Structure and antibacterial activity of 3-(3,4-dimethoxyphenyl) furan-2(5H)-ones

Article abstract of DOI:10.1007/s10870-011-0246-9

Crystalline hydrate of the title compound (5), C₁₉H ₂₆N₂O₅·2(H₂O), was structurally characterized by single crystal X-ray diffraction. It crystallizes in monoclinic system space group P 21/c with a =

Full text of DOI:10.1007/s10870-011-0246-9

J Chem Crystallogr (2012) 42:323–329
DOI 10.1007/s10870-011-0246-9
ORIGINAL PAPER
Structure and Antibacterial Activity of 3-(3,4-Dimethoxyphenyl)
furan-2(5H)-ones
•
Zhu-Ping Xiao Li-Cheng Yi Tian-Fang Yi
•
•
•
Kai-Shuang Xiang Ze-Jun Huang
•
Hai-Liang Zhu
Received: 1 June 2011 / Accepted: 3 December 2011 / Published online: 16 December 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Crystalline hydrate of the title compound (5),
C19H26N2O5Á2(H2O), was structurally characterized by
single crystal X-ray diffraction. It crystallizes in mono-
antimicrobial activities against three Gram-positive
organisms and a Gram-negative organism, and compound 5
was the most active against Staphylococcus aureus ATCC
25923.
˚
clinic system space group P 21/c with a = 7.3987(7) A,
˚
˚
b = 17.8691(16) A, c = 17.0022(13) A, b = 112.944(3)°,
3
V = 2070.0(3) A , Z = 4, R1 = 0.0592, wR2 = 0.1016,
˚
Keywords Synthesis Á Crystal structure Á
3-Arylfuran-2(5H)-one Á Antibacterial
and T = 298(2) K. The X-ray structure determination
revealed that the center furanone ring is nearly coplanar
with 3,4-dimethoxybenzene ring, making a dihedral angle
of 0.860(69)°. Two kinds of centrosymmetric tetramers
characterized by graph-set motifs of R87(36) and R46(32) are
formed through O–HÁÁÁO, O–HÁÁÁN and C–HÁÁÁO hydrogen
bonding interactions, which generate a sheet of edge-fused
rings parallel to the (011) plane. These sheets are further
linked into a three dimensional network by C–HÁÁÁp inter-
actions. Nine 3-(3,4-dimethoxyphenyl)furan-2(5H)-ones
were synthesized and fully characterized by elemental
analysis, MS and 1H NMR. All of them were evaluated for
Introduction
Compounds with c-butyrolactone-core show diverse bio-
logical activities such as anti-oxidative, anti-inflammatory
and antibacterial activity [1–3], and have been receiving
increasing attention in recent years [4, 5]. In 2006, Latt-
mann et al. [6] reported 5-alkoxy-4-aminofuran-2(5H)-ones
(Scheme 1) showing good antibacterial activity against
multiresistant Staphylococcus aureus. Subsequently, Bailly
et al. [7] reported 4,5-diaryl-3-hydroxyfuran-2(5H)-ones
(Scheme 1) being good inhibitors against HIV-1 integrase.
Recently, we determined that 3-arylfuran-2(5H)-ones
(Scheme 1) as potent inhibitors against tyrosyl-tRNA syn-
thetase (TyrRS) [8, 9], which is an aminoacyl-tRNA syn-
thetases (aaRSs). AaRSs are essential enzymes involved in
protein biosynthesis in all living organisms. However, these
enzymes have been subjected to significant evolutionary
divergence, and selective inhibition of bacterial enzymes is
therefore a valuable strategy for the production of antibiotics
[10]. As a part of our ongoing studies on furan-2(5H)-ones,
we designed and synthesized a series of 3-(3,4-dimethoxy-
phenyl)-furan-2(5H)-ones for screening antibacterial activ-
ity. For confirmation of the structure the obtained
compounds (1–9), the single crystal structure of 3-(3,4-
dimethoxyphenyl)-4-(2-(4-methylpiperazin-1-yl)ethoxy)
furan-2(5H)-one (5) was selected to determine.
