Vanillin derivatives as the selective small molecule inhibitors of FtsZ

Article abstract of DOI:10.1007/s00044-013-0886-8

A series of vanillin derivatives have been designed and synthesized and their biological activities were also evaluated as potential inhibitors of FtsZ. These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus. Compounds with potent antibacterial activities were tested for their FtsZ inhibitory activity. Compound 4u showed the most potent antibacterial activity with MIC of 0.28 μg/mL against E. coli strains and exhibited the most potent FtsZ inhibitory activity with polymerization IC₅₀ of 2.1 μM. Docking simulation was performed to position compound 4u into the FtsZ active site to determine the probable binding conformation.

Full text of DOI:10.1007/s00044-013-0886-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0886-8
ORIGINAL RESEARCH
Vanillin derivatives as the selective small molecule inhibitors
of FtsZ
•
Juan Sun Ming-Hui Li Xin-Yi Wang Yang Zhang
•
•
•
•
Rong-Ju Yuan Han-Yu Liu Hai-Liang Zhu
•
Received: 22 September 2013 / Accepted: 23 November 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of vanillin derivatives have been
designed and synthesized and their biological activities
were also evaluated as potential inhibitors of FtsZ. These
compounds were assayed for antibacterial activity against
Escherichia coli, Pseudomonas aeruginosa, Bacillus sub-
tilis, and Staphylococcus aureus. Compounds with potent
antibacterial activities were tested for their FtsZ inhibitory
activity. Compound 4u showed the most potent antibacte-
rial activity with MIC of 0.28 lg/mL against E. coli strains
and exhibited the most potent FtsZ inhibitory activity with
polymerization IC50 of 2.1 lM. Docking simulation was
performed to position compound 4u into the FtsZ active
site to determine the probable binding conformation.
2004). Vanillin (4-hydroxy-3-methoxybenzaldehyde), is
the major component of natural vanilla, which is one of the
most widely used and important flavoring materials
worldwide. In common with many other low-molecular
weight phenolic compounds, vanillin displays antioxidant,
antimicrobial, anticarcinogenic, and antimutagenic prop-
erties and hence has the potential for use as a food pre-
servative (Akihiro et al., 2011; Bythrow, 2005; Daniel
et al., 2003; Fitzgerald et al., 2004). Synthetic vanillin is
also used as an intermediate in the chemical and pharma-
ceutical industries for the synthesis of herbicides and drugs
(Walton et al., 2003). In old medicinal literature, vanilla
was described as a remedy for fevers (Sardari et al., 2000).
Schiff bases, named after Hugo Schiff (Faridbod and
Ganjali, 2007), are some of the most widely used organic
compounds. They are used as pigments and dyes, catalysts,
intermediates in organic synthesis, and as polymer ultra-
violet stabilizers (Ti-Feng and Ming-Hua, 2005). Schiff
bases have also been shown to exhibit a broad range of
biological activities, including antifungal, antibacterial,
anti-malarial, antiproliferative, anti-inflammatory, antivi-
ral, and antipyretic properties (Piotr et al., 2009; Lei et al.,
2007; Mari et al., 2006; Chohan et al., 2007; Venugopala
and Jayashree, 2008; Seshaiah and Atmakuru, 2001; Hacer
et al., 2009). Imine or azomethine groups are present in
various natural, naturally derived, and non-natural com-
pounds (Cleiton et al., 2011). The imine group present in
such compounds has been shown to be critical to their
biological activities (Bringmann et al., 2004; Ana et al.,
2007; Zhan-Yong et al., 2007).
Keywords Vanillin derivatives ꢀ Schiff base ꢀ
Antibacterial activity ꢀ FtsZ inhibitors
Introduction
Although several classes of antibacterial agents are pres-
ently available, resistance in most of the pathogenic bac-
teria to these drugs constantly emerges. In order to prevent
this serious medical problem, the elaboration of new types
of antibacterial agents is a very important task (Martin,
Juan Sun and Ming-Hui Li have contributed equally to this paper.
J. Sun ꢀ M.-H. Li ꢀ H.-L. Zhu (&)
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing
University, Nanjing 210093, People’s Republic of China
e-mail: zhuhl@nju.edu.cn
The bacterial cell division machinery consists of a set of
proteins that are recruited to the site of division where they
assemble to form the divisome. Recruitment of these pro-
teins to the site of division occurs in a specific order, with
FtsZ at the top of this hierarchy (Jeffery and Richard,
X.-Y. Wang ꢀ Y. Zhang ꢀ R.-J. Yuan ꢀ H.-Y. Liu ꢀ H.-L. Zhu
School of Life Sciences, Shandong University of Technology,
Shandong 255049, People’s Republic of China
123

Med Chem Res
2003). As such FtsZ is considered to be the most critical
component of the division machinery. It is an essential
protein for bacterial viability (Frederico and Richard, 2002;
Laura and Petra, 2003; Mariana and Jeff, 2003) and it is a
highly conserved and potentially broad-spectrum antibac-
terial target, it does have structural and functional homol-
ogy, suggesting that FtsZ may also be amenable to
inhibitor development. Finally, because cell division pro-
teins are not targeted by any antibiotics in current clinical
use, it is expected that there will not be any cross resistance
from existing drug-resistant bacterial populations (Lloyd
et al., 2012).
transformation of the fuming nitric acid to acetylizad
vanillin and afforded compound 3. The final step involves
reaction between the various aromatic amine and
4-hydroxy-3-methoxy-2-nitrobenzaldehyde, the mixture
was dissolved in methanol or acetonitrile and then con-
centrated under reduced pressure, recrystallized from eth-
anol form a number of substituted (E)-2-methoxy-3-nitro-
4-((phenylimino) methyl) phenol (Table 1). All of the
synthetic compounds gave satisfactory analytical and
spectroscopic data, which were in full accordance with
their depicted structures.
