Synthesis and biological evaluation of some stilbene-based analogues

Article abstract of DOI:10.1007/s00044-010-9450-y

The phytoalexin 3,5,40-trihydroxy-trans-stilbene (resveratrol) has attracted considerable attention from biologists and chemists due to its diverse biological properties. Owing to the biological importance of this compound, we have synthesized new stilbene-based analogues by using substituted benzyl chlorides and substituted aldehydes in a two-step reaction and evaluated their in vitro antioxidant, antibacterial and antifungal potential. Most of the compounds displayed moderate to significant radical scavenging activity. (E)-1-(3,4-difluorophenyl)-2-(4-fluorophenyl) ethene (4c) showed nearer equipotent antibacterial activity against Staphylococcus aureus. (E)-1,2-bis (4-fluorophenyl)ethene (4a), (E)-1-(3-fluorophenyl)-2-(4-fluorophenyl)ethene (4b), (E)-1-(2,4-dichlorophenyl)-2-(3, 4-dichlorophenyl)ethene (4f), (E)-1-(2,4-dichlorophenyl)-2-(3-chlorophenyl)ethene (4g), (E)-1-(2,4- dichlorophenyl)-2-(4-fluorophenyl)ethene (4j) (E)-1-(4-fluorophenyl)-2-(3- chlorophenyl)ethene (4l) and (E)-1-(4-chlorophenyl)-2-(4-fluorophenyl)ethene (4n) inhibited the growth of Penicillium chrysogenum. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9450-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1158–1163
DOI 10.1007/s00044-010-9450-y
ORIGINAL RESEARCH
Synthesis and biological evaluation of some stilbene-based
analogues
•
Subhas S. Karki Santosh R. Bhutle Ganesh S. Pedgaonkar
•
•
•
•
•
P. K. Zubaidha Rizwan M. Shaikh Chitra G. Rajput
Girish S. Shendarkar
Received: 26 May 2010 / Accepted: 21 September 2010 / Published online: 10 October 2010
ꢀ Springer Science+Business Media, LLC 2010
Abstract The phytoalexin 3,5,40-trihydroxy-trans-stil-
bene (resveratrol) has attracted considerable attention from
biologists and chemists due to its diverse biological prop-
erties. Owing to the biological importance of this com-
pound, we have synthesized new stilbene-based analogues
by using substituted benzyl chlorides and substituted
aldehydes in a two-step reaction and evaluated their in vitro
antioxidant, antibacterial and antifungal potential. Most of
the compounds displayed moderate to significant radical
scavenging activity. (E)-1-(3,4-difluorophenyl)-2-(4-fluo-
rophenyl)ethene (4c) showed nearer equipotent antibacte-
rial activity against Staphylococcus aureus. (E)-1,2-bis
(4-fluorophenyl)ethene (4a), (E)-1-(3-fluorophenyl)-2-(4-
fluorophenyl)ethene (4b), (E)-1-(2,4-dichlorophenyl)-2-(3,
4-dichlorophenyl)ethene (4f), (E)-1-(2,4-dichlorophenyl)-
2-(3-chlorophenyl)ethene (4g), (E)-1-(2,4-dichlorophenyl)-
2-(4-fluorophenyl)ethene (4j) (E)-1-(4-fluorophenyl)-2-(3-
chlorophenyl)ethene (4l) and (E)-1-(4-chlorophenyl)-2-(4-
fluorophenyl)ethene (4n) inhibited the growth of Penicil-
lium chrysogenum.
Keywords Stilbene ꢀ Antioxidant ꢀ Antibacterial ꢀ
Antifungal
Introduction
Stilbene-based compounds are largely present in nature and
have attracted chemist and biologist, because of their wide
range of biological activities (Hart, 1991; Burns et al., 2002).
Stilbene itself does not occur in nature, but hydroxylated
stilbenes have been found in many medicinal plants. One
such example is the trans-3,5,40-trihydroxy stilbene (resve-
ratrol), a phytoalexin present in grapes and plays a role in the
prevention of coronary artery disease associated with red
wine consumption. (Burns et al., 2002; Soleas et al., 1997;
Zhou et al., 2005; Pace-Asciak et al., 1995).