Z.-P. Xiao (&) Á L.-C. Yi Á T.-F. Yi Á K.-S. Xiang Á
Z.-J. Huang Á H.-L. Zhu
School of Chemistry & Chemical Engineering, Key Laboratory
of Ecotourism’s Application Technology, Hunan Province and
Key Laboratory of Hunan Forest Products and Chemical
Industry Engineering, Jishou University, Jishou 416000,
People’s Republic of China
e-mail: xiaozhuping2005@163.com
H.-L. Zhu (&)
State Key Laboratory of Pharmaceutical Biotechnology,
Nanjing University, Nanjing 210093,
People’s Republic of China
e-mail: zhuhl@nju.edu.cn
123

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J Chem Crystallogr (2012) 42:323–329
Scheme 1 The structures
of some furanones
R
O
Ar
X
HN
O
X
Ar
O
Ar
Ar
OH
O
O
O
O
X= Cl, Br
5-alkoxy-4-aminofuran-2 (5H)-one
X= NHR(Ar), OR
4,5-diaryl-3-hydroxyfuran- 2(5H)-one
3-arylfuran-2 (5H)-one
Experimental Section
chromatography on silica gel, eluting with EtOAc/petro-
leum ether.
Reagents and Techniques
3-(3,4-Dimethoxyphenyl)-4-hydroxyfuran-2(5H)-one (1)
2-(3,4-Dimethoxyphenyl)acetic acid was purchased from
Aldrich (USA) and the other chemicals were purchased
from Sinopharm Chemical Reagent Co., Ltd (China).
Separation of the compounds by column chromatography
was carried out with silica gel 60 (200–300 mesh ASTM,
E. Merck). The quantity of silica gel used was 30–70
times the weight charged on the column. Then, the eluates
were monitored using TLC. Melting points (uncorrected)
were determined on a XT4 MP apparatus (Taike Corp.,
Beijing, China). ESI mass spectra were obtained on a
Mariner System 5304 mass spectrometer, and 1H NMR
spectra were recorded on a Bruker AV-300 spectrometer
at 25 °C with TMS and solvent signals allotted as internal
standards. Chemical shifts were reported in ppm (d).
Elemental analyses were performed on a CHN-O-Rapid
instrument and were within 0.4% of the theoretical
values.
Colorless crystal, 53%, mp 210–212 °C, 1H NMR (DMSO-
d6): 3.88 (s, 3H); 3.89 (s, 3H); 4.77 (s, 2H); 6.75 (dd,
J = 8.5 Hz, J = 2.0 Hz, 1H); 6.77 (d, J = 2.1 Hz, 1H);
6.93 (d, J = 8.1 Hz, 1H); EIMS m/z 236 (M?). Anal. Calcd
for C12H12O5: C, 61.01; H, 5.12; Found: C, 61.47; H, 5.10.
4-(2-Bromoethoxy)-3-(3,4-dimethoxyphenyl)furan-2(5H)-
one (2)
Light yellow crystal, 47%, mp 140–142 °C, 1H NMR
(CDCl3): 2.68 (t, J = 5.5 Hz, 2H); 3.88 (s, 3H); 3.90 (s,
3H); 4.20 (t, J = 5.5 Hz, 2H); 4.79 (s, 2H); 6.91 (d,
J = 8.4 Hz, 1H); 7.50 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H);
7.56 (d, J = 1.8 Hz, 1H); EIMS m/z 342 (M?). Anal. Calcd
for C14H15BrO5: C, 49.00; H, 4.41; Br, 23.28; Found: C,
49.13; H, 4.41; Br, 23.24.
