New biscoumarin and dihydropyran derivatives as antimicrobials

Article abstract of DOI:10.1007/s11164-014-1889-x

In an attempt to find a new class of antimicrobial agents, a series of biscoumarin (1-4) and dihydropyran (5 and 6) derivatives were prepared. These compounds were screened for their in vitro antibacterial activity against Staphylococcus aureus (S. aureus ATCC 29213), methicillin-resistant S. aureus (MRSA XJ 75302), vancomycin-intermediate S. aureus (Mu50 ATCC 700699), and USA 300 (Los Angeles County clone, LAC). There are two classical intramolecular O-H···O hydrogen bonds (HBs) in the structures of biscoumarins 1-4 and the corresponding total HB energy were further performed with the density functional theory (DFT) [B3LYP/6-31G] method.

Full text of DOI:10.1007/s11164-014-1889-x

Res Chem Intermed
DOI 10.1007/s11164-014-1889-x
New biscoumarin and dihydropyran derivatives
as antimicrobials
•
Jing Li Jing-ru Meng Di Qu Zi-dan Zhang
•
•
•
•
Fen Li Xiao-hui Yang Xiao-xing Luo
•
•
•
Jiang-tao Li Ming-kai Li
Received: 22 September 2014 / Accepted: 1 December 2014
Ó Springer Science+Business Media Dordrecht 2015
Abstract In an attempt to find a new class of antimicrobial agents, a series of
biscoumarin (1–4) and dihydropyran (5 and 6) derivatives were prepared. These
compounds were screened for their in vitro antibacterial activity against Staphylo-
coccus aureus (S. aureus ATCC 29213), methicillin-resistant S. aureus (MRSA XJ
75302), vancomycin-intermediate S. aureus (Mu50 ATCC 700699), and USA 300
(Los Angeles County clone, LAC). There are two classical intramolecular O–HꢀꢀꢀO
hydrogen bonds (HBs) in the structures of biscoumarins 1–4 and the corresponding
total HB energy were further performed with the density functional theory (DFT)
[B3LYP/6-31G*] method.
Keywords Biscoumarin ꢀ Dihydropyran ꢀ Staphylococcus aureus ꢀ Minimum
inhibitory concentration
Jing Li and Jing-ru Meng contributed equally to this work.
J. Li ꢀ X. Yang ꢀ J. Li (&)
College of Chemistry and Chemical Engineering, The Key Laboratory for Surface Engineering and
Remanufacturing in Shaanxi Province, Xi’an University, Xi’an, China
e-mail: lijiangtao-968@xawl.edu.cn
J. Meng ꢀ D. Qu ꢀ F. Li ꢀ X. Luo ꢀ M. Li (&)
Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University,
Xi’an, China
e-mail: mingkai@fmmu.edu.cn
Z. Zhang
Department of Physics, School of Science, Tianjin University, Tianjin, China
123

J. Li et al.
Introduction
Staphylococcus aureus (S. aureus) is a major pathogen that leads to various of
healthcare-associated infections, and has become a more significant clinical
problem because of resistance to almost all the anti-bacterial agents [1–3].
Naturally occurring strains of methicillin-resistant Staphylococcus aureus (MRSA),
which was first reported from England in 1961 [4], has resulted in the cause of
major outbreaks and epidemics in hospitalized patients. Vancomycin is currently the
most effective antibiotic treatment for MRSA [5]. However, the emergence of
MARS with decreased susceptibility to vancomycin induced to the urgent necessity
of developing new antimicrobials [6, 7].
Because of different substituents on the central linker methylene leading to
chemical modifications, biscoumarin and dihydropyran derivatives have revealed
promising biological activity with interesting potential in therapeutic application
besides their traditional use as anticoagulants, antifungal, anti-inflammatory agents,
etc. [8, 9]. They have also shown important properties as antibiotics (novobiocin
and analogs), anti-AIDS agents (calanolides), and antitumor drugs [10, 11].
Therefore, in light of the above facts, we have successfully synthesized four
biscoumarins (1–4) and two dihydropyrans (5 and 6) (Fig. 1), and all the final
synthesized compounds were tested for their antibacterial activities. Additionally,
for biscoumarins 1–4, their total HB energies were calculated by density functional
theory (DFT) method.
OH HO
OH HO
OH HO
O
O
O
O
O
O
O
O
O
O
O
O
S
S
1
Br
2
3
OH
HO
NH2
NH2
CN
CN
O
O
O
O
O
O
S
S
S
Br
4
O
O
5
6
Fig. 1 Chemical structures of compounds 1–6
123

