31. (E) 6-Fluoro-4-methoxy-20,3,50-trihydroxystilbene (36)
From 6-fluoro-3-hydroxy-4-methoxystyrene (15) and 2,5-
dihydroxy-iodobenzene; yield: 44.4%; off-white solid; mp 158–
160 °C; RF = 0.08 (silica gel, hexane/ethyl acetate, 3:1); IR (KBr):
9:1); IR (KBr):
m = 3489m, 3383br, 1636w, 1613w, 1598w,
1585w, 1528s, 1498w, 1455m, 1441m, 1358m, 1319m, 1270w,
m
= 3383br, 2942w, 1627w, 1508w, 1448w, 1384w, 1303w,
1230m, 1181w, 1153w, 1091w, 1062w, 1042m cmꢁ1; UV–vis
1195w, 1094w, 1017w cmꢁ1
;
UV–vis (methanol): kmax
(methanol): kmax (log
e
) = 204 (4.34), 287 (4.27), 326 (4.25) nm;
(log e
) = 291 (4.11), 349 (4.06) nm; 1H NMR (400 MHz, DMSO-
1H NMR (400 MHz, CDCl3): d = 7.46 (d, 1H, 3J = 7.8 Hz, CH (6)),
7.27 (d, 1H, 3J (trans) = 16.4 Hz, CH@ (1)), 7.15 (t, 1H, 3J = 7.8 Hz,
d6): d = 7.16 (d, 1H, 3J (trans) = 16.4 Hz, CH@ (1)), 7.01 (d, 1H, 3J
4
(trans) = 16.4 Hz, CH@ (2)), 6.88 (d, 1H, J = 2.3 Hz, CH (60)), 6.82
3
4
3
3
CH (4)), 7.07(dt, 1H, JH,F = 11.0 Hz, JH,F = 6.6 Hz, CH (20) + CH
(60)), 6.96 (d, 1H, 3J (trans) = 16.4 Hz, CH@ (2)), 6.94 (t, 1H,
3J = 7.8 Hz, CH (5)), 6.77 (d, 1H, 3J = 7.8 Hz, CH (3)) ppm; 13C NMR
(100 MHz, CDCl3): d = 153.1 (C2, Cquart.), 151.2 (ddd,
(d, 1H, JH,F = 12.2 Hz, CH (5)), 6.73 (d, 1H, J = 8.7 Hz, CH (30)),
6.65 (d, 1H, JH,F = 8.9 Hz, CH (2)), 6.51 (dd, 1H, 3J = 8.7 Hz,
4
4J = 2.3 Hz, CH (40)), 3.77 (s, 3H, OCH3) ppm; 13C NMR (100 MHz,
1
DMSO-d6): d = 153.3 (d, JC,F = 244.3 Hz, C6, Cquart.), 150.1 (C50,
2
3
3
1JC,F = 249.5 Hz, JC,F = 10.5 Hz, JC,F = 4.3 Hz, C30 + C50, Cquart.),
Cquart.), 148.1 (d, JC,F = 11.3 Hz, C4, Cquart.), 147.8 (C20, Cquart.),
1
3
4
139.9 (m, JC,F = 252.7 Hz, C40, Cquart.), 134.1 (dd, JC,F = 12.5 Hz,
4JC,F = 7.7 Hz, C10, Cquart.), 129.2 (C4, CH), 127.3 (C6, CH), 126.6 (d,
5JC,F = 2.4 Hz, CH@), 125.5 (d, 4JC,F = 2.4 Hz, CH@), 123.6 (C1, Cquart.),
143.1 (d, JC,F = 2.2 Hz, C3, Cquart.), 124.3 (C10, Cquart.), 123.7 (d,
4JC,F = 3.0 Hz, CH@), 119.2 (d, JC,F = 3.4 Hz, CH@), 116.8 (C40, CH),
3
2
116.5 (d, JC,F = 13.2 Hz, C1, Cquart.), 115.8 (C30, CH), 115.3 (C60,
2
3
2
121.3 (C5, CH), 116.0 (C3, CH), 110.0 (dd, JC,F = 16.3 Hz,
CH), 111.7 (d, JC,F = 4.7 Hz, C2, CH), 100.6 (d, JC,F = 28.0 Hz, C5,
3JC,F = 4.8 Hz, C20 + C60, CH) ppm; 19F NMR (188 MHz, CDCl3):
CH), 56.1 (OCH3) ppm; 19F NMR (188 MHz, DMSO-d6):
3
3
3
4
d = ꢁ135.1 (dd, JF,F = 19.5 Hz, JF,H = 11.0 Hz, F (30) + F (50)), -
161.7 (tt, 3JF,F = 19.5 Hz, 4JF,H = 6.6 Hz, F (40)) ppm; MS (ESI, MeOH):
m/z = 249.6 (21% [MꢁH]ꢁ); 499.1 (100% [2MꢁH]ꢁ); Anal. Calcd for
C14H9F3O (250.22): C, 67.20; H, 3.63. Found: C, 67.00; H, 3.87.