Crystal structure determination of compound 4u was
carried out on a D-8 venture diffractometer equipped with
graphite-monochromated MoKa (k = 0.71073) radiation
(Fig. 1). The structure was solved by direct methods and
refined on F2 by full-matrix least-squares methods using
SHELX-97. The crystal data, data collection, and refine-
ment parameter for the compound 4u are listed in
Table 2.
Molecular hybridization approach is one of the most
valuable structural modification tools useful for the dis-
covery of ligands and prototypes presenting either opti-
mized affinity for one bioreceptor or the ability to modulate
more than one bioreceptor associated with the target dis-
ease (Fraga, 2009; Claudio et al., 2007; Frye, 2010). The
growing efforts to discover hybrid drugs resulting from the
combination of pharmacophoric moieties of different
known lead. Hence, the impressive results of Vanillin
derivatives and various phenylamine fueled our interest in
combining two scaffolds and exploring their possibilities as
potential anti-FtsZ agents.
Results and discussion
Chemistry
Twenty-one Vanillin analogs (4a–4u) were synthesized by
following the general pathway outlined in Scheme 1. To a
stirred suspension of vanillin in ethyl ether under argon
was added acetic anhydride and then DMAP, to form
compound 2. The next step involves a functional group
Fig. 1 Crystal structure diagrams of compound 4u
Scheme 1 Synthetic route of
vanillin derivatives (4a–4u)
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Med Chem Res
Table 1 Structures of compounds 4a–4u
Table 2 Crystallographical and experimental data for compound 4u
C5
HO
C6
R5
C4
C1
C6'
N
R4
N
C3
H
3CO
C5'
C4'
C2
C1'
C2'
C7
HO
NO2
R1
R3
C3'
H3CO
NO2
R2
Compound
4u
Compounds R1
R2
R3
R4
R5
Empirical formula
Formula weight
Crystal system
Space group
C20H24N2O4
356.41
4a
4b
4c
4d
4e
4f
Cl
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
CH3
H
Monoclinic
C2/c
CH3O
H
NO2
H
˚
a (A)
28.315(2)
7.8580(6)
18.0219(13)
90
H
F
˚
b (A)
H
CH3
CH3O
NO2
H
˚
c (A)
4g
4h
4i
H
a (°)
b (°)
c (°)
H
104.138(90)
90
H
4j
H
H
CH3
CH3O
NO2
Cl
˚
V (A)
3888.4(5)
8
4k
4l
H
H
Z
D calc/g cm-3
1.218
H
H
4m
4n
4o
4p
4q
4r
4s
H
Cl
H
h range (°)
F(000)
2.70–30.83
1,520
Cl
Cl
Cl
H
H
Reflections collected/unique
Data/restraints/parameters
Absorption coefficient (mm-1
R1: WR2 [I [ 2r (I)]
R1: WR2 (all date)
GOOF
42,520/5,213[Rint = 0.020]
4,146/0/241
0.129
CH3
H
H
CH3
H
H
CH3
H
CH3
H
)
CH3
H
0.0750/0.1951
0.0932/0.2128
1.05
H
Cl
H
CH3
Cl
H
4t
NO2
H
4u
(CH3)2CH2
H
H
H
(CH3)2CH2
Antibacterial activity
one substituted derivatives 4a–4l, which showed the
introduction of two substituents leads to the increase of the
antibacterial activity.
All the synthesized compounds (4a–4u) were screened for
their antibacterial activities against two Gram-negative
bacterial strains: Escherichia coli and Pseudomanas aeru-
ginosa and two Gram-positive bacterial strains: Bacillus
subtilis and Staphylococcus aureus by MTT method. The
minimum inhibitory concentrations (MICs) of the com-
pounds against these bacteria were presented in Table 3.
Also included was the activity of reference compound
Kanamycin under identical conditions for comparison. The
results revealed that most of the synthesized compounds
exhibited significant antibacterial activities. Among the
twenty-one vanillin derivatives, the two substituted deri-
vates 4m–4u, whose MIC values ranging from 0.28 to
45.67 lg/mL, displayed higher antibacterial potencies than
Compound 4u exhibited most potent activities with MIC
values of 0.28 lg/mL against E. coli, which is superior to
the positive control kanamycin with corresponding MIC of
0.40 lg/mL. Besides, the data showed compound 4r dis-
played significant activities with MIC values ranging from
2.89 to 11.34 lg/mL against the four bacterial lines,
respectively, indicating that it possessed broad-spectrum
antibacterial activities. Moreover, compound 4p showed
the potent inhibitor against Gram-negative bacteria with
MIC values of 3.45 and 5.12 lg/mL, respectively. Com-
pound 4q displayed significant activities with MIC values
of 2.78 and 6.92 lg/mL against Gram-positive bacteria,
respectively.