New biscoumarin and dihydropyran derivatives as antimicrobials
Experimental
Apparatus and materials
IR spectra (400–4,000 cm-1) were obtained using a Bruker Equinox-55 spectro-
photometer. 1H NMR spectra were obtained using a Varian Inova-400 spectrometer
(at 400 MHz). Mass spectra were obtained using a micrOTOF-Q II mass
spectrometer. The melting points were taken on a XT-4 micro melting apparatus,
and the thermometer was uncorrected.
All antibiotics used were purchased from the National Institute for the Control of
Pharmaceutical and Biological Products (Beijing, China). All other chemicals and
solvents were of analytical grade.
MRSA (XJ 75302) was isolated from cultures of sputum samples from patients in
Xijing Hospital (Xi’an, China). S. aureus strain (ATCC 29213) was purchased from
the Chinese National Center for Surveillance of Antimicrobial Resistance. Mu50
(ATCC 700699) and USA 300 (LAC) were purchased from MicroBiologics (MN,
USA).
Synthesis and characterization of compounds 1–6
Compounds 1–4 were synthesized according to the methods of a previous report
[12]. A mixture of formaldehyde (or thiophene-2-carbaldehyde, 4-bromo-thiophene-
2-carbaldehyde and 5-bromo-thiophene-2-carbaldehyde) (10 mmol) and 4-hydroxy-
coumarin (20 mmol) was dissolved in 100 ml of EtOH. A few drops of piperidine
were added, and the mixture was stirred for 3 h at room temperature. After reaction
completion as determined by TLC, water was added until precipitation occurred.
After filtering the precipitates, they were sequentially washed with ice-cooled water
and ethanol and then dried in a vacuum.
3,30-Methylenedi(4-hydroxycoumarin) (1): m.p. 289–290 °C. IR(KBr pellet cm-1):
1
3051(OH), 1645(CO), 1526(C = C). H NMR (CDCl3, d, ppm): 11.322(s, 2H),
7.988–8.011(q, 2H), 7.571–7.614(m, 2H), 7.347–7.393(m, 4H), 3.847(s, 2H). HRMS
(ESI?): m/z: calcd for [C19H12O6 ? Na?]: 359.0526; found: 359.0544.
3,30-(2-Thienyl-methylene)-bis-(4-hydroxycoumarin) (2): m.p. 206–207 °C. IR(KBr
pellet cm-1): 1,665, 1,612, 1,567, 1,514, 1,356, 767 cm-1. 1H NMR (CDCl3, d, ppm):
11.803(s, 1H), 11.290(s, 1H), 8.017–8.073(m, 2H), 7.617–7.656(q, 2H),
7.399–7.420(d, 4H), 7.214–7.227(d, 1H), 6.940–6.962(t, 1H), 6.855–6.864(t, 1H),
6.200(s, 1H). HRMS (ESI?): m/z: calcd for [C23H14SO6 ? Na?]: 441.0403; found:
441.0411.
3,30-(4-Bromo-2-thienyl-methylene)-bis-(4-hydroxycoumarin) (3): m.p. 207–208 °C.
IR(KBr pellet cm-1): 1,666, 1,620, 1,571, 1,533, 1,363, 1,246, 1,143, 911, 760 cm-1
.
1H NMR (CDCl3, d, ppm): 11.871(s, 1H), 11.307(s, 1H), 8.045–8.090(t, 2H),
7.651–7.690(t, 2H), 7.422–7.443(d, 4H), 7.144(s, 1H), 6.789(s, 1H), 6.169(s, 1H).
HRMS (ESI?): m/z: calcd for [C23H13BrO6S ? Na?]: 518.9508; found: 518.9532.
123

