Synthesis and antimicrobial activity of 7-alkoxyhesperetin derivatives

Article abstract of DOI:10.1007/s00044-010-9462-7

Some new 7-alkoxyhesperetin derivatives, 7-methoxy-(c), 7-butoxy-(d), 7-octyloxy-(e), 7-decyloxy- (f), and 7-dodecyloxyhesperetin(g), were synthesized and confirmed by UV, IR, 1H NMR, and MS spectra data. The series of the synthesized compounds has been screened for their antibacterial activity in vitro and evaluated their structure-activity relationships. Substitution of the H with alkyl groups at C-7-OH led to significant change of their antibacterial activity. The antibacterial activity of 7-alkoxyhesperetin derivatives increased with the elongating of the length of aliphatic chain, and the maximum activity was reached at twelve carbon atoms. Compound f showed the highest antibacterial activity among all the compounds. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9462-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1200–1205
DOI 10.1007/s00044-010-9462-7
ORIGINAL RESEARCH
Synthesis and antimicrobial activity of 7-alkoxyhesperetin
derivatives
•
Baoshun Zhang Xiaoli Ye Zhu Chen
•
•
•
•
•
Xiaofei Jiang Lujiang Yuan Jun Yi
Xuegang Li
Received: 18 May 2010 / Accepted: 28 September 2010 / Published online: 12 October 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Some new 7-alkoxyhesperetin derivatives,
7-methoxy-(c), 7-butoxy-(d), 7-octyloxy-(e), 7-decyloxy-
(f), and 7-dodecyloxyhesperetin(g), were synthesized and
Introduction
Natural products including thousands of compounds are
important for plant biology and human nutrition, and they
have been applied for therapeutic purposes in traditional
medicine. Hesperidin is one of the most abundant flavo-
noids and is present in a large number of fruits and vege-
tables (Garg et al., 2001). Many studies reported that
hesperidin and its derivatives possessed a broad range of
pharmacological properties, including antimicrobial (Bae
et al., 2000), antioxidant (Gorinstein et al., 2007; Etchev-
erry et al., 2008), anti-inflammatory (Galati et al., 1994;
Yeh et al., 2007), antihypertensive (Galati et al., 1996),
antihypercholesterolaemic (Son et al., 1991; Jeong et al.,
2003), antimetastatic (Hsiao et al., 2007; Yeh et al., 2009),
and antitumor (Shen et al., 2004) activities.
1
confirmed by UV, IR, H NMR, and MS spectra data. The
series of the synthesized compounds has been screened for
their antibacterial activity in vitro and evaluated their
structure–activity relationships. Substitution of the H
with alkyl groups at C-7-OH led to significant change of
their antibacterial activity. The antibacterial activity of
7-alkoxyhesperetin derivatives increased with the elongat-
ing of the length of aliphatic chain, and the maximum
activity was reached at twelve carbon atoms. Compound
f showed the highest antibacterial activity among all the
compounds.
Keywords Synthesis ꢀ 7-alkoxyhesperetin derivatives ꢀ
Hesperetin ꢀ Antibacterial activity
Hesperetin, aglycone of hesperidin, was found to show
a significant cholesterol-lowering ability (Lee et al.,
1999). Hesperetin ester and ether derivatives possessing a
long alkyl chain were synthesized and examined for their
hypocholesterolemic activities in high cholesterol-fed
mice. Hesperetin 7-O-lauryl ether and 7-O-oleyl ether
exhibited strong cholesterol-lowering effects (Jeong et al.,
2003).
B. Zhang ꢀ L. Yuan ꢀ J. Yi ꢀ X. Li (&)
College of Pharmaceutical Sciences, Southwest University,
Chongqing 400716, People’s Republic of China
e-mail: xuegangli2000@yahoo.com.cn
Hesperetin dihydrochalcone (DHC), which is the poorly
soluble aglycone portion of neohesperidin DHC, is sweet.
DuBois reported that water-soluble derivatives of hes-
peretin DHC could be prepared by attaching carboxyalkyl
chains to the hydroxyl group at position 4. These com-
pounds, although intensely sweet, were found to suffer
from the poor taste-timing characteristics and have limited
solubility in the pH range of beverage systems. Thus, 15
sulfonated hesperetin DHC derivatives were prepared,
which led to high water solubility throughout the useful pH
range and, as the result of the increase in hydrophilic
X. Ye
College of Life Science, Southwest University,
Chongqing 400716, People’s Republic of China
Z. Chen
Department of Pharmacy, Chongqing Medical
and Pharmaceutical College, Chongqing 400030,
People’s Republic of China
X. Jiang
College of Chemical and Environmental Engineering,
Chongqing Three Gorges University, Chongqing 404000,
People’s Republic of China
123

Med Chem Res (2011) 20:1200–1205
1201
character, might have provided the DHC sweeteners with
improved taste-timing characteristics (DuBois et al., 1977).