123

Med Chem Res
Table 3 Antibacterial activities of synthetic compounds
Table 5 The docking calculation of the synthesized compounds (4a–
4u)
Compounds Minimum inhibitory concentrations (MICs) (lg/mL)
Compound
CDocker_interaction_energy
[DGb (kcal/mol)]
Gram-negative bacteria
Gram-positive bacteria
E. coli P. aeruginosa B. subtilis S. aureus
ATCC35218 ATCC13525 ATCC6633 ATCC6538
4a
4b
4c
4d
4e
4f
-30.0389
-32.9862
-33.8625
-32.3104
-30.0201
-32.6593
-33.6980
-31.5544
-30.7235
-32.6216
-33.2359
-31.1086
-37.5321
-37.8962
-38.0389
-40.1212
-40.0013
-40.5544
-39.7235
-39.1086
-43.5656
4a
4b
4c
4d
4e
4f
[100
30.01
21.31
[50
[100
29.13
[50
[100
[50
[100
33.00
[100
[50
20.96
[50
[50
[100
[50
[100
38.14
28.11
[50
[100
31.26
21.36
[50
[100
33.43
[50
4g
4h
4i
4g
4h
4i
[100
[50
[50
4j
[100
35.12
30.26
[50
[100
41.31
[50
[50
[100
41.30
24.69
[50
4k
4l
4j
[50
4k
4l
[100
[50
4m
4n
4o
4p
4q
4r
4s
[50
4m
4n
4o
4p
4q
4r
4s
41.11
32.18
31.02
3.45
37.56
38.92
38.64
5.12
33.92
41.00
41.33
21.58
2.78
38.99
45.67
45.01
17.19
6.92
21.59
6.12
20.83
5.02
2.89
11.34
26.95
37.82
2.03
4t
18.46
31.20
0.28
15.11
28.47
5.89
20.10
33.89
3.31
4u
4t
4u
Kanamycin 0.40
0.61
1.10
0.89
conducive to the antibacterial activity and compounds with
electron-with-drawing halogen groups on benzoic acid
component were not favorable for activity.
Table 4 FtsZ inhibitory activity of compounds 4m–4u
Compounds
Polymerization IC50 (lM)
Furthermore, compounds 4s and 4t exhibited moderate
antibacterial activities. With MICs of 15.11–26.95 lg/mL
and 28.47–37.82 lg/mL, respectively.
4m
85.80
77.64
72.13
15.47
22.98
9.40
4n
4o
Inhibition of FtsZ polymerization
4p
4q
The GTPase FtsZ inhibitory potency of the selected com-
pounds was examined and the results were summarized in
Table 4. As shown in Table 4, among the tested com-
pounds, compounds 4u showed potent inhibitory activities
with polymerization ID50 of 2.1 lM. Other tested com-
pounds displayed moderate inhibitory activities with ID50
ranging from 9.4 to 85.8 lM. The results were corre-
sponding to the structure relationships (SAR) of their
antibacterial activities.
4r
4s
41.01
50.11
2.10
4t
4u
Colchicine
104.00
Based on the data obtained, we found that compounds
4p–4r with substituted methyl group on benzoic acid
component exhibited significant antibacterial activities
with MICs of 2.78–21.59 lg/mL. A significant loss of
activity was observed when introducing the chlorine group
in the benzene-ring (4m–4o), with MIC values ranging
from 31.02 to 45.67 lg/mL. We proposed that electron-
donating groups on benzoic acid component were
Binding model of compounds into FtsZ structure
Molecular docking of the synthesized compounds and FtsZ
was performed on the binding model based on the FtsZ
protein complex structure (2VAM. pdb). All docking runs
123

Med Chem Res
Fig. 2 2D molecular docking
modeling of compound 4u with
2VAM
were applied LigandFit Dock protocol of Discovery Studio
3.1. The docking calculation of the synthesized compounds
was showed in Table 5. The interaction energy of the
compounds and their antibacterial activity showed the
corresponding results. Among the docking calculation of
the synthesized compounds, compounds 4u showed the
lowest interaction energy. The binding model of compound
4u and FtsZ was depicted in Fig. 2. In the binding model,
compound 4u was nicely bound to the FtsZ with five
interaction bonds. The hydrogen of Ala 73, Gly 108, and
Arg 143 were, respectively, formed three hydrogen bonds
interaction with oxygen atom of nitro group of compound
4u. Besides, between the oxygen atom of the hydroxyl
group and nitrogen atom of Asp 46, as well as between the
nitrogen atom of nitro group and amino hydrogen of Arg
143, there are two optimal H-bonds interaction. Moreover,
the p-cation interactions were existed between benzene
ring and amino acids Arg 143.
Experimental
Chemistry
All chemicals and reagents used in the current study were of
analytical grade. The reactions were monitored by thin layer
chromatography (TLC) on Merck pre-coated silica GF254
plates. Melting points (uncorrected) were determined on a
XT4MP apparatus (Taike Corp., Beijing, China). ESI mass
spectra were obtained on a Mariner System 5304 mass
spectrometer, and all the NMR spectra were recorded on a
Bruker DPX 400 model spectrometer at room temperature
with TMS and solvent signals allotted as internal standards.
Chemical shifts are reported in ppm (d). Elemental analyses
were performed on a CHN-O-Rapid instrument, and were
within 0.4 % of the theoretical values.
Synthesis of 4-formyl-2-methoxyphenyl acetate (2)
To a stirred suspension of vanillin (4.0 g, 26.3 mmol) in dry
ethyl ether (100 mL) under argon was added slowly acetic
anhydride (3.91 mL, 40.8 mmol) and then DMAP (1 mg). The
mixture was stirred at room temperature for 20 min and then
the crystallized white solid were formed at the bottom of the
vessel. The crystallized white solid was filtered off and washed
with water to give the 4-formyl-2-methoxyphenyl acetate.
Conclusions
In summary, a series of novel vanillin derivatives 4a–4u
were synthesized and tested for their inhibitory activities
against E. coli, P. aeruginosa, B. subtilis, and S. aureus.
Many of them exhibited potent antibacterial and FtsZ
inhibitory activities. Particularly, Compound 4u were
proved to be the most potent compounds against E. coli.