J. Li et al.
3,30-(5-Bromo-2-thienylmethylene)-bis-(4-hydroxycoumarin)(4): m.p. 217–218 °C.
IR(KBr pellet cm-1): 1,673, 1,620, 1,552, 1,492, 1,356, 1,318, 1,205, 1,099, 971,
767 cm-1. 1H NMR (CDCl3, d, ppm): 11.890(s, 1H), 11.299(s, 1H), 8.036–8.090(q,
2H), 7.646–7.685(t, 2H), 7.420–7.441(d, 4H), 6.910–6.919(d, 1H), 6.634–6.647(q,
1H), 6.118–6.122(d, 1H). HRMS (ESI?): m/z: calcd for [C23H13BrO6S ? Na?]:
518.9508; found: 518.9589.
Dihydropyran derivatives (5 and 6) were also synthesized according to a reported
procedure [13]. A mixture of 3,5-cyclohexanedione (1,1-dimethyl-3,5-cyclohexanedi-
one) (10 mmol), thiophene-3-carbaldehyde (10 mmol), malononitrile (10 mmol) and
4-(dimethylamino)pyridine (DMAP) (1 mmol) in ethanol (100 ml) was refluxed for
2–3 h and then cooled to room temperature. After filtering the precipitates, they were
sequentially washed with ice-cooled water and ethanol and then dried under a vacuum.
2-Amino-4-(3-thienyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
(5): m.p. 196–197 °C. IR(KBr pellet cm-1): 3,311, 3,174, 2,191, 1,654, 1,365,
1,213, 997, 765 cm-1 1H NMR (DMSO-d6, d, ppm): 7.412–7.432 (q, 1H),
.
7.133–7.143 (q, 1H), 7.028 (s, 2H), 6.903–6.919 (q, 1H), 4.317 (s, 1H), 2.574–2.601
(t, 2H), 2.299–2.323 (t, 2H), 1.894–1.984 (m, 2H). HRMS (ESI?): m/z: calcd for
[C14H12N2O2S ? Na?]: 295.0512; found: 295.0554.
2-Amino-4-(3-thienyl)-3-cyano-7,7-dimethyl-5-oxo-4H-5,6,7,8-tetrahydrobenzo[b]pyran
(6): m.p. 225–226 °C. IR(KBr pellet cm-1): 3,383, 3,207, 2,191, 1,670, 1,606,
1,365, 1,213, 1,133, 1,038, 765 cm-1. 1H NMR (DMSO-d6, d, ppm): 7.412–7.432 (q,
1H), 7.133–7.143 (q, 1H), 7.028 (s, 2H), 6.903–6.919 (q, 1H), 4.317 (s, 1H),
2.574–2.601 (t, 2H), 2.299–2.323 (t, 2H), 1.894–1.984 (m, 2H). HRMS (ESI?): m/z:
calcd for [C16H16N2O2S ? Na?]: 323.0825; found: 323.0833.
X-ray crystallography
For X-ray diffraction experiments, single crystals of compounds 4 and 6 were both
grown from methanol. The X-ray diffraction data were collected on a Bruker
SMART APEX II CCD diffractometer equipped with a graphite monochromated
˚
Mo-Ka radiation (k = 0.71073 A) by using the x-2h scan technique at room
temperature. The structure was solved by direct methods using SHELXS-97 [14] and
refined using the full-matrix least squares method on F2 with anisotropic thermal
parameters for all non-hydrogen atoms by using SHELXL-97. Hydrogen atoms were
generated geometrically. The crystal data and details concerning data collection and
structure refinement are given in Table 1. Molecular illustrations were prepared
using the XP package. Parameters in CIF format are available as Electronic
Supplementary Publication from Cambridge Crystallographic Data Centre.
Quantum chemical calculations
All calculations were carried out using the Gaussian 09 package [15]. Density
functional theory [16], Becke’s three-parameter hybrid function (B3LYP) [17], and
LYP correlation function [18] were used to fully optimize all of the geometries on the
energy surface without constraints. To obtain precise results that are in conjunction
123