General Procedure for Preparation of Compounds 1–9
4-(2-(Cyclohexylamino)ethoxy)-3-(3,4-
dimethoxyphenyl)furan-2(5H)-one (3)
Compounds 1 and 2 were obtained according to the pro-
cedure previously described [11, 12], which were further
treated as follows to produce compounds 3–9 (Scheme 2;
Table 2). A mixture of compound 2 (0.5 mmol) and tri-
ethylamine (225 lL, 1.5 mmol) was dissolved in 15 mL of
dry DMF and heated to 50 °C. The solution was received
3–4 interval injections of an appropriate amine (0.6 mmol)
within 2 h. The mixture was then stirred for 6–10 h. After
30 mL of water was added, the resulted mixture was
extracted thrice with EtOAc. The combined organic layer
washed with brine and dried over MgSO4. Removement of
the solvent under reduced pressure gave a brown oil, which
was purified by column chromatography on silica gel,
eluting with CHCl3/CH3OH (saturated with ammonia, from
37/1 to 80/1) to give compounds 3–5. As for the synthesis
of compounds 6–9, a mixture of compound 1 (0.5 mmol),
an appropriately substituted aniline (0.6 mmol) and p-tol-
uene sulphonic acid (3.4 mg, 0.02 mmol) was heated to
90 °C for 10 min. Five mL toluene was then added and
refluxed for 3–7 h. After toluene was removed under
reduced pressure, the residue was purified by column
Colorless crystal, 68%, mp 137–139 °C, 1H NMR
(CDCl3): 0.80–1.02 (m, 3H); 1.23–1.42 (m, 3H); 1.60–1.74
(m, 4H); 1.93 (bs, 1H); 3.23 (t, J = 6.4 Hz, 2H); 3.32–3.43
(m, 1H); 3.54 (t, J = 6.3 Hz, 2H); 3.85 (s, 3H); 3.89 (s,
3H); 4.88 (s, 2H); 6.80 (d, J = 1.8 Hz, 1H); 6.81 (dd,
J = 8.0 Hz, J = 1.8 Hz, 1H); 6.86 (d, J = 8.3 Hz, 1H);
EIMS m/z 361 (M?). Anal. Calcd for C20H27NO5: C,
66.46; H, 7.53; N, 3.88; Found: C, 66.51; H, 7.51; N, 3.87.
3-(3,4-Dimethoxyphenyl)-4-(2-(piperidin-1-
yl)ethoxy)furan-2(5H)-one (4)
Colorless crystal, 89%, mp 116–117 °C, 1H NMR
(CDCl3): 1.38–1.49 (m, 2H); 1.51–1.67 (m, 4H); 2.46 (t,
J = 5.0 Hz, 4H); 2.73 (t, J = 5.5 Hz, 2H); 3.90 (s, 3H);
3.91 (s, 3H); 4.22 (t, J = 5.5 Hz, 2H); 4.87 (s, 2H); 6.89 (d,
J = 8.4 Hz, 1H); 7.50 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H);
7.54 (d, J = 1.8 Hz, 1H); EIMS m/z 347 (M?). Anal. Calcd
for C19H25NO5: C, 65.69; H, 7.25; N, 4.03; Found: C,
65.60; H, 7.27; N, 4.04.
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J Chem Crystallogr (2012) 42:323–329
325
Scheme 2 Synthetic rout of
3-(3,4-dimethoxyphenyl)furan-
2(5H)-ones
O
O
O
O
OEt
EtO
Br
MeO
MeO
MeO
MeO
O
NaH
O
OH
CO2H
EtONa
MeO
OMe
1
O
O
O
O
Br
Br
amine
O
R
Br
MeO
MeO
OMe
OMe
2
3-5
(See Table 2 for details)
O
O
amine
R
(See Table 2 for details)
MeO
OMe
6-9
3-(3,4-Dimethoxyphenyl)-4-(2-(4-methylpiperazin-1-yl)
ethoxy)furan-2(5H)-one (5)
(d, J = 8.8 Hz, 2H); 5.44–5.55 (m, 4H); 5.60 (d, J =
8.0 Hz, 1H); 5.75 (t, J = 8.0 Hz, 1H). 13C NMR (DMSO-
d6):172.82; 160.04; 159.63; 158.92; 140.70; 135.58;
133.19; 127.57; 124.78; 124.15; 123.64;123.28; 114.70;
113.21; 97.49; 66.40; 56.83; 56.68. EIMS m/z 345 (M?).
Anal. Calcd for C18H16ClNO4: C, 62.52; H, 4.66; Cl,
10.25; N, 4.05; Found: C, 62.60; H, 4.67; Cl, 10.23; N,
4.04.
1
Colorless crystal, 64%, mp 69–71 °C, H NMR (DMSO-
d6): 2.16 (s, 3H); 2.23–2.38 (m, 4H); 2.42–2.55 (m, 4H);
2.73 (t, J = 5.3 Hz, 2H); 3.75 (s, 3H); 3.76 (s, 3H); 4.34 (t,
J = 5.4 Hz, 2H); 5.11 (s, 2H); 6.97 (d, J = 8.4 Hz, 1H);
7.49 (d, J = 2.0 Hz, 1H); 7.53 (dd, J = 8.4 Hz,
J = 2.0 Hz, 1H); EIMS m/z 362 (M?). Anal. Calcd for
C19H26N2O5: C, 62.97; H, 7.23; N, 7.73; Found: C, 62.88;
H, 7.25; N, 7.74.