Preliminary SARs and molecular modeling study provided
further insight into interactions between the enzyme and its
ligand. The result provided valuable information for the
design of FtsZ inhibitors as antibacterial agents.
Synthesis of 4-formyl-2-methoxy-3-nitrophenyl
acetate (3)
To a stirred and cooled fuming nitric acid (12 mL) was
added slowly compound 2 (2.4 g) over 2 h. The dark
123

Med Chem Res
brown reaction mixture was stirred for 5 h and then poured
into crushed ice. The yellow precipitate was filtered off and
washed with cold water (300 mL), to form compound 3.
1H). 13C NMR (300 MHz, CDCl3) d: 130.22(C-1), 141.82(C-
2), 145.04(C-3), 156.05(C-4), 118.97(C-5), 127.31(C-6),
174.12(C-7), 136.31(C0-1), 151.64(C0-2), 115.75(C0-3),
124.44(C0-4), 125.48(C0-5), 118.06(C0-6), 56.52(–OCH3),
62.81(R1–OCH3). MS (ESI): 303 (C15H15N2O5, [M?H]?).
Anal. Calcd for C15H14N2O5: C, 59.60; H, 4.67; N, 9.27;
Found: C, 59.85; H, 4.33; N, 9.11.
Synthesis of 4-hydroxy-3-methoxy-2-
nitrobenzaldehyde (4)
Compound 3 was dissolved in a solution of NaOH (7.5 g)
in water (200 mL) and the dark red solution stirred for 1 h.
The solution was acidified (pH 1) with diluted hydrochloric
acid, the precipitate filtered off, washed with water, and
dried in vacuo to give compound 4 as yellow solid.
(E)-2-Methoxy-3-nitro-4-(((2-
nitrophenyl)imino)methyl)phenol (4d)
1
M.p. 133–134 °C. H NMR (300 MHz, CDCl3): 3.35 (s,
3H), 6.81–6.83 (d, J = 6.0 Hz, 1H), 6.95 (m, 3H), 7.11 (s,
1H), 7.61 (m, 1H), 8.53 (s, 1H), 9.22 (s, 1H). 13C NMR
(300 MHz, CDCl3) d: 129.33(C-1), 139.32(C-2), 145.34(C-
3), 153.75(C-4), 118.07(C-5), 125.00(C-6), 168.21(C-7),
148.15(C0-1), 135.19(C0-2), 125.81(C0-3), 129.33(C0-4),
134.78(C0-5), 122.71(C0-6), 61.90(–OCH3). MS (ESI): 318
(C14H12N3O6, [M?H]?). Anal. Calcd for C14H11N3O6: C,
53.00; H, 3.49; N, 13.24; Found: C, 53.24; H, 3.28; N, 13.55.
General method of synthesis of vanillin derivatives
(4a–4u)
An equivocal compound 4 (1 mmol) and substituted aro-
matic amine (1 mmol) in methanol or acetonitrile was
stirred for 4–6 h at room temperature, then reaction mix-
ture was concentrated under reduced pressure, recrystal-
lized from ethanol to give vanillin derivatives 4a–4z.
(E)-4-(((3-Fluorophenyl)imino)methyl)-2-methoxy-3-
(E)-4(((2-Chlorophenyl)imino)methyl)-2-methoxy-3-
nitrophenol (4e)
nitrophenol (4a)
M.p. 97–98 °C. 1H NMR (300 MHz, CDCl3): 3.80 (s, 3H),
6.82 (s, 1H), 7.01–7.02 (m, 3H), 7.03–7.04 (d, J = 3.0 Hz,
1H), 7.28 (m, 1H), 9.00 (s, 1H), 9.23 (s, 1H). 13C NMR
(300 MHz, CDCl3) d: 127.45(C-1), 142.93(C-2), 145.64(C-
3), 154.15(C-4), 120.47(C-5), 127.45(C-6), 156.50(C-7),
163.31(C0-1), 104.02(C0-2), 168.13(C0-3), 114.33(C0-4),
127.57(C0-5), 121.63(C0-6), 62.50(–OCH3). MS (ESI): 291
(C14H12FN2O4, [M?H]?). Anal. Calcd for C14H11FN2O4:
C, 57.93; H, 3.82; N, 9.65; Found: C, 58.12; H, 3.88; N, 9.61.
M.p. 101–102 °C. 1H NMR (300 MHz, CDCl3): 3.81 (s, 3H),
6.47 (m, 1H), 6.96–6.97 (d, J = 3.0 Hz, 1H), 7.11–7.13 (m,
3H), 7.23–7.24 (d, J = 3.0 Hz, 1H), 8.34 (s, 1H), 9.74 (s, 1H).
13C NMR (300 MHz, CDCl3) d: 125.18(C-1), 139.80(C-2),
144.72(C-3), 157.98(C-4), 118.70(C-5), 126.30(C-6), 168.12
(C-7), 152.69(C0-1), 127.45(C0-2), 130.41(C0-3), 128.00(C0-4),
131.59(C0-5), 115.35(C0-6), 61.94(–OCH3). MS (ESI): 307
(C14H12ClN2O4, [M?H]?). Anal. Calcd for C14H11ClN2O4: C,
54.83; H, 3.62; N, 9.13; Found: C, 54.62; H, 3.88; N, 9.35.
