Synthesis, crystal structure, ABTS radical-scavenging activity, antimicrobial and docking studies of some novel quinoline derivatives

Article abstract of DOI:10.1016/j.molstruc.2014.04.009

In this study, a series of nine novel 2-chloroquinolin-3-yl ester derivatives have been synthesized via a two-step protocol from 2-chloroquinoline-3-carbaldehyde. The structures of all these compounds were confirmed by spectral data. The single crystal X-

Full text of DOI:10.1016/j.molstruc.2014.04.009

Journal of Molecular Structure xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, crystal structure, ABTS radical-scavenging activity,
antimicrobial and docking studies of some novel quinoline derivatives
c
c
d
Sumaiya Tabassum a, T.H. Suresha Kumara a,b, , Jerry P. Jasinski , Sean P. Millikan , H.S. Yathirajan ,
P.S. Sujan Ganapathy e, H.B.V. Sowmya a, Sunil S. More f, Gopalpur Nagendrappa a, Manpreet Kaur d,
Gilish Jose a
⇑
a P.G. Department of Chemistry, Jain University, 127/2, Bull Temple Road, Chamarajpet, Bangalore 560026, India
b Department of Chemistry, UBDT, College of Engineering, Davangere, Karnataka 577004, India
c Department of Chemistry, Keene State College, Keene, NH 03435-2001, USA
d Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
e Centre for Advanced Studies in Biosciences, Jain University, Bangalore 560019, India
f P.G. Department of Biochemistry, C.P.G.S., Jain University, Jayanagar 3rd block, Bangalore 560011, India
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
ꢀ
ꢀ
New series of 2-chloroquinolin-3-yl
ester derivatives were synthesized.
Chemical structures of the
compounds were characterized by 1H
NMR, 13C NMR, LCMS spectral
analysis and elemental analysis.
X-ray crystallographic study of 6a and
6e were carried out.
ꢀ
ꢀ
In vitro antimicrobial and ABTS
radical-scavenging activity screening
were carried out.
ꢀ
The docking studies were carried out.
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, a series of nine novel 2-chloroquinolin-3-yl ester derivatives have been synthesized via a
two-step protocol from 2-chloroquinoline-3-carbaldehyde. The structures of all these compounds were
confirmed by spectral data. The single crystal X-ray structure of two derivatives, (2-chloroquinolin-
3-yl)methyl acetate [6a] and (2-chloro-6-methylquinolin-3-yl)methyl acetate [6e] have also been deter-
mined. The synthesized compounds were further evaluated for their ABTS radical-scavenging activity and
antimicrobial activities. Amongst all the tested compounds, 6a exhibited maximum scavenging activity
with ABTS. Concerning antibacterial and antifungal activities, compound (2-chloro-6-methoxyquinolin-
3-yl)methyl 2,4-dichlorobenzoate [6i] was found to be the most active in the series against B. subtilis,
S. aureus, E. coli, K. pneumonia, C. albicans and A. niger species. The structure-antimicrobial activity rela-
tionship of these derivatives were studied using Autodock.
Received 23 November 2013
Received in revised form 3 April 2014
Accepted 3 April 2014
Available online xxxx
Keywords:
Vilsmeier–Haack reaction
Quinoline
Single crystal X-ray structure
Docking studies
Ó 2014 Elsevier B.V. All rights reserved.
Antimicrobial studies
ABTS Radical-scavenging activity
Introduction
Quinoline is a remarkable, interesting nitrogen heterocyclic
scaffold of paramount importance to human race. Its skeleton is
⇑
Corresponding author. Tel.: +91 9916588466, mobile: +91 09916588466.
E-mail address: suresha.kumara@gmail.com (T.H. Suresha Kumara).
http://dx.doi.org/10.1016/j.molstruc.2014.04.009
0022-2860/Ó 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: S. Tabassum et al., J. Mol. Struct. (2014), http://dx.doi.org/10.1016/j.molstruc.2014.04.009

2
S. Tabassum et al. / Journal of Molecular Structure xxx (2014) xxx–xxx
often an attractive framework in the design of several synthetic
compounds against diverse pharmacological targets leading to
the discovery of potent drugs. The chemistry of quinoline and its
derivatives have been enjoying a relative renaissance of interest
due to the growing abundance of quinoline components in various
natural products, pharmaceuticals and new materials. The utility of
quinoline derivatives in the areas of medicine [1], food, catalyst,
dye [2], materials, refineries and electronics [3,4] is well estab-
lished. These compounds are found to possess various bioactivities
such as anti-malarial [5–7], anti-bacterial [8–11], anti-fungal
[12–14], anti-cancer agents [15–18]. They are widely used as anti-
biotics [19], alkaloids, rubber, chemicals and flavoring agents.