New biscoumarin and dihydropyran derivatives as antimicrobials
Table 1 Crystal data, data collection, and structure refinement
Compound 4
Compound 6
Formula
C23H13BrO6S
497.30
C16H16N2O2S
300.0932
Monoclinic
P21/c
Mr
Crystal system
Space group
Monoclinic
P21/c
˚
a/A
9.8301 (6)
10.2686 (9)
20.3329 (15)
90
11.3333 (6)
9.2903 (7)
14.6589 (10)
90
˚
b/A
˚
c/A
a/°
b/°
c/°
95.321 (5)
90
98.658 (5)
90
3
˚
V/A
2,043.6 (3)
4
1,525.84 (17)
4
Z
D
calc/g cm-3
1.616
1.299
l (Mo Ka)/mm-1
2.153
0.217
h range/°
2.76 to 25.00
7,159
2.60 to 25.00
6,261
Reflections collected
No. unique data [R(int)]
No. data with I C 2r(I)
R1
3,596 [0.0235]
2,376
2,681 [0.0294]
1,921
0.0648
0.1382
xR2 (all data)
CCDC
0.2030
0.3900
1,017,804
1,035,052
with experimental results, three basis sets, namely 6-31G*, 6-31 ? G**, and
6-311G*, were tested. Frequency calculations at the B3LYP (with basis sets 6-31G*)
level of theory were carried out to confirm stationary points as minima and to obtain
the zero-point energies and the thermal correlation data at 1 atm and 298 K.
Minimal inhibitory concentration (MIC) assay
According to the method described previously [19], MICs was observed in sterilized
96-well polypropylene microtiter plates in a final volume of 200 ll of culture
medium. All four of the S. aureus strains (5 9 105 CFU/ml) were cultured overnight
in 100 ll of broth. Mueller–Hinton (MH) broth, then 100 ll of the culture medium
with the test compound (0.12–256 lg/ml in serial twofold dilutions), or with control
antibiotics were added into the 96-well plates. After being incubated at 37 °C for
20 h in an incubator, 50 ll of 0.2 % triphenyl tetrazolium chloride (TTC) was
added to each well and incubated at 35 °C for 1.5 h. The TTC-based MIC was
determined as the lowest concentration that showed no red color change indicating
complete growth inhibition. The data were from three repeated experiments.
123

J. Li et al.
Bacterial growth inhibition
Bacterial growth inhibition was determined by the time–kill curves according to the
published method [20]. In the four S. aureus strains culture medium, compound 2
was added to the culture medium to a final concentration of 8, 16, or 32 lg/ml. The
bacteria were then cultivated in the automated Bioscreen C system (Lab Systems,
Helsinki, Finland) in 300 ll working volume in the wells at 35 °C, which comprised
150 ll MH broth and 150 ll compound 2 solution. The optical density of the
bacterial suspensions was measured automatically at 600 nm, which indicates the
concentration of bacterial during the 24-h culture period. Statistical data for each
experiment were obtained from three independent assays performed in duplicate.
Results
Molecular structure
The crystal structures of compounds 4 and 6 are given in Fig. 2. In the crystal
structure of compound 4, a methylene group links two identical 4-hydroxycoumarin
moieties and one hydrogen atom is replaced with a 5-bromo-thiophene group.
Additionally, a hydroxyl group and a lactone carbonyl group from the two
identical 4-hydroxycoumarin molecules, respectively, constitute two classical
asymmetrical intramolecular H-bonds, which further stabilized its entire structure
˚
[d(O2—O6) = 2.667 and d(O3—O5) = 2.610 A].
In the crystal structure of compound 6, the newly formed pyran ring is essentially
planar because the C3 atom makes a maximum deviation from the C1-O1-C5 plane
˚
of 0.7058 A. The adjacent ketone ring is also essentially planar because the C7 atom
˚
makes a maximum deviation of 0.5621 A from the C5-C4-C9 plane. The thiophene
ring makes a 89.519° angle with the pyran ring plane, and the atoms C14 deviate
from that plane by 2.6938 A.
˚
Fig. 2 Crystal structures of compounds 4 and 6
123