(E)-2-Methoxy-3-nitro-4-((m-tolylimino)methyl)phenol (4f)
(E)-2-Methoxy-3-nitro-4-((o-tolylimino)methyl)phenol (4b)
1
M.p. 102–103 °C. H NMR (300 MHz, CDCl3): 3.51 (s,
M.p. 97–98 °C. 1H NMR (300 MHz, CDCl3): 2.96 (s, 3H),
3.71 (m, 3H), 6.88 (s, 1H), 7.10(m, 2H), 7.72 (m, 3H), 8.55
(s, 1H), 9.02 (s, 1H). 13C NMR (300 MHz, CDCl3) d:
125.35(C-1), 139.94(C-2), 146.33(C-3), 154.18(C-4),
118.77(C-5), 127.20(C-6), 157.95(C-7), 166.45(C0-1),
127.20(C0-2), 130.30(C0-3), 127.55(C0-4), 129.01(C0-5),
115.98(C0-6), 61.70(–OCH3), 19.08(–CH3). MS (ESI): 287
(C15H15N2O4, [M?H]?). Anal. Calcd for C15H14N2O4: C,
62.93; H, 4.93; N, 9.79; Found: C, 62.71; H, 5.11; N, 9.45.
3H), 3.79 (m, 3H), 6.86–6.87 (d, J = 3.0 Hz, 1H), 6.91 (m,
1H), 7.23–7.24 (m, 2H), 7.61–7.62 (m, 2H), 9.11 (s, 1H),
9.42 (s, 1H). 13C NMR (300 MHz, CDCl3) d: 127.98(C-1),
139.98(C-2), 144.21(C-3), 154.18(C-4), 118.71(C-5),
127.45(C-6), 160.70(C-7), 144.21(C0-1), 121.07(C0-2),
139.86(C0-3), 123.22(C0-4), 130.35(C0-5), 115.36(C0-6),
61.91(–OCH3), 19.85(–CH3). MS (ESI): 287 (C15H15
N2O4, [M?H]?). Anal. Calcd for C15H14N2O4: C, 62.93;
H, 4.93; N, 9.79; Found: C, 63.01; H, 4.79; N, 9.91.
(E)-2-Methoxy-4-(((2-methoxyphenyl)imino)methyl)-3-
(E)-2-Methoxy-4-(((3-methoxyphenyl)imino)methyl)-3-
nitrophenol (4c)
nitrophenol (4g)
1
1
M.p. 104–105 °C. H NMR (300 MHz, CDCl3): 3.72 (m,
3H), 3.88 (s, 3H), 7.01–7.03 (d, J = 6.0 Hz, 1H), 7.22 (m,
M.p. 104–106 °C. H NMR (300 MHz, CDCl3): 2.82 (m,
3H), 3.88 (m, 3H), 7.02–7.03 (d, J = 3.0 Hz, 1H), 7.19 (s,
2H), 7.24 (m, 2H), 7.68–7.71 (m, 1H), 9.02 (s, 1H), 9.23 (s,
1H), 7.25–7.27 (m, 3H), 7.96–7.97 (d, J = 3.0 Hz, 1H), 8.88
123

Med Chem Res
(s, 1H), 8.90 (s, 1H). 13C NMR (300 MHz, CDCl3) d:
127.86(C-1), 140.93(C-2), 144.73(C-3), 154.17(C-4), 118.37
(C-5), 127.86(C-6), 157.05(C-7), 154.17(C0-1), 102.13(C0-2),
162.10(C0-3), 108.85(C0-4), 131.59(C0-5), 109.29(C0-6),
60.10(–OCH3), 57.07(R2–OCH3). MS (ESI): 303
(C15H15N2O5, [M?H]?). Anal. Calcd for C15H14N2O5: C,
59.60; H, 4.67; N, 9.27; Found: C, 59.49; H, 4.78; N, 9.08.
8.99 (s, 1H). 13C NMR (300 MHz, CDCl3) d: 127.36(C-1),
140.93(C-2), 144.75(C-3), 157.85(C-4), 118.70(C-5),
127.97(C-6), 157.85(C-7), 145.60(C0-1), 121.07(C0-2),
115.35(C0-3), 160.43(C0-4), 114.77(C0-5), 119.94(C0-6),
61.90(–OCH3), 56.53(R3–OCH3). MS (ESI): 303
(C15H15N2O5, [M?H]?). Anal. Calcd for C15H14N2O5: C,
59.60; H, 4.67; N, 9.27; Found: C, 59.39; H, 4.48; N, 9.13.
(E)-2-Methoxy-3-nitro-4-(((3-
(E)-2-Methoxy-3-nitro-4-(((4-
nitrophenyl)imino)methyl)phenol (4h)
nitrophenyl)imino)methyl)phenol (4l)
1
M.p. 151–152 °C. 1H NMR (300 MHz, CDCl3): 4.00 (s, 3H),
6.99 (s, 1H), 7.11–7.13 (m, 3H), 7.23–7.24 (m, 2H), 9.01 (s,
1H), 9.22 (s, 1H). 13C NMR (300 MHz, CDCl3) d: 126.01(C-
1), 142.13(C-2), 145.94(C-3), 156.05(C-4), 120.17(C-5),
126.01(C-6), 157.43(C-7), 154.58(C0-1), 112.12(C0-2),
149.55(C0-3), 121.89(C0-4), 131.71(C0-5), 122.35(C0-6),
59.90(–OCH3). MS (ESI): 318 (C14H12N3O6, [M?H]?).
Anal. Calcd for C14H11N3O6: C, 53.00; H, 3.49; N, 13.24;
Found: C, 52.89; H, 3.56; N, 13.09.