3-(3,4-Dimethoxyphenyl)-4-(2-methoxyphenylamino)
furan-2(5H)-one (8)
Colorless crystal, 85%, mp 120–121 °C, 1H NMR
(CDCl3): 3.86 (s, 3H); 3.92 (s, 6H); 5.05 (s, 2H); 6.91–6.98
(m, 4H); 7.07–7.19 (m, 3H); 7.57 (s, 1H). 13C NMR
(DMSO-d6):172.78; 160.05; 159.97; 159.64; 158.90;
140.72; 133.17; 127.57; 124.75; 124.22; 123.61;115.06;
114.75; 113.24; 97.49; 66.40; 56.81; 56.68; 55.91. EIMS
m/z 341 (M?). Anal. Calcd for C19H19NO5: C, 66.85; H,
5.61; N, 4.10; Found: C, 66.74; H, 5.62; N, 4.11.
4-(2-Chlorophenylamino)-3-(3,4-dimethoxyphenyl)
furan-2(5H)-one (6)
Colorless crystal, 68%, mp 162–164 °C, 1H NMR
(CDCl3): 2.28 (s, 3H); 2.31 (s, 3H); 3.42 (s, 2H); 5.41 (d,
J = 8.0 Hz, 1H); 5.51–5.61 (m, 4H); 5.72 (t, J = 7.7 Hz,
1H); 5.79 (s, 1H); 5.91 (d, J = 8.0 Hz, 1H). 13C NMR
(DMSO-d6):172.77; 160.05; 159.67; 158.90; 140.68;
134.77; 134.11; 127.13; 126.74; 125.85; 125.04;121.07;
114.75; 113.16; 97.47; 66.42; 56.83; 56.69. EIMS m/z 345
(M?). Anal. Calcd for C18H16ClNO4: C, 62.52; H, 4.66; Cl,
10.25; N, 4.05; Found: C, 62.48; H, 4.66; Cl, 10.26; N,
4.04.
3-(3,4-Dimethoxyphenyl)-4-(2-nitrophenylamino)
furan-2(5H)-one (9)
Colorless crystal, 85%, mp 120–121 °C, 1H NMR (DMSO-
d6): 3.60 (s, 3H); 3.73 (s, 3H); 5.09 (s, 2H); 6.79 (s, 1H);
6.92 (s, 2H); 7.19-7.28 (m, 2H); 7.47 (td, J = 8.4 Hz,
J = 1.3 Hz, 1H); 8.03 (dd, J = 8.3 Hz, J = 1.3 Hz, 1H);
9.78 (s, 1H). 13C NMR (DMSO-d6):172.75; 160.14;
159.97; 158.90; 140.72; 137.60; 134.12; 133.66; 126.52;
122.58; 118.67;114.98; 114.15; 113.52; 97.43; 66.38;
4-(3-Chlorophenylamino)-3-(3,4-dimethoxyphenyl)
furan-2(5H)-one (7)
Colorless crystal, 71%, mp 200–203 °C, 1H NMR
(CDCl3): 2.27 (s, 3H); 2.30 (s, 3H); 3.41 (s, 2H); 5.38
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56.81; 56.66; 55.90. EIMS m/z 356 (M?). Anal. Calcd for
C18H16N2O6: C, 60.67; H, 4.53; N, 7.86; Found: C, 60.61;
H, 4.54; N, 7.87.
O7 were located in difference Fourier maps. All other H
atoms were positioned geometrically and refined as riding
˚
atoms, with C–H of 0.93 A for aromatic H atoms, 0.96 A
˚
˚
for CH3 groups and 0.97 A for CH2 groups, Uiso(H) values
X-ray Structure Determination of 5
were set at 1.2 times Ueq(C) for aromatic H atoms and CH2,
and 1.5 times Ueq(C) for CH3.