Additional industrial applications include their use as corrosion
inhibitors, preservatives [20], solvents, resins, transition metal
complex catalyst for uniform polymerization and luminescence
chemicals [21]. The literature survey revealed that, the synthetic
quinoline and substituted quinoline derivatives are associated
with a wide range of biological properties in curing a lot of dis-
eases. Amongst them, quinoline esters are one of the most impor-
tant derivatives, however only few methods have been reported in
the literature [22–32] for their synthesis. Recently, quinoline-
4-methyl esters are found to serve as human nonpancreatic secre-
tory phospholipase A2 inhibitors [33] and quinoline dicarboxylic
esters are used as biocompatible fluorescent tags [34]. As a result,
the synthesis of quinoline and its derivatives have always attracted
considerable attention especially from biochemists and synthetic
organic chemists who are concerned with human and animal
health care problems. In view of these observations and with a
view to further explore the pharmacological profile of this class
of compounds, the present study aims to put in considerable
efforts to synthesize 2-chloroquinolin-3-yl ester derivatives, purify
and characterize them. As quinoline and substituted quinoline
derivatives are known to exhibit various biological activities such
as antimicrobial, anti-inflammatory, analgesic, anti-tuberculosis,
antiviral, the proposed research work is expected to result in the
synthesis of biologically active of these derivatives. We also herein
report, the crystal structures of two derivatives, the crystal struc-
ture analysis was carried out with the intention of eliciting struc-
tural information which could facilitate further understanding of
structural requirements for improved biological activity, ABTS rad-
ical-scavenging activity and antimicrobial activity of the synthe-
sized derivatives.
for novel antimicrobial agents. In virtual screening, a molecular
docking played a crucial role in finding putative binding protein
for a compound either from genomic or protein database [43]. Auto
Dock 3 was used to perform the docking of a set of molecules with-
glucosamine-6-phosphate synthase(GlcN-6-P synthase), an elite
target protein to inhibit the growth of microbes. This is the first
report exploring the biological potential of these synthesized mol-
ecules as antimicrobial agents and providing evidence for exploita-
tion of these compounds for further therapeutic applications.
Experimental
General procedures
Open capillary method was employed to determine the melting
points and were found uncorrected. The NMR spectra was recorded
at 400 MHz (1H NMR) and 100 MHz (13C NMR), referenced to an
internal standard (TMS) or residual solvent protons and chemical
shifts (d) reported in ppm. Mass spectra were recorded on LC–MS
(Shimadzu QP 5000 spectrometer). CHN analysis was performed
using Elementar vario MICRO cube analyzer. All chromatographic
purifications were performed on 60–120 silica gel columns by
using 9.5:0.5 ratio of petroleum ether and ethyl acetate as eluent.
Samples were recrystallized from DCM or ethyl acetate. Chemicals
and solvents used for the chemical synthesis were acquired from
commercial sources of analytical grade.
Synthesis of 2-chloroquinoline-3-carbaldehyde (4a) [44–55]
To a stirred solution of N-phenylacetamide(3a) (5 mmoles) in
dry DMF (15 mmoles), POCl3 (60 mmoles) was added drop-wise.
The mixture was refluxed for overnight on water bath at
85–90 °C. The reaction mixture was quenched with crushed ice
present in a 500 mL beaker and stirred well for some time. The
precipitate obtained was filtered, dried and purified by recrystalli-
zation processby using ethyl acetate to afford pure compound 4a in
82% yield. Similarly, the other aldehydes 4b–c were prepared by
using the procedures reported earlier.