New biscoumarin and dihydropyran derivatives as antimicrobials
1
2
H3
R= H
R=
O3
O5
S
S
R
H
C3
C1
C11
O
3
R=
R=
O
C13
Br
Br
O2
O6
S
H6
4
Fig. 3 Schematic presentation of compounds 1–4
Table 2 Experimental and calculated parameters of the selected bond lengths and bond angles of
compound 4
Name definition
X-ray
1.215
6-31G*
6-31 ? G**
6-311G*
C11–O5
C1–O2
C1–O1
1.230
1.233
1.233
1.236
1.222
1.226
1.215
1.351
1.372
1.370
1.371
C11–O4
1.365
1.375
1.372
1.374
C2–C10
1.515
1.526
1.526
1.526
C
12–C10
10–C20
1.520
1.527
1.526
1.526
C
1.519
1.521
1.521
1.520
O1–C1–O2
O4–C11–O5
C1–C2–C10
116.16
114.73
114.58
118.04
114.32
113.06
113.69
138.76
51.51
115.74
115.77
114.14
118.88
113.52
114.50
113.94
134.25
50.07
115.94
115.93
114.10
119.02
113.71
114.70
113.89
133.62
50.53
115.99
116.04
113.95
118.67
113.62
114.64
113.94
134.07
50.46
C11–C12–C10
C2–C10–C12
C2–C10–C20
C
12–C10–C20
C1–C2–C10–C20
11–C12–C10–C20
C1–C2–C10–C12
11–C12–C10–C2
C
89.05
92.54
92.85
92.48
C
80.39
83.40
83.38
83.33
Quantum chemical calculations
Geometric parameters of compounds 1–4
The fully optimized molecular structures of compounds 1–4 with atomic numbering
calculated at B3LYP level of theory are shown in Fig. 3. For compound 4, selected
calculated geometric parameters under three different basis sets and experimental
geometric parameters is presented in Table 2.
123

J. Li et al.
From Table 2, we can see that the values under three different basis sets are very
close, which also agree with the experimental findings. Between theoretical and
experimental data, the average discrepancy of the selected bond lengths is
˚
\
B3LYP/6-31G* showed sufficient agreement with experimental data and lower
0.02 A, and the average discrepancy of the selected bond angles is \ 2°.
computational cost, so further theoretical study was performed at this level.
Estimation of the single and total HB energies in compounds 1–4
We take compound 4 for example to estimate single and total HB energies. In
compound 4, a global minimum structure is stabilized by two HBs (4ab) and two
higher energy structures is stabilized by one HB (4a and 4b), respectively.
The O6—H6ꢀꢀꢀO2 HB energy was calculated to be -52.399729 kJ/mol from the
coor
4ab
energy difference between 4ab and 4a by the equation E(O6—H6ꢀꢀꢀO2) = E
-
coor
4a
E
, in which 4a is a global minimum structure with one HB (O3—H3ꢀꢀꢀO5).
Similarly, the O3—H3ꢀꢀꢀO5 HB energy was calculated to be -71.130046 kJ/mol by
coor
4ab
coor
- E , in which 4b was obtained from the
4b
the equation E(O3—H3ꢀꢀꢀO5) = E
global minimum structure of 4ab, but H3 was rotated around the C3—O3 bond until
O3—H3ꢀꢀꢀO5 HB rupture occurred. We can see that O3—H3ꢀꢀꢀO5 HB strength is
stronger than that of O6—H6ꢀꢀꢀO2, which is consistent with the fact that the distance
˚
˚
of O3—O5 (2.610 A) is shorter than that of O6—O2 (2.667 A). The total HB energy
coor
4ab
in compound 4 was estimated to be -123.529775 kJ/mol by the equation 2E
coor
-
coor
4a
(E
? E ). The total HB energy in compounds 1–3 is -119.160943,
4b
-125.4805215 and -122.274786 kJ mol-1, respectively (Table 3).
Table 3 Total electronic energies (in hartree) and HB energies (in kJ/mol) of hydrogen bonded con-
formers of compounds 1–4 calculated at B3LYP/6-31G* level of theory
System
Total electronic energiesa
E (O6—H6ꢀꢀꢀO2)
-59.5804715
E (O3—H3ꢀꢀꢀO5)
E (total HB)
1ab
1a
-1,182.371051
-1,182.348358
-1,182.348358
-1,734.116678
-1,734.096324
-1,734.089239
-4,305.229694
-4,305.209554
-4,305.203262
-4,305.225972
-4,305.206014
-4,305.19888
-119.160943
1b
2ab
2a
-59.5804715
-72.0410945
-69.397216
-71.130046
-125.4805215
-122.274786
-123.529775
-53.439427
-52.87757
-52.399729
2b
3ab
3a
3b
4ab
4a
4b
a
ZP corrected
123