X-ray diffraction data were collected using a Bruker
SMART APEX CCD diffractometer with graphite-mono-
Antimicrobial Activity
˚
chromated Mo-Ka radiation (k = 0.71073 A) at room tem-
perature. A crystal with dimensions 0.3 mm 9 0.3 mm 9
0.2 mm was used. Data having theta less than or equal to
25° were integrated and the structure was solved by the
direct method using the SHELXS-97 program [13], which
refined by the full-matrix least-squares method using the
SHELXL-97 program [13]. Crystal data and experimental
details are listed in Table 1. The H atoms bonded to O6 and
The antibacterial activities of the synthesized compounds
were tested against two Gram-positive bacterial strains
(B. subtilis ATCC 6633, S. aureus ATCC 25923) and a
Gram-negative bacterial strain (E. coli ATCC 35218) using
LB medium, while the antifungal activities of the com-
pounds were tested against C. albicans ATCC 10231 (Gram-
positive) using RPMI-1640 medium. The MIC50s of the test
compounds were determined by a colorimetric method using
the dye MTT [14]. A stock solution of the synthesized
compound (1,000 lg/mL) in DMSO was prepared and gra-
ded quantities of the test compounds were incorporated in
specified quantity of sterilized liquid medium (50% (v/v) of
DMSO in PBS). A specified quantity of the medium con-
taining the test compound was poured into 96-well plates.
Suspension of the microorganism was prepared to contain
approximate 105 cfu/mL and applied to 96-well plates with
serially diluted compounds to be tested and incubated at
37 °C for 24 h. In the case of fungi, plates were incubated at
27 °C for 48 h. Fifty lL of PBS containing 2 mg of MTT/mL
was added to each well. Incubation was continued at room
temperature for 4–5 h. The content of each well was removed,
and 100 lL of 10% sodium dodecyl sulfate containing 5%
isopropanol and 1 mol/L HCl was added to extract the dye.
After 12 h of incubation at room temperature, the optical
density (OD) was measured with a microplate reader at
550 nm. The observed MIC50s were presented in Table 2.
Table 1 Crystal data and experimental crystallographic details
Empirical formula
Formula weight
Temperature (K)
C19H30N2O7
398.45
298(2)
˚
Wavelength (A)
0.71073
Monoclinic
P 21/c
Crystal system
Space group
Cell dimensions
˚
a (A)
7.3987(7)
˚
b (A)
17.8691(16)
˚
c (A)
17.0022(13)
a (8)
b (8)
c (8)
90
112.944(3)
90
3
˚
Volume (A )
2070.0(3)
Z
4
Density (calculated) (Mg/m3)
Absorption coefficient (mm-1
F000
1.279
)
0.097
856
Results and Discussion
Crystal size
0.2 mm 9 0.3 mm 9 0.3 mm
2.60°–28.28°
-9 B h B 9
-23 B k B 22
-15 B l B 22
13818/5094
h range for data collection
Index ranges
Nine 3-(3,4-dimethoxyphenyl)furan-2(5H)-ones were syn-
thesized by the routes outlined in Scheme 2. Compounds
2–8 derived from compound 1, and the structure of lactone-
core in these compounds could be determined dependent on
that of 1. At high field in 1H NMR spectrum of 1, except of
methyl group signals at dH 3.88 and 3.89, there are two
proton signals displaying as singlet at dH 4.77, which
strongly indicated that the lactone-core is furan-2(5H)-one
(4-hydroxyfuran-2(5H)-one) instead of furan-2(3H)-one or
furan-2,4(3H,5H)-dione. The furan-2(5H)-one skeleton was
further confirmed by the crystal structure of compound 5.
Compound 5, 3-(3,4-dimethoxyphenyl)-4-(2-(4-meth-
ylpiperazin-1-yl)ethoxy)furan-2(5H)-one, co-crystallizes
with two water molecules in the monoclinic space group P
Reflections collected/unique
reflections
Rint
0.0520
Refinement method
Full-matrix least-squares on
F2
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I [ 2r(I)]
R indices (all data)
5094/0/273
0.963
R1 = 0.0592, wR2 = 0.1016
R1 = 0.1155, wR2 = 0.1193
0.167/-0.199
-3
)
˚
Largest diff. peak and hole (eA
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J Chem Crystallogr (2012) 42:323–329
327
Table 2 Inhibitory activity (MIC50) of the synthetic compounds against microbes
Compound
R
MIC50 (lg/mL)
A
B
C
D
1
2
OH
[100
[100
78
[100
[100
[100
[100
[100
3
[100
23
[100
[100
4
5
95
87
8.7
[100
[100
[100
[100
7.3
6
7
[100
[100
49
84
96
[100
[100
62
79
31
8
9
[100
[100
98
77
[100
[100
Note: A, Bacillus subtilis ATCC 6633; B, Staphylococcus aureus ATCC 25923; C, Candida albicans ATCC 10231; D, Escherichia coli ATCC
35218
21/c and the structure of the crystalline hydrate with the
corresponding atomic numbering scheme is shown in
Fig. 1. In the center lactone moiety, C8–C11 and C8–O1 are
typical double bonds with bond length of 1.350(2) and
˚
1.210(2) A respectively, while bond distances of others are
followed in the range of typical single bonds (Table 3). The
center five-member ring is therefore identified as a furan-
2(5H)-one, which are consistent with the analogues previ-
ously reported [11, 12]. An sp3 orbital of O2, O3, O4 or O5
is conjugated with the attached double bond, which shortens
˚
the bond length of C–O from about 1.43 A [15, 16] to 1.36
˚
˚
A. O3–C10 (1.333(2) A) is further shortened by the strong
electron withdrawing effect of carbonyl group (C8–O1),
which is intermediated by p molecular orbital of C7–C10.