Synthesis of (2-chloroquinolin-3-yl)methanol (5a) [56–59]
Oxidative stress generates reactive oxygen species, such as
superoxide (Oꢁ2 ), hydroxyl (OHꢁ) and peroxyl (OOHꢁ, ROOꢁ) radi-
cals, and are a crucial etiological factor to the pathophysiology of a
variety of degenerative or pathological conditions such as ageing,
cancer, coronary heart disease, Alzheimer’s disease, atherosclerosis
and inflammation [35–36]. Human body has multiple mechanisms
especially enzymatic and non-enzymatic antioxidant systems to pro-
tect the cellular molecules against reactive oxygen species (ROS)
induced damage [37]. However due to the overproduction of reactive
species and/or inadequate antioxidant defense, it culminates in
severe or continued oxidative stress. The harmful action of the free
radicals can, however be blocked by antioxidant substances, which
scavenge the free radicals and detoxify the organism [38]. Many syn-
thetic antioxidants such as butylated hydroxyl anisole (BHA) and
butylated hydroxyl toluene (BHT) are very effective and have been
added to food stuffs during food processing but they may possess
toxic side effects and also acts as carcinogens [39]. Therefore there
is a necessity to synthesize potent compounds that would have bet-
ter scavenging activity and possess fewer side effects.
To a stirred mixture of2-chloroquinoline-3-carbaldehydes (4a)
(0.052 mol) in methanol (6 mL), NaBH4 (0.078 mol) was added
portion wise under ice cold conditions for 15 min. The reaction
mixture was stirred for 30 min. After the completion of reaction,
the reaction mixture was quenched with ice cold water and acidi-
fied very slowly with dil. HCl. The solid obtained was filtered,
washed, dried and recrystallized from dichloromethane to afford
pure compound 5a in 80% yield. Similarly, the other alcohols
5b–c were prepared by using the procedures reported earlier.
Synthesis of (2-chloroquinolin-3-yl)methyl acetate (6a)
A
mixture of (2-chloroquinolin-3-yl)methanol (5a) (0.20 g,
0.00095 mol) and acid chloride (0.21 g, 0.0028 mol) was stirred
in DMF along with activated K2CO3 at room temperature. The reac-
tion was monitored by TLC. After completion of the reaction, the
reaction mixture was quenched with ice cold water. The obtained
solid was filtered, washed, dried and further purified by column
chromatography using 9.5:0.5 mixture of petroleum ether and
ethyl acetate to afford pure product 6a in 56% yield. Similarly,
the other esters 6b–I were prepared (Table 1).
Infectious diseases are threatening millions of people around
the world and the recent upsurge in widespread antibiotic resis-
tance among pathogens [40–42] and the undesirable side effects
associated with constant use of drugs has prompted the search
Please cite this article in press as: S. Tabassum et al., J. Mol. Struct. (2014), http://dx.doi.org/10.1016/j.molstruc.2014.04.009

S. Tabassum et al. / Journal of Molecular Structure xxx (2014) xxx–xxx
3
Spectral dataof(2-chloroquinolin-3-yl)methyl acetate derivatives
(6a–i)
(2-Chloro-6-methylquinolin-3-yl)methyl benzoate (6f)
Yellow crystal; 1HNMR (400 MHz, CDCl3): d 8.16ꢁ8.13 (m, 1H),
7.96 (d, J = 11.6 Hz, 2H), 7.60ꢁ7.59 (m, 1H), 7.50 (t, J = 9.6 Hz, 3H),
7.28 (d, J = 2.0 Hz, 2H), 5.61 (s, 2H), 2.56 (s, 3H); 13C NMR
(400 MHz, CDCl3): d 166.2, 151.1, 146.0, 137.6, 137.5, 133.4,
133.1, 131.1, 130.3, 129.9, 129.8, 128.6, 128.0, 127.8, 127.1,
126.6, 63.6, 24.0; MS (m/z): 312.0 [M+H]+; Anal. Calcd for C18H14
ClNO2: C, 69.35; H, 4.53, N, 4.49; found: C, 69.47; H, 4.50, N, 4.41.
(2-Chloroquinolin-3-yl)methyl acetate (6a)
White crystal; 1H NMR (400 MHz, CDCl3): d 8.20 (d, J = 0.4 Hz,
1H), 8.04ꢁ8.02 (m, 1H), 7.84 (dd, J = 8.4, 1.2 Hz, 1H), 7.75ꢁ7.73
(m, 1H), 7.57ꢁ7.56 (m, 1H), 5.35 (s, 2H), 2.18 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 170.9, 150.1, 147.7, 138.5, 131.2, 128.8,
128.2, 128.0, 127.8, 127.4, 63.5, 21.3; MS (m/z): 236.1 [M+2H]+;
Anal. Calcd for C12H10ClNO2: C, 61.16, H, 4.28, N, 5.94; found: C,
61.05, H, 4.13, N, 5.79.