New biscoumarin and dihydropyran derivatives as antimicrobials
Table 4 MIC of compounds 1–6 and antibiotics in Mueller-Hinton broth culture
Drugs
MIC (lg/ml)
S. aureas
(ATCC 29213)
MRSA
(XJ 75302)
Mu50
(ATCC 700699)
LAC
(USA 300)
Compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Ceftazidime
Ceftriaxone
Gentamicin
Piperacillin
[256
4–8
[256
[256
[256
4–8
8–16
16–32
64–128
64–128
[256
32–64
32–64
[256
[256
8 (S)
32–64
32–64
32–64
[256
32–64
[256
[256
[256
[256
[256 (R)
[256 (R)
64 (R)
[128 (R)
256 (R)
256 (R)
32 (R)
[128 (R)
64 (R)
32 (R)
0.25 (S)
64 (R)
2 (S)
0.12 (S)
2 (S)
S drug susceptibility, R drug resistance
Minimal inhibitory concentration (MIC) assay
One drug-sensitive S. aureus (S. aureus ATCC 29213) strain and three MRSA strains
(MRSA XJ 75302, Mu50, USA 300 LAC) were used in the systematic analysis of the
antibacterial activities of compounds 1–6 in vitro, as is shown in Table 4. Compared with
dihydropyran derivatives 5 and 6, biscoumarins 1–4 have better bactericidal effects
against the four types of S. aureus strains, especially for compound 2 with the MIC values
of 4–32 lg/ml. Compared with the MIC values of the above compounds, the MIC values
of ceftazidime, ceftriaxone, gentamicin, and piperacillin against S. aureus (ATCC 29213)
strains were lower (\8 lg/ml) but were higher against resistant strains at varying degrees.
Bacterial growth inhibition
Because of the minimum MIC values in compound 2, the growth rate of S. aureus in liquid
medium containing the different concentrations (8, 16, or 32 lg/ml) were further
determined. Compared with compound 2 exhibiting almost completely growth inhibition
on these pathogens at 16 or 32 lg/ml, other compounds hardly showed any inhibitory
effects at these concentrations (data was not shown), which is consistent with the results of
the MIC values. S. aureus growth in MH broth without any compounds, which was used as
the control sample, did not exhibit any significant growth inhibitory effect. This
experiment was repeated three times and the typical result was shown in Fig. 4.
Discussion
Due to the emergence of vancomycin-resistant S. aureus and treatment failure of
MRSA infections, new antimicrobials need to be developed urgently. In this work,
123

J. Li et al.
Fig. 4 Concentration-dependent inhibition of compound 2 on the growth of four S. aureus strains
we successfully synthesized biscoumarin and dihydropyran derivatives, and then
studied their in vitro antibacterial activities.
Both MIC and bacterial growth inhibition results showed that compound 2
exerting potent bactericidal effects against four S. aureus strains tested. However,
compared with compound 2, other compounds exerted almost no effect on any S.
aureus.
Two intramolecular O–HꢀꢀꢀO HBs in the biscoumarins 1–4 were considered as an
important factor for biological activity by assisting the molecule to attain the correct
configuration. The calculated results are creditable because of the fully optimized
molecular structure of compound 2 calculated at B3LYP level of the theory using
three different basis sets (6-31G*, 6-31 ? G**, and 6-311G*) were in agreement
with its available X-ray data.
The total HB stabilization energies in compounds 1–4 were estimated to be
-119.160943, -125.4805215, -122.274786, and -123.529775 kJ/mol, respec-
tively. The values in compounds 2–4 are all higher than that of compound 1 because
of the effect of thiophene group; the value in compound 2 is higher than those of
compounds 3 and 4 because of the effect of bromine atom. These values suggest that
the most potent antibacterial activity in compound 2 is consistent with the stronger
HB strengths.
Conclusions
With the emergence of methicillin-resistant, vancomycin-intermediate resistant, or
multi-drug resistant S. aureus, more appropriate antibiotics should be developed.
123