M.p. 143–145 °C. H NMR (300 MHz, CDCl3): 3.76 (s,
3H), 6.96–6.97 (d, J = 3.0 Hz, 1H), 7.23–7.24 (m, 3H),
7.68–7.71 (m, 2H), 9.12 (s, 1H), 9.62 (s, 1H). 13C NMR
(300 MHz, CDCl3) d: 127.82(C-1), 140.93(C-2), 145.94(C-
3), 156.15(C-4), 119.97(C-5), 130.07(C-6), 157.96(C-7),
166.33(C0-1), 118.30(C0-2), 124.54(C0-3), 145.87(C0-4),
124.96(C0-5), 118.98(C0-6), 61.50(–OCH3). MS (ESI): 318
(C14H12N3O6, [M?H]?). Anal. Calcd for C14H11N3O6: C,
53.00; H, 3.49; N, 13.24; Found: C, 53.11; H, 3.57; N, 13.33.
(E)-4-(((4-Bromophenyl)imino)methyl)-2-methoxy-3-
(E)-4-(((3,4-Dichlorophenyl)imino)methyl)-2-methoxy-3-
nitrophenol (4i)
nitrophenol (4m)
1
M.p. 153–155 °C. H NMR (300 MHz, CDCl3): 3.77 (m,
M.p. 95–96 °C. 1H NMR (300 MHz, CDCl3) : 3.71 (s, 3H),
6.96–6.97 (d, J = 3.0 Hz, 1H), 7.12–7.14 (m, 2H), 7.33–7.34
(d, J = 3.0 Hz, 1H), 7.72 (s, 1H), 8.79 (s, 1H), 8.86 (s, 1H).
13C NMR (300 MHz, CDCl3) d: 128.01(C-1), 140.93(C-2),
144.34(C-3), 155.05(C-4), 119.97(C-5), 127.82(C-6), 161.83
(C-7), 149.55(C0-1), 118.71(C0-2), 132.92(C0-3), 126.95
(C0-4), 132.15(C0-5), 121.52(C0-6), 61.50(–OCH3). MS (ESI):
350 (C14H11Cl2N2O4, [M?H]?). Anal. Calcd for C14H10
Cl2N2O4: C, 49.29;H, 2.95; N, 8.21; Found: C, 49.33;H, 2.78;
N, 8.36.
3H), 7.06 (s, 2H), 7.19–7.20 (m, 2H), 7.25–7.27 (m, 2H), 9.02
(s, 1H), 9.45 (s, 1H). 13C NMR (300 MHz, CDCl3) d:
127.45(C-1), 139.80(C-2), 144.94(C-3), 154.15(C-4), 118.71
(C-5), 128.97(C-6), 160.70(C-7), 152.68(C0-1), 120.85(C0-2),
132.70(C0-3), 118.03(C0-4), 131.59(C0-5), 122.88(C0-6),
61.83(–OCH3). MS (ESI): 350 (C14H12BrN2O4, [M?H]?).
Anal. Calcd for C14H11BrN2O4: C, 47.89; H, 3.16; N, 7.98;
Found: C, 47.95; H, 3.30; N, 7.72.
(E)-2-Methoxy-3-nitro-4-((p-tolylimino)methyl)phenol (4j)
(E)-4-(((2,4-d-Dichlorophenyl)imino)methyl)-2-methoxy-3-
M.p. 101–102 °C. 1H NMR (300 MHz, CDCl3): 2.80 (s, 3H),
3.81 (m, 3H), 7.19 (s, 1H), 7.35–7.36 (m, 2H), 7.55–7.57 (m,
2H), 7.66–7.67 (d, J = 3.0 Hz, 1H), 8.34 (s, 1H), 8.60 (s, 1H).
13C NMR (300 MHz, CDCl3) d: 127.82(C-1), 139.92(C-2),
145.04(C-3), 154.15(C-4), 118.75(C-5), 127.97(C-6), 154.15
(C-7), 152.67(C0-1), 118.34(C0-2), 130.41(C0-3), 134.11
(C0-4), 130.41(C0-5), 121.66(C0-6), 62.80(–OCH3), 19.05
(–CH3). MS (ESI): 287 (C15H15N2O4, [M?H]?). Anal. Calcd
for C15H14N2O4: C, 62.93; H, 4.93; N, 9.79; Found: C, 63.11;
H, 4.82; N, 9.57.
nitrophenol (4n)
M.p. 107–108 °C. 1H NMR (300 MHz, CDCl3): 3.82 (s, 3H),
6.77–6.78 (m, 2H), 7.19 (s, 1H), 7.55 (s, 1H), 7.68–7.71 (m,
1H), 9.12 (s, 1H), 9.45 (s, 1H). 13C NMR (300 MHz, CDCl3)
d: 127.45(C-1), 139.73(C-2), 145.94(C-3), 156.75(C-4),
118.91(C-5), 127.80(C-6), 160.06(C-7), 148.60(C0-1), 122.88
(C0-2), 130.41(C0-3), 131.65(C0-4), 130.69(C0-5), 121.67
(C0-6), 61.91(–OCH3). MS (ESI): 350 (C14H11Cl2N2O4,
[M?H]?). Anal. Calcdfor C14H10Cl2N2O4:C, 49.29;H, 2.95;
N, 8.21; Found: C, 49.41; H, 2.99; N, 8.09.