Although, lots of new hesperidin derivatives and their
bioactivities were studied, no previous studies are available
on the synthesis and antibacterial activity in vitro of a
series of 7-alkoxyhesperetin derivatives. The aim of this
study is to synthesize these compounds and evaluate their
structure and antibacterial activity relationships.
dosage and bacterial concentration. At the same time, this
method is also used to decide the initial dosage of the
compounds (400 lg/mL) against the microorganisms and
the concentration of the bacteria (105 CFU/mL), but this
method cannot easily measure the MICs of these com-
pounds. The 2-fold serial dilution test is the another
method used to evaluate the antibacterial effect. In the
second method, the initially dilute concentration of these
compounds and the designed bacterial concentration are
based on the screening result of the first method, and then
the MICs of the active compounds can easily be obtained.
Diameter of inhibitory zone (DIZ) and minimum
inhibitory concentration (MIC) of 7-alkoxyhesperetin
derivatives against microbial are presented in Tables 1 and 2.
Antibacterial activities of compounds c–g were increased
4- to 64-fold over that of compounds a–b which possessed
relatively weaker inhibitory effects. Compounds c–g dis-
played broad antibacterial spectra and exerted stronger
antibacterial effects. The antibacterial effect of 7-alkoxy-
hesperetin derivatives increased with the increase of the
length of aliphatic chain, and the maximum activity was
reached at twelve carbon atoms. Four selected bacterial
strains Bacillus subtilis, Staphylococcus aureus, Proteus
vulgaris, and Escherichia coli were more sensitive to the
synthesized compounds. 7-Alkoxyhesperetin derivatives
displayed a good range of inhibition (1.5–3.9 mm)
against different bacteria strains at the dose level of
400 lg/mL; compound f showed the maximum activity
(MIC = 6.25 lg/mL) against Staphylococcus aureus among
all the compounds, perhaps due to the attribution of the
presence of long alkoxy group. Besides, compounds pos-
sessing hydroxyl and methoxy groups in the benzene ring
were found to be moderately to highly active against all the
bacterial strains. Rest of the compounds were found to be
either inactive or presenting a MIC value more than
400 lg/mL.
Results and discussion
Chemistry
The spectra data and other characterization of compounds
b–g are shown in the experimental section. The IR spectra of
the compounds show absorption bands at m = 3418 cm-1
for OH, m = 2850–2924 cm-1 for CH3 and CH2, m =
1635 cm-1 for C=O, and 1440–1574 cm-1 for Ar-stretching
mode. 1H NMR spectra of the compounds show a common
d = 2.7 (dd, J = 2.8, 17.1 Hz, 1H, 3-H cis), 3.8 (s, 3H, 40-
OCH3), 3.0 (dd, J = 12.67, 17.09 Hz, 1H, 3-H trans), 5.3
(dd, J = 2.75, 12.52 Hz, 1H, 2-H), 5.9–6.9 (m, 5H, Ar–H),
and 12.0 (s, 1H, 5-OH) ppm. The distinct 1H NMR spectra of
7-alkoxylhesperetin derivatives show d = 0.8 (CH3),
1.2–1.7 (CH2) and 3.9 (OCH2) ppm. All these spectra data
confirm the structure of the compounds.