However, bond length shortening caused by carbonyl group
may be prevent due to the rigidity of center furanone ring
Fig. 1 Molecular structure of compound 5. Displacement ellipsoids
are drawn at the 30% probability level. Dashed lines indicate
hydrogen bonds
˚
[17], and is not observed in C8–O2 (1.362(2) A).
The furan-2(5H)-one motif and the attached benzene
ring (3,4-dimethoxy benzene ring) are nearly co-planar,
making a dihedral angle of 0.860(69)8. This is consistent
with other 4-O-analogues [12, 13], and is quite different
with the 4-N-analogues [11]. In comparison with C7–C8
˚
˚
(1.43–1.47 A), the bond distance of C7–C10 (1.33–1.37 A)
significantly decreased, causing an increase in steric strain
between 4-substituent and 3-benzene ring. Therefore, both
123

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J Chem Crystallogr (2012) 42:323–329
˚
discontinuity, forming a centrosymmetric tetramer char-
acterized by a graph-set motif of R87(36) (Fig. 2). On the
other hand, the above mentioned three hydrogen bonds also
link four molecules of I but in continuity, forming another
centrosymmetric tetramer characterized by a graph-set
motif of R64(32) (Fig. 2). The combination of these motifs
(R87(36) and R64(32)) generates a sheet of edge-fused rings
parallel to the (011) plane.
Table 3 Selected bond lengths (A) and bond angles (°) for com-
pound I
Bond
Dist.
Bond
Dist.
C(1)–C(7)
C(4)–O(5)
C(5)–O(4)
C(7)–C(8)
C(7)–C(10)
C(8)–O(1)
C(8)–O(2)
C(9)–C(10)
C(9)–O(2)
C(10)–O(3)
1.469(2)
1.366(2)
1.363(2)
1.459(3)
1.350(2)
1.210(2)
1.362(2)
1.491(2)
1.423(2)
1.333(2)
C(11)–O(3)
C(12)–N(1)
C(13)–N(1)
C(16)–N(1)
C(14)–N(2)
C(15)–N(2)
C(17)–N(2)
C(18)–O(4)
C(19)–O(5)
1.445(2)
1.463(2)
1.462(2)
1.455(2)
1.459(3)
1.455(2)
1.469(3)
1.425(2)
1.426(2)
In the structure of 5, C–HÁÁÁp interactions were found
between C9s and the benzene rings with HÁÁÁp distances of
˚
2.710 A (Fig. 3). These weak intermolecular contacts
consequently link the above mentioned sheets into a three
dimensional network.
As shown in Table 2, all the tested compounds inactive
against Gram-negative organism (E. coli ATCC 35218).
They showed moderate to good activities against S. aureus
ATCC 25923, while show quite weak activities against the
other Gram-positive organisms. The effect of 4-substituent
was described based on MIC50s against S. aureus ATCC
25923. Substitution of arylamino group (6–9) for
4-hydroxyl group (1) maintained the potency or showed a
mild increase in activity, while the 2-bromoethoxy group is
present at this place, leading to an inactive compound (2).
However, the bromine atom in the side chain of 2 was
replaced by an aliphatic amino group (3–5), resulting in a
3- to 10-fold increase in activity, with compound 5 being
the most active (MIC50 = 7.3 lg/mL).