d = ꢁ128.2 (dd, JF,H = 12.2 Hz, JF,H = 8.9 Hz, F) ppm; MS (ESI,
MeOH): m/z = 275.3 (45% [MꢁH]ꢁ), 321.2 (100% [M+HCO2]ꢁ),
550.8 (16% [2MꢁH]ꢁ); Anal. Calcd for C15H13FO4 (276.26): C,
65.21; H, 4.74. Found: C, 65.03; H, 4.96.
5.1.29. (E) 2,20,50-Trihydroxystilbene (34)
From 10 and 2,5-dihydroxy-iodobenzene; yield: 49.8%; off-
white solid; mp 218–220 °C; RF = 0.67 (silica gel, hexane/ethyl ace-
5.1.32. (E)-20,3,4,50-Tetrahydroxystilbene (37)50
From 13 and 2,5-dihydroxyiodobenzene; yield: 39.5%; off-white
solid; mp 162–164 °C; RF = 0.47 (silica gel, hexane/ethyl acetate,
tate, 1:1); IR (KBr):
m = 3287br, 2362w, 1603w, 1581w, 1508w,
1:1); IR (KBr):
m
= 3356br, 1601w, 1523m, 1453m, 1363w,
1455w, 1376w, 1236w, 1197w, 1156w, 1097w cmꢁ1; UV–vis
1190m, 1109w cmꢁ1
;
UV–vis (methanol): kmax (log ) = 294
e
(methanol): kmax (log e
) = 284 (4.17), 341 (4.24) nm; 1H NMR
(4.15), 347 (4.21) nm; 1H NMR (400 MHz, methanol-d4): d = 7.17
(d, 1H, 3J (trans) = 16.4 Hz, CH@ (1)), 6.99 (d, 1H, 4J = 1.9 Hz, CH
(2)), 6.93 (d, 1H, 4J = 2.9 Hz, CH (60)), 6.90 (d, 1H, 3J
(trans) = 16.4 Hz, CH@ (2)), 6.83 (dd, 3J = 8.1 Hz, 4J = 1.9 Hz, CH
(6)), 6.72 (d,1H, 3J = 8.1 Hz, CH (5)), 6.63 (d, 1H, 4J = 8.7 Hz, CH
(400 MHz, methanol-d4): d = 7.52 (d, 1H, 3J = 7.7 Hz, CH (6)), 7.40
(d, 1H, 3J (trans) = 16.4 Hz, CH@ (1)), 7.35 (d, 1H, 3J
(trans) = 16.4 Hz, CH@ (2)), 7.03 (t, 1H, 3J = 7.4 Hz, CH (4)), 7.01
4
(d, 1H, J = 2.9 Hz, CH (60)), 6.81 (t, 1H, 3J = 7.4 Hz, CH (5)), 6.78
(d, 1H, 3J = 7.4 Hz, CH (3)), 6.64 (d, 1H, J = 8.5 Hz, CH (30)), 6.53
3
(30)), 6.51 (dd, 3J = 8.7 Hz, J = 2.9 Hz, CH (40) ppm; 13C NMR
4
(dd, 1H, 3J = 8.5 Hz, J = 2.9 Hz, CH (40)), 4.81 (br s, 3H, OH) ppm;