(2-Chloro-6-methylquinolin-3-yl)methyl 2,6-dichlorobenzoate (6g)
White crystal; 1H NMR (400 MHz, CDCl3): d 8.25 (s, 1H), 7.90 (d,
J = 8.4 Hz, 1H), 7.56 (t, J = 1.6 Hz, 2H), 7.29ꢁ7.27 (m, 3H), 5.63 (s,
2H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3): d 164.3, 148.6,
146.0, 143.0, 137.9, 137.5, 135.2, 133.2, 133.1, 132.1, 131.2,
128.0, 127.0, 126.8, 126.6, 126.1, 64.6, 21.6; MS (m/z): 382.0
[M+H]+; Anal. Calcd for C18H12Cl3NO2: C, 56.80; H, 3.18, N, 3.68;
found: C, 56.89; H, 3.26, N, 3.53.
(2-Chloroquinolin-3-yl)methyl benzoate (6b)
Off white powder; 1H NMR (400 MHz, CDCl3): d 8.58 (d, J = 8.2
Hz, 1H), 8.13 (t, J = 8.0 Hz, 1H), 8.06ꢁ8.03 (m, 2H), 7.96ꢁ7.94 (m,
1H), 7.87 (t, J = 9.6 Hz, 1H), 7.79 (s, 2H), 7.50ꢁ7.48 (m, 2H), 5.65
(d, J = 0.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 166.1, 149.8,
147.4, 138.2, 133.4, 130.8, 129.8, 129.7, 128.8, 128.6, 128.4,
128.3, 128.0, 127.7, 127.4, 127.0, 63.5; MS (m/z): 298.0 [M+H]+;
Anal. Calcd for C17H12ClNO2: C, 68.58, H, 4.06, N, 4.70; found: C,
68.39, H, 4.19, N, 4.91.
(2-Chloro-6-methoxyquinolin-3-yl)methyl acetate (6h)
White powder; 1H NMR (400 MHz, CDCl3): d 8.10 (s, 1H), 7.92
(d, J = 9.2 Hz, 1H), 7.39 (dd, J = 9.2, 2.7 Hz, 1H), 7.09 (s, 1H), 5.33
(s, 2H), 3.93 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3): d
170.6, 158.4, 147.0, 143.3, 136.8, 129.7, 128.2, 128.0, 123.4,
105.2, 63.1, 55.7, 20.9; MS (m/z): 266.0 [M+H]+; Anal. Calcd for
(2-Chloroquinolin-3-yl)methyl 2,4-dichlorobenzoate (6c)
White crystal; 1H NMR (400 MHz, CDCl3): d 8.22 (s, 1H), 7.90-
7.88 (m, 3H), 7.58 (t, J = 2.0 Hz, 1H), 7.51 (t, J = 2.4 Hz, 1H),
7.34ꢁ7.31 (m, 2H), 5.58 (s, 2H); 13C NMR (100 MHz, CDCl3): d
168.9, 146.0, 139.5, 138.3, 137.7, 136.0, 133.5, 133.3, 132.9,
131.5, 131.2, 128.0, 127.2, 127.1, 126.7, 126.6, 64.4; MS (m/z):
364.0 [M+H]+; Anal. Calcd for C17H10Cl3NO2: C, 55.69, H, 2.75, N,
3.82; found: C, 55.47, H, 2.84, N, 3.92.
C13H12ClNO3: C, 58.77; H, 4.55, N, 5.27; found: C, 58.86; H, 4.58,
N, 5.14.
(2-Chloro-6-methoxyquinolin-3-yl)methyl 2,4-dichlorobenzoate (6i)
Pale brown powder; 1H NMR (400 MHz, CDCl3): d 8.20 (s, 1H),
7.91ꢁ7.89 (m, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 9.2,
2.8 Hz, 1H), 7.33 (dd, J = 8.4, 2.0 Hz, 1H), 7.09 (d, J = 2.8 Hz, 2H),
5.58 (s, 2H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3): d 163.3,
157.5, 146.1, 142.5, 137.9, 136.5, 134.2, 131.8, 130.2, 128.7,
127.1, 126.7, 126.4, 126.2, 122.6, 104.2, 63.4, 54.6; MS (m/z):
396.0 [M+H] +; Anal. Calcd for C18H12Cl3NO3: C, 54.50; H, 3.05, N,
3.53; found: C, 54.43; H, 3.09, N, 3.59.