Antibacterial activity of 7-alkoxyhesperetin derivatives
Agar well diffusion assay and 2-fold serial dilution test are
two different methods to evaluate the antibacterial activity
of 7-alkoxyhesperetin derivatives. Agar well diffusion
assay is the first method to compare the antibacterial
activities of the different kinds of synthesized compounds
under the same condition of the designed compound
Table 1 Average diameters of
Sr. no
Compound
Gram-positive bacteria
Gram-negative bacteria
inhibitory zone (mm) of
7-alkoxyhesperetin derivatives
on microbials at the dose level
of 400 lg/mL
B. subtilis
S. aureus
P. vulgaris
E. coli
1
2
3
4
5
6
7
8
9
Negative control
–
–
–
–
Streptomycin sulfate
2.2
–
2.8
–
4.6
0.8
1.6
2.2
2.0
2.6
3.3
2.8
5.3
–
a
b
c
d
e
f
0.8
0.7
1.8
2.0
2.0
1.5
–
–
1.8
2.6
3.1
3.9
3.6
0.7
1.6
2.5
2.2
1.8
All experiments were run in
triplicate; – not detected
g
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Med Chem Res (2011) 20:1200–1205
Table 2 Minimum inhibitory concentration (MIC, lg/mL) of 7-alkoxyhesperetin derivatives on microbials
Sr. no
Compound
Gram-positive bacteria
Gram-negative bacteria
B. subtilis
S. aureus
P. vulgaris
E. coli
1
2
3
4
5
6
7
8
9
Negative control
–
–
–
–
Streptomycin sulfate
50
25
3.13
200
100
50
1.56
–
a
b
c
d
e
f
–
–
200
200
100
50
–
–
100
25
200
100
25
50
100
50
12.5
6.25
6.25
25
50
12.5
25
g
100
All experiments were run in triplicate; – not detected
1
Conclusion
Melting points, TLC, UV, IR, MS, and H NMR, were
used to confirm the structures of new compounds. Melting
points (M. P.) were taken on the Netzsch Differential
Scanning Calorimetry (DSC 200PC) and are uncorrected.
Thin-layer chromatography (TLC) was run on the silica
gel-GF254-coated glass plates with mixtures of petroleum
(60–90 °C) and ethyl acetate as developer and visualized at
254 nm with ultraviolet light. Ultraviolet (UV) spectra
were obtained in methanol with a Hitachi Model U-1800
spectrophotometer. Infrared (IR) spectra were recorded on
a Perkin–Elmer Model 137 instrument using KBr pellets.
Mass spectrometry (MS) spectra were collected on Agilent
5973N instrument using ESI mode. Proton nuclear mag-
netic resonance (1H NMR) spectra were determined using
Bruker Model Avance DMX 300 spectrometer (300 M)
with TMS as an internal standard and CDCl3/DMSO as
solvent.
In this study, 7-alkoxyhesperetin derivatives were synthe-
sized successfully. Substitution of the H with alkyl groups
at C-7-OH exhibit promising antibacterial activity. As we
know, with the elongating of the hydrocarbon chains of
7-alkoxyhesperetin, the antibacterial effect increased cor-
respondingly. A major reason is probably attributed to the
increase of the hydrophobic property, because the synthe-
sized compounds were mainly dependent on the hydro-
phobic interaction with membrane proteins of bacteria to
inhibit bacteria growth (Ye et al., 2005).
Bacteria biofilms are biomolecular lipid layers: the
hydrocarbon chains in lipid bilayers provide a virtually
impenetrable barrier to ionic and polar substances since
their hydrophobic property. The fat-soluble substances
simply diffuse through the lipid bilayer below their con-
centration gradients (Trudy and James, 2000). The stronger
hydrophobic property of the substances makes it easier for
them to diffuse through membranes (Liu et al., 2001).
Moreover, according to the study on the structure–
activity relationships of synthesized compounds, it is
concluded that this method is useful as a template for future
development through modification or derivatisation to
design more potent biologically active compounds, and this
preliminarily biological study is encouraging to further
explore their broad spectra pharmacological activities.
Microorganisms and media
Four pathogenic microorganisms used for the antibacterial
assay were kindly provided by Chongqing Medical Uni-
versity. They are Gram-positive (G?) bacteria, viz.,
Bacillus subtilis (ATCC 9372), Staphylococcus aureus
(ATCC 25923), Gram-negative (G-) bacteria, viz., Proteus
vulgaris (ATCC 14153), and Escherichia coli (ATCC
25922). The bacteria were grown in beef-extract peptone
medium.
Experimental
Agar well diffusion assay
Chemistry
Antibacterial activities of synthesized compounds were
tested by agar diffusion method (Wang et al., 2009; Yang
et al., 2007). Overnight culture of the respective test bac-
teria was adjusted to 105 CFU (colony-forming units) per
mL, 1 mL; of such a culture was added to 15 mL respec-
tive medium, evenly mixed and poured into Petri dishes
Hesperetin (99% purity) was provided by Chemistry
Institute of Pharmaceutical Resource of Southwest Uni-
versity; other reagents were of analytical grade purchased
from Chongqing Chemical Reagent Co. Ltd (P.R. China).