(E)-2-Methoxy-4-(((4-methoxyphenyl)imino)methyl)-3-
nitrophenol (4k)
(E)-4-(((2,5-Dichlorophenyl)imino)methyl)-2-methoxy-3-
nitrophenol (4o)
1
M.p. 104–105 °C. H NMR (300 MHz, CDCl3): 3.41 (s,
3H), 3.52 (m, 3H), 6.82–8.83 (d, J = 3.0 Hz, 1H), 6.99 (s,
1
M.p. 115–116 °C. H NMR (300 MHz, CDCl3): 4.00 (s,
3H), 6.86–6.87 (d, J = 3.0 Hz, 1H), 7.25–7.27 (m, 3H),
1H), 7.01–7.03 (m, 3H), 7.55–7.56 (m, 2H), 8.83 (s, 1H),
123

Med Chem Res
7.55 (s, 1H), 8.65 (s, 1H), 8.84 (s, 1H). 13C NMR
(300 MHz, CDCl3) d: 127.45(C-1), 139.88(C-2), 152.82
(C-3), 154.07(C-4), 118.75(C-5), 127.77(C-6), 160.74(C-
7), 145.64(C0-1), 124.60(C0-2), 134.10(C0-3), 127.99(C0-4),
131.96(C0-5), 115.49(C0-6), 62.41(–OCH3). MS (ESI): 350
(C14H11Cl2N2O4, [M?H]?). Anal. Calcd for C14H10
Cl2N2O4: C, 49.29; H, 2.95; N, 8.21; Found: C, 49.20; H,
2.81; N, 8.33.
301 (C16H17N2O4, [M?H]?). Anal. Calcd for C16H16N2O4:
C, 63.99; H, 5.37; N, 9.33; Found: C, 65.11; H, 5.21; N, 9.45.
(E)-4-(((3-Chloro-4-methylphenyl)imino)methyl)-2-
methoxy-3-nitrophenol (4s)
M.p. 67–68 °C. 1H NMR (300 MHz, CDCl3): 2.80–2.82 (m,
3H), 3.03–3.06 (m, 3H), 7.19–7.20 (m, 2H), 7.27–7.28 (m,
1H), 7.55 (s, 1H), 7.60–7.61 (d, J = 3.0 Hz, 1H), 8.92 (s, 1H),
9.74 (s, 1H). 13C NMR (300 MHz, CDCl3) d: 127.75(C-1),
140.93(C-2), 145.60(C-3), 154.95(C-4), 121.68(C-5), 127.57
(C-6), 160.93(C-7), 150.49(C0-1), 115.93(C0-2), 137.37(C0-
3), 130.41(C0-4), 139.85(C0-5), 118.75(C0-6), 62.82(–OCH3),
19.05(–CH3). MS (ESI): 321 (C15H14ClN2O4, [M?H]?).
Anal. Calcd for C15H13ClN2O4: C, 56.17; H, 4.09; N, 8.73;
Found: C, 56.26; H, 3.91; N, 8.90.
(E)-4-(((2,5-Dimethylphenyl)imino)methyl)-2-methoxy-3-
nitrophenol (4p)
1
M.p. 175–176 °C. H NMR (300 MHz, CDCl3): 2.75 (s,
2H), 2.99–3.01 (m, 4H), 3.71 (s, 3H), 6.99 (s, 1H), 7.21–
7.23 (d, J = 6.0 Hz, 1H), 7.47–7.49 (m, 2H), 7.68–7.70
(m, 1H), 8.34 (s, 1H), 8.46 (s, 1H). 13C NMR (300 MHz,
CDCl3) d: 127.10(C-1), 141.21(C-2), 145.66(C-3), 157.02
(C-4), 119.97(C-5), 127.25(C-6), 159.31(C-7), 152.90(C0-
1), 122.95(C0-2), 132.61(C0-3), 129.82(C0-4), 134.11(C0-5),
118.23(C0-6), 61.50(–OCH3), 19.05(R1–CH3),22.31(R4–
CH3). MS (ESI): 301 (C16H17N2O4, [M?H]?). Anal. Calcd
for C16H16N2O4: C, 63.99; H, 5.37; N, 9.33; Found: C,
64.77; H, 5.41; N, 9.24.
(E)-4-(((4-Chloro-2-nitrophenyl)imino)methyl)-2-methoxy-
3-nitrophenol (4t)
1
M.p. 152–153 °C. H NMR (300 MHz, CDCl3): 3.80 (s,
3H), 6.96–6.97 (d, J = 3.0 Hz, 1H), 7.00 (s, 1H),
7.32–7.33 (m, 2H), 7.55 (s, 1H), 8.56 (s, 1H), 8.81 (s, 1H).
13C NMR (300 MHz, CDCl3) d: 130.21(C-1), 139.37(C-2),
144.99(C-3), 154.75(C-4), 118.97(C-5), 124.26(C-6),
161.39(C-7), 143.90(C0-1), 136.61(C0-2), 127.84(C0-3),
131.38(C0-4), 136.31(C0-5), 121.60(C0-6), 61.98(–OCH3).
MS (ESI): 352 (C14H11ClN3O6, [M?H]?). Anal. Calcd for
C14H10ClN3O6: C, 47.81; H, 2.87; N, 11.95; Found: C,
47.67; H, 42.96; N, 12.08.
(E)-4-(((3,4-Dimethylphenyl)imino)methyl)-2-methoxy-3-
nitrophenol (4q)
1
M.p. 165–166 °C. H NMR (300 MHz, CDCl3) : 2.80 (m,
4H), 3.01 (s, 1H), 3.03 (s, 1H), 3.79 (s, 3H), 7.25–7.27
(m, 3H), 7.71 (s, 1H), 7.72–7.74 (d, J = 6.0 Hz, 1H), 8.23
(s, 1H), 8.62 (s, 1H). 13C NMR (300 MHz, CDCl3) d:
127.34(C-1), 140.93(C-2), 149.94(C-3), 154.18(C-4),
118.92(C-5), 128.08(C-6), 160.22(C-7), 143.53(C0-1),
118.23(C0-2), 145.04(C0-3), 127.53(C0-4), 131.59(C0-5),
115.36(C0-6), 61.30(–OCH3), 19.06(R2–CH3), 18.60(R3–
CH3). MS (ESI): 301 (C16H17N2O4, [M?H]?). Anal. Calcd
for C16H16N2O4: C, 63.99; H, 5.37; N, 9.33; Found: C, 65.08;
H, 5.48; N, 9.22.