Stilbene derivatives such as the 3,5,40-trihydroxy-trans-
stilbene and combretastatin A-4 are the plant microcom-
ponents, and they exhibit a variety of biological activities
including antineoplastic, chemopreventive, antioxidant and
antiestrogenic (Simoni et al., 2006; Griggs et al., 2001;
Mokni et al., 2007; Cirla and Mann, 2003). Moran et al., in
2009 have synthesized fluorinated stilbene analogues and
evaluated against variety of cell lines, primarily the non-
small lung carcinoma cell lines. They explained that (E)-
3,5-difluoro-40-acetoxy stilbene showed greater potency
than that of 3,5,40-trihydroxy-trans-stilbene. In the litera-
ture, several active stilbenes were identified, such as cis-
3,5,40-trimethoxy-30-amino stilbene and cis-3,5,40-trimeth-
oxy-30-hydroxy stilbene were found to induce HL60
apoptotic at nanomolar concentration (IC50 = 30 nm)
(Roberti et al., 2003).
S. S. Karki (&) ꢀ S. R. Bhutle
Department of Pharmaceutical Chemistry, KLE University’s
College of Pharmacy, Rajajinagar, Bangalore 560010,
Karnataka, India
e-mail: subhasskarki@gmail.com
G. S. Pedgaonkar ꢀ R. M. Shaikh ꢀ C. G. Rajput
School of Pharmacy, Swami Ramanand Teerth Marathwada
University, Nanded, Maharashtra, India
P. K. Zubaidha
School of Chemical Sciences, Swami Ramanand Teerth
Marathwada University, Nanded, Maharashtra, India
3,5,40-Tihydroxy-trans-stilbene displays anti-cyclooxy-
genase activity (Jang et al., 1997; MacCarrone et al., 1999;
Szewczuk et al. 2004). Various potentially beneficial
G. S. Shendarkar
Nanded College of Pharmacy, Nanded, Maharashtra, India
123

Med Chem Res (2011) 20:1158–1163
1159
General procedure for synthesis of 1-(substituted phenyl)-
2-(substituted phenyl)ethene (4c, 4d, 4g and 4j)
health effects of resveratrol have been attributed to its
intrinsic antioxidant capabilities (Knutson and Leeuwen-
burgh, 2008; Leifert and Abeywardena, 2008; Vingtdeux
et al., 2008; Udenigwe et al., 2008). 3,5,40-Trihydroxy-
trans-stilbene however, has also been shown to act as
prooxidant. This prooxidant effect is held likely to be
responsible for cytotoxic, anti-proliferative and even pro-
apoptotic effects of the compound (Ahmad et al., 2003;
Lastra and Villegas, 2007).
Sodium hydride (72 mg, 3 mmol) was added in portions to
a well stirred suspension of phosphonium chloride (2) (2
mmol) and aryl aldehyde (3) (2 mmol) in benzene (20 mL)
at 0–5ꢁC, and the mixture was allowed to warm to room
temperature. After additional stirring for 16 h, excess
sodium hydride was quenched by adding methanol (5 mL).
Then chloroform (30 mL) and water was added. The
organic and aqueous layers were separated. The aqueous
layer contained the phosphonium oxide as an impurity and
was discarded. The organic layer was dried over anhydrous
MgSO4, the solvent removed in vacuo, and the residue
purified by preparative TLC using petroleum ether: ethyl
acetate (7:3 v/v) as the eluent.
One documented problem with resveratrol is its limited
bioavailability owing to its metabolism in the liver. Studies
carried out by Kang et al. (2009) have shown that circu-
lating resveratrol has a serum half-life of 8–14 min because
it is rapidly metabolized by sulfation and glucuronation.
To be useful as a chemotherapeutic, resveratrol must
have greater bioavailability and a straightforward approach
to increasing bioavailability involves finding analogues
with comparable activity that lack the hydroxy groups of
resveratrol which consequently cannot be sulfated or glu-
curonated. Thus, we present here such 14 stilbene-based
analogues.
(E)-1-(3,4-difluorophenyl)-2-(4-fluorophenyl)ethene (4c)
White solid. Yield 37%. M. p. = 121–124ꢁC. Anal. Calcd.
for C14H9F3: C, 71.79; H, 3.87; Found: C, 71.23; H, 3.55.
1
FT-IR (KBr, cm-1) vmax: 3131, 1591, 1484, 1121, 995. H
NMR d: 7.70-7.63 (m, 4H), 7.57 (m, 2H), 7.48 (d, 2H),
7.44 (m, 1H).