(2-Chloroquinolin-3-yl)methyl 2,6-dichlorobenzoate (6d)
White powder; 1H NMR (400 MHz, CDCl3): d 8.36 (s, 1H), 8.03
(d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.74ꢁ7.73 (m, 1H),
7.57ꢁ7.56 (m, 1H), 7.29ꢁ7.27 (m, 3H), 5.67 (s, 2H); 13C NMR
(100 MHz, CDCl3): d 164.4, 149.5, 147.4, 138.5, 133.0, 132.1,
131.3, 131.0, 128.4, 128.1, 128.0, 127.7, 127.4, 127.0, 126.8,
126.6, 64.6; MS (m/z): 365.8 [M+H]+; Anal. Calcd for C17H10Cl3NO2:
C, 55.69, H, 2.75, N, 3.82; found: C, 55.49, H, 2.86, N, 3.90.
X-ray crystallography
Single crystal of C12H10ClNO2 [6a] was obtained by slow evap-
oration of its ethyl acetate solution at 303 K and single crystal of
C13H12ClNO2 [6e], by the slow evaporation of its dichloromethane
(2-Chloro-6-methylquinolin-3-yl)methyl acetate (6e)
solution at 283 K. A suitable crystal was selected and placed on a
Nylon Loop on an Xcalibur, Eos, Gemini X-ray diffractometer. The
crystal was kept at 173(2) K during data collection. Using Olex2
[60], the structure was solved with the Superflip [61] structure
solution program using Charge Flipping and refined with the Shel-
XL [62] refinement package using Least Squares minimization. The
details are presented in Tables 2a and 2b.
White crystal; 1H NMR (400 MHz, CDCl3): d 8.11 (s, 1H), 7.93 (d,
J = 8.4 Hz, 1H), 7.60 (d, J = 4.8 Hz, 2H), 5.33 (s, 2H), 2.54 (s, 3H), 2.18
(s, 3H); 13C NMR (100 MHz, CDCl3): d 170.5, 148.7, 145.9, 137.5,
137.4, 133.0, 128.0, 127.7, 127.1, 126.5, 63.1, 27.2, 20.7; MS (m/
z): 250.0 [M+H]+; Anal. Calcd for C13H12ClNO2: C, 62.53, H, 4.84,
N, 5.61; found: C, 62.17, H, 4.79, N, 5.66.
Table 1
Synthesis of 2-chloroquinolin-3-yl ester derivatives (6a–i).
Compounds
R
R1
Reaction time for completion
m.p. (°C)
Yield (%)
6a
6b
6c
6d
6e
6f
6g
6h
6i
AH
AH
AH
AH
ACH3
ACH3
ACH3
AOCH3
AOCH3
ACH3
AC6H5
-2,4 Dichlorobenzoyl
-2,6 Dichlorobenzoyl
ACH3
AC6H5
-2,6 Dichlorobenzoyl
ACH3
2 h
1 h
1 h
2 h
o
o
o
o
o
75
56
70
73
70
50
74
74
76
73
136
134
146
85–87
126
175
112
148
-2,4 Dichlorobenzoyl
o = Overnight.
Please cite this article in press as: S. Tabassum et al., J. Mol. Struct. (2014), http://dx.doi.org/10.1016/j.molstruc.2014.04.009

4
S. Tabassum et al. / Journal of Molecular Structure xxx (2014) xxx–xxx
Crystal structure determination of [6a]
with potassium persulfate (a blue chromogen) and is reduced in
the presence of such hydrogen donating antioxidants.
Chemicals and Reagents Used:
Preparation of ABTS solution
Solution I: ABTS (2,20-azinobis-(3-ethylbenzothiazoline-6-sul-
fonic acid) (2 mM solution is prepared using distilled water).
Solution II: Potassium persulfate (17 mM solution is prepared
using distilled water).
0.3 mL of solution II was added to 50 mL of solution I. The reac-
tion mixture was left to stand at room temperature overnight in
dark before use.
Preparation of Test Solution
5 mg of each of the drug samples and the standard (ascorbic
acid) were accurately weighed separately and dissolved in 1 mL
of Dimethyl sulphoxide (DMSO).
Method
1 mL of distilled DMSO was added to 0.2 mL of various concen-
trations of the drug samples or standard, and 0.16 mL of ABTS solu-
tion was added to make a final volume of 1.36 mL. The absorbance
was measured spectrophotometrically, after 7 min at 734 nm using
a Spectrophotometer. Blank was maintained without ABTS.