New biscoumarin and dihydropyran derivatives as antimicrobials
Our results showed that in the six compounds, compound 2 had the most potent anti-
bacterial efficiency, possibly because 2-thiophene groups on the methylene group
further strengthen the HB strengths. To further define the mechanism of anti-
bacterial activity in vivo, additional experiments should be carried out.
Acknowledgments This work was supported by grants from the Industrial Research Project of Science
and Technology Department of Shaanxi Province (No. 2013K09-25), National Natural Science
Foundation of China (No. 81001460 and No. 81273555) and Innovation Plan of Science and Technology
of Shaanxi Province (2014KTCL03-03). The authors thank the High Performance Computing Center of
Tianjin University and Prof. Xuehao He for the services provided.
References
1. F. Barbier, A. Andremont, M. Wolff, L. Bouadma, Curr. Opin. Pulm. Med. 19, 216 (2013)
2. M.W. Climo, D.S. Yokoe, D.K. Warren, T.M. Perl, M. Bolon, L.A. Herwaldt, R.A. Weinstein, K.A.
Sepkowitz, J.A. Jernigan, K. Sanogo, E.S. Wong, N. Engl, J. Med. 368, 533 (2013)
3. P.N. Malani, JAMA 309, 1408 (2013)
4. V.M. Dukic, D.S. Lauderdale, J. Wilder, R.S. Daum, M.Z. David, PLoS one 8, e52722 (2013)
5. P.S. Pottinger, Med. Clin. North Am. 97, 601 (2013)
6. B. Tarai, P. Das, D. Kumar, J. Lab Physicians 5, 71 (2013)
7. F. Borges, F. Roleira, N. Milhazes, E. Uriarte, L. Santana, Front. Med. Chem. 4, 23 (2009)
8. Z. Nowakowska, Eur. J. Med. Chem. 42, 125 (2007)
9. S.K. Ray, S. Rout, V.K. Singh, Org. Biomol. Chem. 11, 2412 (2013)
10. M.R. Lambu, S. Kumar, S.K. Yousuf, D.K. Sharma, A. Hussain, A. Kumar, F. Malik, D. Mukherjee,
J. Med. Chem. 56, 6122 (2013)
11. N.G. Rokof’eva, N.K. Utkina, E.L. Chaikina, A.E. Makarchenko, Comp. Biochem. Physiol. B Bio-
chem. Mol. Biol. 139, 167 (2004)
12. C.A. Kontogiorgis, D.J. Hadjipavlou-Litina, J. Med. Chem. 48, 6400 (2005)
13. H. Eshghi, G.H. Zohuri, R. Sandaroos, S. Damavandi, Heterocycl. Commun. 18, 67 (2012)
14. G.M. Sheldrick, SHELXL-97, Program for Solution Crystal Structure and Refinement (University of
¨
Gottingen, Gottingen, 1997)
15. M.J. Frisch, G.W. Trucks, H.B. Schlegel et al., Gaussian 09, Revision A.02 (Gaussian Inc., Wal-
lingford, 2009)
16. W. Kohn, L.J. Sham, Phys. Rev. 140, A1133 (1965)
17. A.D. Becke, J. Chem. Phys. 98, 5648 (1993)
18. C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37, 785 (1988)
19. Clinical and Laboratory Standards Institute, Performance Standards for Antimicrobial Susceptibility
Testing: Nineteenth Informational Supplement M100-S19 (Wayne, PA, 2009)
20. M. Motyl, K. Dorso, J. Barrett, Current Protocols in Pharmacology. (Wiley-Liss, New York, 2005)
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