Experimental
(E)-1-(2,4-difluorophenyl)-2-(4-fluorophenyl)ethene (4d)
Chemistry
White solid. Yield 38%. M. p. = 121–124ꢁC. Anal. Calcd.
for C14H9F3: C, 71.79; H, 3.87; Found: C, 71.31; H, 3.41.
FT-IR (KBr, cm-1) vmax: 3119, 1598, 1484, 1184, 995.
All the chemicals used were procured from Sigma-Aldrich,
SD Fine Chemicals and Rankem Chemicals, and purified
using standard procedures wherever required. Melting
points were recorded in open capillary tube on ‘Superfit
Melting Point Apparatus’ and are uncorrected. IR spectra
were recorded on KBr disk on the ‘Nicolate IR’ instrument
(E)-1-(2,4-dichlorophenyl)-2-(3-chlorophenyl)ethene (4g)
1
and are reported in cm-1. H NMR spectra were recorded
Yellowish white solid. Yield 35%. M. p. = 122–126ꢁC.
Anal. Calcd. for C14H9Cl3: C, 59.30; H, 3.20; Found: C,
59.28; H, 3.29. FT-IR (KBr, cm-1) vmax: 3111, 1590, 1481,
on a ‘Bruker-300’ instrument with tetramethylsilane (TMS)
as the internal standard in CDCl3 as a solvent. Stilbene
analogues namely 4a (Bevington et al., 1995), 4b (Ager
et al., 1972), 4e and 4h (Kvaran et al., 2000), 4f (Bunce
et al., 1990), 4i (Traylor and Stewart, 1986), 4k (Siegrist
et al., 1969), 4l (Gupta et al., 1984), 4m (Murata et al.,
2002) and 4n (Prukala, 2006) were prepared according to
literature.
995, 755 cm-1
.
(E)-1-(2,4-dichlorophenyl)-2-(4-fluorophenyl)ethene (4j)
White solid. Yield 40%. M. p. = 124–127ꢁC. Anal. Calcd.
for C14H9Cl2F: C, 62.95; H, 3.40; Found: C, 62.53; H,
3.51. FT–IR (KBr, cm-1) vmax: 3055, 1591, 1471, 1120,
1
995, 755. H NMR d: 7.67–7.66 (m, 4H), 7.58–7.51 (m,
3H), 7.53 (d, J = 16.2 Hz, 1H), 7.59 (d, J = 16.2 Hz, 1H).
General procedure for synthesis
of benzyl(chloro)triphenylphosphorane (2)
Biological activity
A stirred solution of substituted benzyl chloride (1) (31.7
mmol) in acetonitrile (CH3CN) (20 mL) was treated with
triphenylphosphine (PPh3) (8.57 g, 32.7 mmol) and the
mixture was vigorously stirred with refluxing for 12 h and
then evaporated. The crude product was purified by crys-
tallization from chloroform/ethanol, affording 95% yield as
a white solid.
DPPH-free radical scavenging assay (Blois, 1958; Bondet
et al., 1997)
The free radical scavenging ability of the test compounds
were determined by using the DPPH-free radical
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Med Chem Res (2011) 20:1158–1163
scavenging assay. An ethanolic solution of DPPH (33 mg
in 1000 mL) (3 mL) was mixed with different concentra-
tion of each test compound (500–2500 lg/mL) (3 mL) and
the absorbance of DPPH change at 517 nm was measured
30 min later. A reaction solution without DPPH was used
as blank and DPPH solution as control. Ascorbic acid was
used as standard.
compounds in DMSO as a solvent was used. A 2% solution
of griseofulvin was used as standard. A drug-free control
was included and plates were observed for growth after
48 h of static incubation at 30ꢁC.
Results and discussion
Antibacterial assay (Norris et al., 1972; Rao
and Venugopala, 2007)
Chemistry
The synthesis of some of the stilbene analogues namely 4c,
4d, 4g and 4j were carried out by reacting substituted
benzyl chlorides and substituted benzaldehydes in a two-
step reaction as per Scheme 1 by a Wittig reaction. The
products thus formed were E and Z isomers and were
purified by preparative TLC. As discussed earlier in
introduction, the aim of this work was to synthesize and
evaluate stilbene analogues that lack hydroxyl groups of
resveratrol; therefore, we have used fluorine, chlorine and
methyl groups as substituents on the basis of the principle
of bioisosterism in rational drug design.