(E)-4-(((2,6-Diisopropylphenyl)imino)methyl)-2-methoxy-
3-nitrophenol (4u)
M.p. 178–179 °C. 1H NMR (300 MHz, CDCl3): 3.15–3.18
(m, 3H), 3.22–3.24 (m, 4H), 3.25–3.26 (m, 3H), 3.28–3.29
(d, J = 3.0 Hz, 1H), 3.30–3.32 (m, 4H), 3.55 (s, 3H),
3.56–3.57 (d, J = 3.0 Hz, 1H), 7.11–7.13 (m, 3H),
7.23–7.24 (d, J = 3.0 Hz, 1H), 7.68–7.71 (m, 1H), 8.52 (s,
1H), 8.92 (s, 1H). 13C NMR (300 MHz, CDCl3) d: 126.71(C-
1), 141.33(C-2), 145.64(C-3), 153.85(C-4), 118.97(C-5),
127.71(C-6), 161.01(C-7), 143.56(C0-1), 130.16(C0-2),
127.98(C0-3), 124.55(C0-4), 128.33(C0-5), 131.55(C’-6),
61.96(–OCH3), R1: 19.06(CH3)–28.05(CH2)–21.55(CH3),
R5: 21.98(CH3)–28.87(CH2)–23.40(CH3). MS (ESI): 357
(C20H25N2O4, [M?H]?). Anal. Calcd for C20H24N2O4: C,
67.40; H, 6.79; N, 7.86; Found: C, 67.55; H, 6.61; N, 7.93.
(E)-4-(((2,6-Dimethylphenyl)imino)methyl)-2-methoxy-3-
nitrophenol (4r)
M.p. 171–173 °C. 1H NMR (300 MHz, CDCl3): 2.99 (s, 2H),
3.03–3.05 (m, 3H), 3.33(s, 1H), 3.81–3.83 (m, 3H), 6.89–6.90
(d, J = 3.0 Hz, 1H), 7.19 (s, 1H), 7.25–7.27 (m, 3H), 8.60 (s,
1H), 9.47 (s, 1H). 13C NMR (300 MHz, CDCl3) d: 127.12(C-
1), 139.94(C-2), 144.75(C-3), 160.37(C-4), 118.97(C-5),
127.83(C-6), 154.25(C-7), 148.33(C0-1), 124.54(C0-2),
129.28(C0-3), 126.07(C0-4), 130.55(C0-5), 123.74(C0-6),
62.81(–OCH3), 19.06(R1–CH3), 15.92(R5–CH3). MS (ESI):
Antibacterial activity
The antibacterial activity of the synthesized compounds
was tested against B. subtilis, E. coli, P. aeruginosa, and S.
aureus using MH medium (Mueller–Hinton medium:
123

Med Chem Res
Experimental protocol of docking study
casein hydrolysate 17.5 g, soluble starch 1.5 g, beef extract
1,000 mL). The MICs of the test compounds were deter-
mined by a colorimetric method using the dye MTT (3-
(4,5-dimethylth-iazol-2-yl)-2,5-diphenyl tetrazoliumbro-
mide). A stock solution of the synthesized compound
(100 lg/mL) in dimethyl sulfoxide (DMSO) was prepared
and graded quantities of the test compounds were incor-
porated in specified quantity of sterilized liquid MH med-
ium. A specified quantity of the medium containing the
compound was poured into microtitration plates. Suspen-
sion of the microorganism was prepared to contain
approximately 105 cfu/mL and applied to microtitration
plates with serially diluted compounds in DMSO to be
tested and incubated at 37 °C for 24 h. After the MICs
were visually determined on each of the microtitration
plates, 50 lL of PBS (phosphate buffered saline 0.01 mol/
L, pH 7.4, Na2HPO4ꢀ12H2O 2.9 g, KH2PO4 0.2 g, NaCl
8.0 g, KCl 0.2 g, and distilled water 1,000 mL) 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 isopropanol con-
taining 5 % 1 mol/L HCl was added to extract the dye.
After 12 h of incubation at room temperature, the optical
density was measured with a microplate reader at 550 nm.
The observed MICs are presented in Table 3.
Automated docking studies were carried out using Dis-
covery Studio (version 3.1) as implemented through the
graphical user interface DS-CDocker protocol.
The three-dimensional structures of the aforementioned
compounds were constructed using Chem. 3D ultra 11.0
software [Chemical Structure Drawing Standard; Cam-
bridge Soft corporation, USA (2009)], then they were
energetically minimized by using MOPAC with 100 iter-
ations and minimum RMS gradient of 0.10. The Gasteiger-
Hu¨ckel charges of ligands were assigned. The crystal
structures of FtsZ protein (PDB code: 2VAM) complex
were retrieved from the RCSB Protein Data Bank (http://
www.rcsb.org/pdb/home/home.do). All bound waters and
ligands were eliminated from the protein and the polar
hydrogens and the Kollman-united charges were added to
the proteins.
Acknowledgments This work was supported by Major Projects on
Control and Rectification of Water Body Pollution (No. 2011ZX07204-
001-004), and was supported by the project (No. BY2012136) from
the Science & Technology Agency of Jiangsu Province and by the
projects (Nos. CXY1213 & CXY1222) from the Science & Technol-
ogy Bureau of Lianyuangang City of Jiangsu Province.
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