4
(100 MHz, methanol-d4): d = 151.3 (C50, Cquart.), 148.9 (C20, Cquart.),
146.4 (C4, Cquart.), 146.2 (C3, Cquart.), 131.8 (C10, Cquart.), 129.3
(CH@), 126.9 (C1, Cquart.) 121.8 (CH@), 120.0 (C6, CH), 117.4 (C30,
CH), 116.4 (C5, CH), 115.9 (C40, CH), 113.8 (C2, CH), 112.7 (C60,
CH) ppm; MS (ESI, MeOH): m/z = 243.4 (48% [MꢁH]ꢁ); 487.0
(100% [2MꢁH]ꢁ); Anal. Calcd for C14H12O4 (244.24): C, 68.85; H,
4.95. Found: C, 68.74; H, 5.07.
13C NMR (100 MHz, methanol-d4): d = 155.8 (C2, Cquart.), 151.2
(C50, Cquart.), 148.9 (C20, Cquart.), 129.0 (C4, CH), 127.1 (C10, Cquart.),
127.0 (C6, CH), 126.4 (C1, Cquart.), 124.0 (CH@), 123.8 (CH@),
120.7 (C5, CH), 117.4 (C30, CH), 116.5 (C3, CH), 116.1 (C40, CH),
112.7 (C60, CH) ppm; MS (ESI, MeOH): m/z = 227.4 (48% [MꢁH]ꢁ),
273.1 (58% [M+HCO2]ꢁ), 455.0 (100% [2MꢁH]ꢁ); Anal. Calcd for
C14H12O3 (228.24): C, 73.67; H, 5.30. Found: C, 73.56; H, 5.44.
5.1.33. (E) 3-Hydroxy-30,4,50-trimethoxystilbene (38)
From 3-hydroxy-4-methoxystyrene (14) and 3,5-dimethyliodo-
benzene; yield: 58.7%; white solid; mp 94–96 °C (lit.: 90–91 °C,35
89–90.50
5.1.30. (E) 20,40-Dimethoxy-2-hydroxystilbene (35)
From 10 and 2,4-dimethoxyiodobenzene: yield: 57.7%; white
solid; mp 85–88 °C; RF = 0.50 (silica gel, hexane/ethyl acetate,
3:1); IR (KBr):
m = 3428br, 3063w, 2995m, 2932w, 1743w, 1602s,

S. Albert et al. / Bioorg. Med. Chem. 19 (2011) 5155–5166
5165
5.1.34. (E) 4-Methoxy-20,3,50-trihydroxystilbene (39)
Table 2
Organisms and growth conditions used in the agar diffusion test
From 14 and 2,5-dihydroxyiodobenzene; yield: 51.6%; mp 181–
183 °C; white solid; RF = 0.61 (silica gel, hexane/ethyl acetate, 1:1);
Organism
Ref. number
Growth temp (°C)
Medium
IR (KBr):
m = 3298br, 2898w, 1636w, 1605w, 1558w, 1522m,
Bacillus brevis
Bacillus subtilis
ATTC 9999
ATTC6633
ATCC222
ATCC381
ATCC10647
FSU2721
FSU769
37
37
37
37
28
28
37
28
28
NB
NB
NB
NB
HA
HA
HA
HA
HA
1453s, 1383s, 1272m, 1223m, 1195m, 1163w, 1129m, 1093w,
1022m cmꢁ1; UV–vis (methanol): kmax (log
e) = 211 (4.30), 294
Enterobacter dissolvens
Micrococcus luteus
Nematospora coryli
Penicillium notatum
Mucor miehei
(4.02), 347 (4.08) nm; 1H NMR (400 MHz, acetone-d6): d = 8.01
(br s, 1H, OH), 7.79 (br s, 1H, OH), 7.63 (br s, 1H, OH), 7.30 (d,
1H, 3J (trans) = 16.4 Hz, CH@ (1)), 7.08 (d, 1H, 4J = 1.9 Hz , CH (2)),
7.04 (d, 1H, J = 1.9 Hz, CH (60)) 7.01 (d, 1H, 3J (trans) = 16.4 Hz,
4
Colletotrichum graminicola
Botrytis cinerea
M2
FSU 883
CH@ (2)), 6.96 (dd, 1H, 3J = 8.3 Hz, 4J = 1.9 Hz, CH (6)), 6.90 (d,
1H, 3J = 8.3 Hz, CH (5)), 6.72 (d, 1H, J = 8.7 Hz, CH (30)), 6.58 (dd,
4
3J = 8.7 Hz, 4J = 1.9 Hz, CH (6)), 3.83 (s, 3H, OCH3) ppm; 13C NMR
(100 MHz, acetone-d6): d = 150.0 (C50, Cquart.), 147.4 (C3, Cquart.),
146.8 (C20, Cquart.), 146.2 (C4, Cquart.), 131.1 (C1, Cquart.), 127.4
(CH@), 124.7 (C10, Cquart.) 121.1 (CH@), 118.1 (C6, CH), 116.0 (C30,