The agar cup plate method was used for the assessment of
in vitro antibacterial activity of the synthesized compounds
against Escherichia coli and Staph. aureus. Nutrient agar
plates were prepared by using pour plate technique and
wells were prepared using a sterile cork borer. A 2%
concentration of the synthesized compounds in dimethyl
sulfoxide (DMSO) was used. A 2% solution of penicillin
was used as the standard. A drug-free control was included
and the values of zone of inhibition (mm) were determined
after 24 h of static incubation at 37ꢁC.
Antifungal assay (Shastri and Varudkar, 2009 Rivillas-
´
Acevedo and Soriano-Garcıa, 2007)
Biological evaluation
Free radical scavenging activity
The poison plate method was used for the assessment of in
vitro antifungal activity of the synthesized compounds
against A. niger and P. chrysogenum. Potato dextrose agar
plates were prepared by using pour plate technique for
each compound. A 2% concentration of the synthesized
All synthesized stilbene analogues were tested for their in
vitro antioxidant activity by using the 1,1-diphenyl-1-
picrylhydrazyl (DPPH•)-free radical scavenging assay; the
method first employed by Blois in 1958. DPPH• is a stable
CHO
Step 1
Step 2
R
Cl
PPh3Cl
PPh3
NaH
R'
+
R'
R
CH3CN
C6H6
R
4
1
2
3
4a, R= 4-F, R' = 4'-F
4b, R= 4-F, R' = 3'-F
4c, R= 4-F, R' = 3',4'-F
R= 4-F; 2,4-Cl; 4-Me
R'= 4-F; 3-F; 3,4-F; 2,4-F; 2,4-Cl;
4d, R= 4-F, R' = 2',4'-F
4e, R= 2,4-Cl, R' = 2',4'-Cl
4f, R= 2,4-Cl, R' = 3',4'-Cl
4g, R= 2,4-Cl, R' = 3'-Cl
4h, R= 2,4-Cl, R' = 4'-Cl
3,4-Cl; 3-Cl; 4-Cl; 4-Cl; 4-Me; 4-F
4i, R= 4-Me, R' = 4'-Me
4j, R= 2,4-Cl, R' = 4'-F
4k, R= 2,4-Cl, R' = 4'-Me
4l, R= 4-F, R' = 3'-Cl
4m, R=4-F, R' = 4'-Me
4n, R=4-F, R' = 4'-Cl
Scheme 1 Synthesis of resveratrol analogues (4a–4n)
123

Med Chem Res (2011) 20:1158–1163
1161
Table 1 % Radical scavenging activities of synthesized compounds
(4a–4n)
Table 1 continued
Sl. no Concentration (lg/mL) Absorbance RSA
SD
Sl. no Concentration (lg/mL) Absorbance RSA
SD
4l
1000
500
2500
1500
1000
500
2500
1500
1000
500
50
0.471
0.490
0.399
0.442
0.465
0.472
0.398
0.427
0.433
0.458
0.020
0.030
0.050
0.072
35.57
32.97
45.42
39.53
36.39
35.43
45.55
41.59
40.77
37.35
94.69
92.04
86.74
80.90
0.7238
0.4932
2.1716
1.0684
0.4932
0.8543
0.7616
1.3049
0.7108
1.2159
0.4738
0.3619
0.3619
0.3619
2500
1500
1000
500
0.338
0.403
0.458
0.474
0.369
0.387
0.423
0.435
0.379
0.391
0.405
0.410
0.347
0.363
0.380
0.400
0.319
0.364
0.375
0.405
0.307
0.335
0.372
0.391
0.282
0.321
0.368
0.404
0.386
0.397
0.413
0.429
0.453
0.460
0.470
0.476
0.444
0.455
0.460
0.474
0.445
0.460
0.465
0.477
0.440
0.455
53.81
44.87
37.39
35.16
49.52
47.06
42.13
40.49
48.15
46.51
44.60
43.91
52.53
50.34
48.02
45.28
56.36
50.21
48.70
44.60
58.00
54.17
49.11
46.51
61.42
56.09
49.66
44.73
47.20
45.69
43.50
41.31
38.03
37.07
35.70
34.88
39.26
37.76
37.07
35.16
39.12
37.07
36.39
34.75
39.81
37.76
0.3442
0.3619
0.9108
0.7238
0.8543
1.1197
0.3619
0.3619
0.7616
0.4932
0.7616
0.8321
0.4104
0.2736
0.8321
1.8096
0.7616
0.3619
0.9575
0.6839
0.8321
0.2736
0.4738
0.7238
1.0684
0.3619
0.3619
0.4104
0.7238
0.9477
0.5472
2.1368
0.4932
0.8207
0.6268
0.6268
0.9575
0.7616
0.8970
0.3619
0.8543
0.3619
1.1925
0.4104
0.4932
0.9864
4a
4b
4c
4d
4e
4f
4m
4n
AA
2500
1500
1000
500
2500
1500
1000
500
40
30
2500
1500
1000
500
20
%RSA percentage radical scavenging activity
SD standard deviation
AA ascorbic acid
2500
1500
1000
500
free radical that can accept an electron or a hydrogen