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Med Chem Res (2011) 20:1200–1205
1203
(9 cm in diameter). The compounds were, respectively,
dissolved in H2O containing 1% DMF to reach final con-
centrations ranging from 0.78 to 400 lg/mL as the test
solutions and sterilized by filtration through 0.45-lm ster-
ilizing Millipore express filter. The discs (6 mm in diam-
eter) were then applied; 10 lL of the test solutions and
control were added to each disc, respectively. Petri dishes
were incubated at 37 °C for 24 h (bacteria). The average
diameters of inhibition zone (DIZ) surrounding the discs
were measured visually, which did not include the diameter
of the paper disc. DIZ was expressed in millimeters. The
H2O/1% DMF was used as negative control. Streptomycin
sulfate was used as antibacterial positive control. All the
experiments were run in triplicate.
3-H cis), 3.01 (dd, J = 12.67, 17.09 Hz, 1H, 3-H trans), 3.8
(s, 3H, 40-OCH3), 5.29 (dd, J = 2.75, 12.52 Hz, 1H, 2-H),
and 5.88–6.95 (m, 5H, Ar–H); MS (m/z, %): 300.78 (M?-
1,12), 285.74 (100), 241.73 (62), 198.76 (47), 173.76 (21),
and 124.81 (36).
Synthesis of 7-alkoxyhesperetin derivatives
The 7-alkoxyhesperetin derivatives were synthesized
according to the previous literature (Shan et al., 2008). A
250-mL, three-necked flask, equipped with magnetic stir
bar and condenser, was charged with 1.0 g (3.31 mmol) of
purified hesperetin, 2.4 g (17.4 mmol) of dry K2CO3, and
70 mL of dry acetone, 1.2 mL of RBr (Fig. 1), The solu-
tion was refluxed for 7.5 h at 56 °C, Then to the mixture
solution was added 0.2 g (0.662 mmol) of hesperetin, and
1.2 g (8.7 mmol) of dry K2CO3, and allowed to continue to
react at 56 °C for 3 h. The slurry was cooled at 45 °C and
dried in vacuo. The crude product was purified by a silica-
gel column (petroleum ether:ethyl acetate = 10:1, V/V) to
obtain the target compound as colorless crystalline solid.
Minimum inhibitory concentration (MIC)
Minimum inhibitory concentration (MIC) was determined
as the lowest concentration of compound which completely
inhibited the bacterial growth after incubation time. MIC
was evaluated using the 2-fold serial dilution test (Ma,
2001). The compounds were dissolved in H2O containing
1% DMF and diluted to different concentrations ranging
from 0.78 to 400 lg/mL. The mixtures of serious dilutions
of compounds and the microbes (105 CFU/mL) in different
media were incubated at 37 °C for 24 h (bacteria).
Microbial growth was tested by measuring the absorbance
at 655 nm with a spectrophotometer. The H2O/1% DMF
was used as a control. Streptomycin sulfate was used as
positive control. All the experiments were run in triplicate.
7-Methoxyhesperetin
Rf: 0.55 (petroleum ether:acetic ether = 1:1,V/V); yield:
28.9%; Mp 167–169 °C; UV (MeOH, kmax): 288 nm; IR
Procedure for preparing hesperetin from hesperidin
The hesperetin was synthesized by literature procedure
(Thomas Seitz and Wingard, 1978). A 500-mL, three-
necked flask, equipped with magnetic stir bar and con-
denser, was charged with 3.5 g (5.73 mmol) of purified
hesperidin, 280 mL of dry CH3OH, and 10 mL of 96%
H2SO4. The solution was refluxed for 7.5 h and poured into
1.2 L of ethyl acetate. The mixture was washed with 15%
aqueous NaCl (1 9 280 mL), H2O (3 9 420 mL, final was
colorless), saturated aqueous NaCl, and dried (Na2SO4).
Evaporation afforded pale-yellow powder. The crude
product was dissolved in acetone (70 mL) and added
dropwise (60 min) to a vigorously stirred (overhead)
mixture of 700 mL solution (H2O:acetic acid = 150:1,v/v)
maintained at 95–100 °C. The slurry was cooled to 45 °C
and the hesperetin filtered and dried in vacuo.