CH), 114.7 (C40, CH), 111.8 (C2, CH), 111.3 (C60, CH), 111.1 (C5,
CH), 54.9 (OCH3) ppm; MS (ESI, MeOH): m/z = 257.3 (93% [MꢁH]
ꢁ); 303.0 (100% [M+HCO2]ꢁ); 542.9 (54% [2MꢁH]ꢁ); Anal. Calcd
for C15H14O4 (258.27); C, 69.76; H, 5.46. Found: C, 69.49; H, 5.61.
The test compounds were dissolved in methanol in a final con-
centration of 10 mg/ml, and 5 ml of the solution were pipetted
onto paper discs (6 mm diameter; Macherey-Nagel, Düren,
Germany) and left for drying before they were placed onto test
plates.
Test organisms and cultivation conditions are listed in Table 2.
Inhibition zone measurements and types of inhibition (incomplete
or complete) were determined after 24–72 h.
5.1.35. (E) 3-Hydroxy-20,4,40-trimethoxystilbene (40)
From 14 und 2,4-dimethoxyiodobenzene: yield: 54.7%; mp 139–
140 °C; white solid; RF = 0.46 (silica gel, hexane/ethyl acetate, 3:1);
5.2.2. Cytotoxicity assay29
IR (KBr):
m = 3382br, 2990m, 2962m, 2932m, 2837m, 1604s,
The cytotoxicity of the compounds was evaluated using the
sulforhodamine-B (SRB) (Sigma Aldrich) microculture colorimet-
ric assay. In short, exponentially growing cells were seeded into
96-well plates on day 0 at the appropriate cell densities to pre-
vent confluence of the cells during the period of experiment.
After 24 h, the cells were treated with serial dilutions of the
1577s, 1517s, 1500s, 1460s, 1440m, 1416m, 1348w, 1323m,
1291s, 1250s, 1202s, 1157s, 1120s, 1038s, 1023s cmꢁ1; UV–vis
(methanol): kmax (log
e
) = 210 (4.60), 294 (4.48), 330 (4.65) nm; 1H
3
NMR (400 MHz, CDCl3): d = 7.45 (d, 1H, J = 8.5 Hz, CH (60)), 7.23
(d, 1H, 3J (trans) = 16.4 Hz, CH@ (1)), 7.13 (d, 1H, 4J = 1.9 Hz, CH
(2)), 6.94 (dd, 1H, 3J = 8.6 Hz, 4J = 1.9 Hz, CH (6)), 6.88 (d, 1H, 3J
(trans) = 16.4 Hz, CH@ (2)), 6.79 (d, 1H, 3J = 8.6 Hz, CH (5)), 6.49
compounds (0–100 lm) for 96 h. The final concentration of
DMSO or DMF solvent never exceeded 0.5%, which was non-toxic
to the cells. The percentages of surviving cells relative to un-
treated controls were determined 96 h after the beginning of
drug exposure. After a 96 h treatment, the supernatant medium
from the 96 well plates was thrown away, and the cells were
fixed with 10% TCA. For a thorough fixation, the plates were al-
lowed to rest at 4 °C. After fixation, the cells were washed in a
strip washer. The washing was done four times with water using
alternate dispensing and aspiration procedures. The plates were
4
(dd, 1H, 3J = 8.5 Hz, J = 2.5 Hz, CH (50)), 6.45 (d, 1H, 4J = 2.5 Hz, CH
(30)), 3.88 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.81 (s, 3H, OCH3) ppm;
13C NMR (100 MHz, CDCl3): d = 160.2 (C40, Cquart.), 157.9 (C20, Cquart.),
145.9 (C3, Cquart.), 145.7 (C4, Cquart.), 132.2 (C1, Cquart.), 126.9 (C60,
CH), 126.6 (CH@), 121.8 (CH@), 119.7 (C10, Cquart.), 118.9 (C6, CH),