radical to become a stable diamagnetic molecule. The
radical scavenging potential of the synthesized compounds
were determined by measuring the decrease in absorbance
of DPPH• (originally purple in colour) at 517 nm, repre-
senting the formation of its reduced form, 1,1-diphenyl-2-
picryl-hydrazine, which is yellow in colour. All experi-
ments were carried out in triplicate and repeated at least
three times. Results are expressed as percentage radical
scavenging activity and were calculated by the following
formula:
2500
1500
1000
500
2500
1500
1000
500
4g
4h
4i
2500
1500
1000
500
% Radical scavenging activity
Control ꢁ Sample
¼
ꢂ 100
Control
2500
1500
1000
500
The activities of the synthesized compounds are shown in
Table 1. The antioxidant activity of all synthesized stilbene
analogues were evaluated at 10–50 times higher concen-
tration of ascorbic acid (standard). Compounds 4a, 4d,
4e, 4f and 4g showed %RSA [ 50% radical scavenging
activity, while compounds 4b, 4c, 4h, 4m and 4n showed
%RSA [ 40% activity.
2500
1500
1000
500
4j
2500
1500
1000
500
Antibacterial activity
4k
The antibacterial activity of the synthesized stilbene ana-
logues was determined by screening against E. coli and
Staph. aureus bacterial species using the agar cup plate
assay method. The antibacterial activities of the stilbene
2500
1500
123

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Med Chem Res (2011) 20:1158–1163
penicillin, while all other compounds showed moderate
Table 2 Antibacterial activity of compounds (4a–4n) against Staph.
aureus and E. coli
antibacterial activity against Staph. aureus.
Compound
E. coli
(mm)
S. aureus
(mm)
Antifungal activity
4a
-ve
-ve
-ve
-ve
-ve
-ve
-ve
-ve
-ve
-ve
-ve
-ve
-ve
-ve
-ve
17
24
28
36
30
24
28
26
24
20
18
12
22
-ve
20
-ve
40
The antifungal activity of the stilbene analogues was
determined by screening against A. niger and Penicillium
chrysogenum fungal species using the poison plate assay
method and results are presented as the growth of organism
observed or not. The antifungal activities of all synthesized
stilbene analogues are shown in Table 3. All compounds
showed negative antifungal activity against A. niger.
Compounds 4a, 4b, 4f, 4g, 4j, 4l and 4n inhibited the
growth of P. chrysogenum and proved their antifungal
potential.
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
Conclusion
DMSO
Penicillin
The antioxidant activity was evaluated by DPPH-free
radical scavenging assay and compounds showed moderate
(%RSA [ 40) to significant (%RSA [ 50) radical scav-
enging activity.
-ve no antibacterial activity
mm Zone of inhibition in mm
All compounds showed negative antibacterial activity
against E. coli. Compound 4c showed nearly equipotent
antibacterial activity against S. aureus as compared to
penicillin, while all other compounds showed moderate to
significant antibacterial activity against S. aureus. All
compounds showed negative antifungal activity against
A. niger. Compounds 4a, 4b, 4f, 4g, 4j, 4l and 4n inhibited
the growth of P. chrysogenum.
Table 3 Antifungal activity of compounds against Aspergillus niger
and Penicillium chrysogenum
Compound
Aspergillus
niger
Penicillium
chrysogenum
4a
?ve
?ve
?ve
?ve
?ve
?ve
?ve
?ve
?ve
?ve
?ve
?ve
?ve
?ve
?ve
-ve
-ve
-ve
?ve
?ve
?ve
-ve
-ve
?ve
?ve
-ve
?ve
-ve
?ve
-ve
?ve
-ve
4b
4c
4d
4e
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4g
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