1''
4'' 3''-2'' 1''
CH3(CH2)2CH2
8'' 7''-2'' 1''
e CH3(CH2)6CH2
Rf: 0.29 (Petroleum ether:acetic ether = 2:1, V/V);
Yield: 65.4%; Mp 224–226 °C; UV (MeOH, kmax): 288,
325 nm; IR (KBr, mmax cm-1): 3499, 3433 (OH), 1635
R=: c CH3
d
12'' 11''-2'' 1''
CH3(CH2)10CH2
16'' 15''-2'' 1''
g CH3(CH2)14CH2
f
1
(C=O), 1586, 1514, 1473, and 1442 (Ar); H NMR (300
MHz, CDCl3, d ppm): 2.67 (dd, J = 2.84, 17.08 Hz, 1H,
Fig. 1 Protocol for the synthesis of 7-alkoxyhesperetin derivatives
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Med Chem Res (2011) 20:1200–1205
(KBr, mmax cm-1): 3399 (OH), 2946 (CH3), 1645 (C=O),
and 1593, 1515, 1568, and 1455 (Ar); 1H NMR (300 MHz,
CDCl3, d ppm): 2.75 (dd, J = 2.85, 17.16 Hz, 1H, 3-H
cis), 3.03 (dd, J = 12.96, 17.13 Hz,1H, 3-H trans), 3.81 (s,
3H, 40-OCH3), 3.92 (s, 3H,7-OCH3), 5.3 (dd, J = 2.58,
12.75 Hz, 1H, 2-H), 5.7 (s, 1H, 30-OH), 6.05 (d, 2H, 6,
8-H), 6.88–7.04 (m, 3H, 20,50, 60-H), and 12.02 (s, 1H,
5-OH); MS (m/z, %): 316.68 (M??1, 16), 298.82(13),
192.69 (54), 176.71 (100), and 166.71 (75).
(17), 347.01 (46), 320.98 (95), 302.83 (38), 176.72 (100),
and 152.72 (60).
7-Hexadecyloxyhesperetin
Rf: 0.75 (petroleum ether:acetic ether = 2:1,V/V); yield:
5.3%; Mp 110–113 °C; UV (MeOH, kmax): 286.5 nm; IR
(KBr, mmax cm-1): 3423 (OH), 2919, 2851 (CH3, CH2),
1
1637 (C=O), and 1517 (Ar); H NMR (300 MHz, CDCl3,
d ppm): 0.86 (t, 3H, 1600-CH3), 1.26–1.78 (m, 28H, 200-1500-
CH2), 2.8 (dd, J = 2.3, 17.1 Hz, 1H, 3-H cis), 3.02 (dd,
J = 12.7, 17.13 Hz, 1H, 3-H trans), 3.92 (s, 3H, 40-OCH3),
3.95 (d, 2H, 100-OCH2), 5.29 (dd, J = 2.57, 12.78 Hz, 1H,
2-H), 5.71 (s, 1H, 30-OH), 6.03 (d, 2H, 6, 8-H), 6.87–7.76
(m, 3H, 20, 50, 60-H), 12 (s, 1H, 5-OH); MS (m/z, %):
527.18 (M??1, 75), and 372.98 (100).
7-Butoxyhesperetin
Rf: 0.57 (petroleum ether:acetic ether = 1:1, V/V); yield:
15%; Mp 111–113 °C, UV (MeOH, kmax): 286.5 nm; IR
(KBr, mmax cm-1): 3543, 3436 (OH), 2961, 2944, 2874
1
(CH3, CH2), 1631 (C=O), 1594, 1521, and 1444 (Ar). H
NMR (300 MHz, CDCl3, d ppm): 0.94 (t, 3H, 400-CH3),
1.42–1.77 (m, 4H, 200, 300-CH2), 2.74 (dd, J = 2.67, 17.04
Hz, 1H, 3-H cis), 3.02 (dd, J = 12.96, 17.1Hz, 1H, 3-H
trans), 3.91 (d, 3H, 40-OCH3), 3.97 (d, 2H, 100-OCH2), 5.29
(dd, J = 2.35, 12.75 Hz, 1H, 2-H), 6.03 (s, 1H, 30-OH),
6.05 (d, 2H, 6, 8-H), 6.87–6.73 (m, 3H, 20, 50, 60-H), 12 (s,
1H, 5-OH); MS (m/z, %): 358.92 (M??1, 7), 302.81 (10),
234.74 (32), 208.72 (53), 176.71 (100), and 152.73 (62).
Acknowledgments This study was supported by the Fundamental
Research Funds for the Central Universities, P.R. China (XDJK2009C087)
(XDJK2009C095) and Medicinal & Scientific Research projects of
Chongqing Municipal Health Bureau, P.R. China (2009-2-140).
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12.1 (s, 1H, 5-OH); MS (m/z, %): 471 (M??1, 9), 453.07
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