Angle
(°)
Angle
(°)
C(1)–C(7)–C(8)
C(1)–C(7)–C(10)
C(4)–O(5)–C(19)
C(5)–O(4)–C(18)
C(7)–C(10)–O(3)
C(9)–C(10)–O(3)
124.63(18) C(12)–N(1)–C(13) 111.08(16)
129.97(17) C(12)–N(1)–C(16) 111.93(14)
117.30(15) C(13)–N(1)–C(16) 108.17(16)
116.92(15) C(14)–N(2)–C(15) 108.86(17)
126.06(17) C(14)–N(2)–C(17) 110.19(17)
122.85(17) C(15)–N(2)–C(17) 110.43(18)
C(10)–O(3)–C(11) 117.18(14)
4-O-analogues and 4-N-analogues show larger angle of
C1–C7–C10 (128.98–131.38) than that of C1–C7–C8
(120.68–125.18).
In the packing diagram, a molecule of 5 anchors a water
molecule, which is defined as I, with O–HÁÁÁN and C–HÁÁÁO
hydrogen bonding interactions to form a graph-set motif of
R22(6) (Fig. 2). On one hand, another water molecule forms
two hydrogen bonds utilizing O atom in the motif of R22(6)
and N2 as the acceptors respectively. These two hydrogen
bonds and the hydrogen bond with O1 as the acceptor
(Table 4) alternatively link four molecules of I in
Conclusions
Among the obtained nine 3-(3,4-dimethoxyphenyl)furan-
2(5H)-ones, compound 5 shows good antibacterial activity
against S. aureus ATCC 25923 with MIC50 of 7.3 lg/mL,
which could be used as a lead compound for further
modification to search novel antibacterials. The central
Fig. 2 Part of the crystal
structure of 5, showing the
formation of R87(36) and R64(32)
motifs, built from O–HÁÁÁO, C–
HÁÁÁO and O–HÁÁÁN hydrogen
bonds (dashed lines). For the
sake of clarity, the H atoms not
involved in the hydrogen bonds
have been omitted
123

J Chem Crystallogr (2012) 42:323–329
329
˚
conts/retrieving.html [or from the Cambridge Crystallo-
graphic Data Centre (CCDC), 12 Union Road, Cambridge
CB2 1EZ, UK; fax: ?44(0) 1223-336033; e-mail:deposit@
ccdc.cam.ac.uk].
Table 4 Hydrogen-bond geometry (A, °)
D–HÁÁÁA
D–H
HÁÁÁA
DÁÁÁA
D–HÁÁÁA
C2–H2ÁÁÁO1
C6–H6ÁÁÁO3
0.93
2.29
2.965(2)
2.963(2)
3.004(3)
2.993(2)
2.883(2)
2.989(3)
3.293(3)
3.543(2)
128.7
127.6
171(3)
160(2)
169(3)
170(3)
142.1
145.0
0.93
2.30
Acknowledgments The work was financed by the Planned Science
and Technology Project of Hunan Province, China (grant No.
2011FJ3056), by Hunan Provincial Natural Science Foundation of
China (grant No. 11JJ3113), by the Key Laboratory of Ecotourism’s
Application Technology, Hunan Province (grant No. JDSTLY
01103), by a grant from National Natural Science Foundation (Youth
Science Funds, No. 31100421) of China and by aid program for
Science and Technology Innovative Research Team (Chemicals of
Forestry Resources and Development of Forest Products) in Higher
Educational Institutions of Hunan Province.
O7–H7BÁÁÁN2
O6–H6AÁÁÁN1i
O6–H6BÁÁÁO1ii
O7–H7AÁÁÁO6iii
C11–H11BÁÁÁO6iv
C9–H9AÁÁÁCgv
0.84(3)
0.98(3)
0.83(3)
0.90(3)
0.97
2.18(3)
2.05(3)
2.07(3)
2.10(3)
2.47
0.970
2.710
Symmetry transformations used to generate equivalent atoms:
i = x - 1, -y ? 1.5, z - 0.5; ii = -x ? 1, -y ? 2, -z ? 1;
iii = x ? 1, y, z; iv = x ? 1, -y ? 1.5, z ? 0.5; v = -x ? 2, -y,
-z ? 1, Cg is the centroid of C1–C6
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furan-2(5H)-one skeleton was confirmed by the crystal
structure of compound 5, which disclosed that furan-2(5H)-
ones with 4-OR or 4-NHR show larger angle of C(–O or
–N)–C–C(Ar) than that of C(=O)–C–C(Ar).
Supplementary Material
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CCDC deposit number of CCDC 827892 for 5 contains the
supplementary crystallographic data for this paper. These
data can be obtained free of charge at www.ccdc.cam.ac.uk/
123