111.7 (C2, CH), 110.6 (C5, CH), 104.9 (C50, CH), 98.5 (C30, CH), 55.9
(OCH3), 55.5 (OCH3), 55.74 (OCH3) ppm; MS (ESI, MeOH): m/
z = 285.2 (100 % [MꢁH]ꢁ); 570.7 (4% [2MꢁH]ꢁ); Anal. Calcd for
C17H18O4 (286.32): C, 71.31; H, 6.34. Found: C, 71.11; H, 6.52.
then dyed with 100 lL of 0.4% SRB (sulforhodamine B) for about
20 min. After dying the plates were washed with 1% acetic acid
to remove the excess of the dye and allowed to air-dry over-
night. One-hundred microliters of 10 mm Tris base solution were
added to each well and absorbance was measured at 570 nm
5.2. Biology
5.2.1. Antibacterial and antifungal activity
Test organisms were obtained from the American Type Culture
Collection (ATCC, Manassas, USA) or the Jena Microbial Resource
Collection (JMRC, Jena, Germany), respectively. Bacteria were
grown in 8 g/l nutrient broth (AppliChem, Darmstadt, Germany)
at 37 °C or kept on slants (NB amended with 1.5% [w/v] agar; Roth,
Karlsruhe, Germany) at 4 °C. Fungal cultures were grown in HA
medium (5 g/l malt extract; AppliChem, Darmstadt, Germany/4 g/
l yeast extract; Roth, Karlsruhe, Germany/4 g/l glucose; Roth, Kar-
lsruhe, Germany or kept on slants (HA amended with 1.5% [w/v]
agar) at 4 °C.
The antimicrobial activities of the test compounds and the anti-
biotics used as reference substances were determined according to
Zähner.51 In brief, fungal plates were prepared with HA medium
supplemented with 1.5% (w/v) agar. After autoclaving and cooling
to 45 °C fungal spores or yeast cells were added to a final density of
105 colony forming units (cfu)/ml. Twenty milliliters of this prepa-
ration were poured into each Petri dish.
(using
a 96 well plate reader, (Tecan Spectra, Crailsheim,
Germany). The IC50 was estimated by linear regression between
the value before and after the 50% line is crossed in a dose–re-
sponse curve.
Acknowledgments
We like to thank Dr. Dieter Ströhl for the NMR measurements
and Dr. Ralph Kluge for the ESI-MS spectra. C. graminicola strain
M2 was kindly provided by R. L. Nicholson, Purdue University.
We thank PD Dr. R. Paschke from Biosolutions Halle GmbH for
support. We are grateful to the Hans-Böckler-Stiftung (Düssel-
dorf) for a scholarship to S. Albert. The cell line was kindly pro-
vided by Dr. T. Müller (Dept. of Haematology/Oncology, Univ.
Halle).
Supplementary data
Bacterial test plates were prepared with NB supplemented with
1.5% (w/v) agar. After autoclaving and cooling to 45 °C, bacterial
spores or vegetative cells were added to a final density of 106 cfu/
ml. Fifteen ml of this preparation were poured into each Petri dish.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2011.07.015.

5166
S. Albert et al. / Bioorg. Med. Chem. 19 (2011) 5155–5166
30. Seppänen, S.-K.; Syrjälä, L.; von Weissenberg, K.; Teeri, T. H.; Paajanen, L.;
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