The radical scavenging activity (%) is calculated by the following
formula,
ðAbsorbance of control ꢁ Absorbance of sampleÞ
ꢂ 100
Crystal Data for C12H10NO2Cl (M = 235.66): Monoclinic, space
group P21/c (No. 14), a = 8.1324(4) Å, b = 10.9545(4) Å,
Absorbance of control
c = 12.1817(5) Å,
b = 93.323(4)°,
(Mo K
measured
V = 1083.40(8) Å3,
Z = 4,
T = 173(2) K,
l
a
) = 0.335 mmꢁ1, Dcalc = 1.445 g/mm3, 13,335
Bacterial susceptibility testing
In vitro antibacterial activity of synthesized compounds was
studied against Gram-negative and Gram-positive bacteria by the
agar well diffusion [64]. Nutrient agar (Hi Media, India) was used
as the bacteriological medium. The compounds were dissolved in
10% aqueous dimethylsulfoxide (DMSO) to a final concentration
reflections
(6.7 6 2h 6 65.78),
3727
unique
(Rint = 0.0303) which were used in all calculations. The final R1
was 0.0421 (I > 2 (I)) and wR2 was 0.1160 (all data).
r
Crystal structure determination of [6e]
of 100
and 100
100
l
g/100
g/100
L of inoculum was aseptically introduced on to the surface
l
L. Pure DMSO was taken as the negative control
l
lL Streptomycin as the positive control.
l
of sterile agar plates and sterilized cotton swabs were used for the
even distribution of the inoculum. Wells were prepared in the agar
plates using a sterile cork borer of 6.0 mm diameter. 100 lL of test
and control compound were introduced in the well. The same
procedure was used for all the strains. The plates were incubated
aerobically at 35 °C and examined after 24 h [65,66]. The diameter
of the zone of inhibition produced by each agent were measured
with a ruler and compared with those produced by the commercial
antibiotic Streptomycin.
Fungal susceptibility testing
The antifungal activity of the synthesized compounds was
tested using agar well diffusion method. The potato dextrose agar
plates were inoculated with each fungal culture (10 days old) by
point inoculation. A well of about 6.0 mm diameter with sterile
cock borer was aseptically punched on each agar plate. The synthe-
Crystal Data for C13H12ClNO2 (M = 249.69): Monoclinic, space
group P21/c (No. 14), a = 24.0571(7) Å, b = 7.5420(2) Å,
sized test compound (100
well; a negative control well was too made with 100
vent DMSO and 100 g/100 L Nystatin as the positive control.
lg/100
lL) was introduced into the
c = 13.6211(4) Å,
b = 103.070(3)°,
a
V = 2407.37(12) Å3,
Z = 8,
lL of the sol-
T = 173(2) K, (Cu K
l
) = 2.724 mmꢁ1, Dcalc = 1.378 g/mm3, 13,833
l
l
reflections measured (11.328 6 2h 6 144.99), 4705 unique
(Rint = 0.0359) which were used in all calculations. The final R1
was 0.0587 (I > 2r(I)) and wR2 was 0.1642 (all data).
Plates were kept in laminar flow for 30 min for pre diffusion of
compound to occur and then incubated at 28 °C for 48 h. Resulting
zone of inhibition (in mm) was measured using a Hi media zone
scale [67].
ABTS assay [63]
Molecular docking studies
ABTS [2,20-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)]
Radical Cation Scavenging Method.
Automated docking was used to determine the orientation of
inhibitors bound in the active site of GlcN-6-P synthase as target
for antimicrobial activity. A Lamarckian genetic algorithm method,
implemented in the program AutoDock 3.0, was employed. The
Principle:
The pre-formed radical mono cation of 2,20-azinobis-(3-ethyl-
benzothiazoline-6-sulfonic acid) is generated by oxidation of ABTS
Please cite this article in press as: S. Tabassum et al., J. Mol. Struct. (2014), http://dx.doi.org/10.1016/j.molstruc.2014.04.009

S. Tabassum et al. / Journal of Molecular Structure xxx (2014) xxx–xxx
5
ligand molecules (6a–i) were designed and the structure was ana-
lyzed by using ChemDraw Ultra 6.0. 3D coordinates were prepared
using PRODRG server [68]. The protein structure file (PDB ID: 1XFF)
was taken from PDB (www.rcsb.org/pdb) was edited by removing
the hetero-atoms, adding C terminal oxygen [69]. For docking cal-
culations, Gasteigere – Marsili partial charges [70] were assigned
to the ligands and non-polar hydrogen atoms were merged. All tor-
sions were allowed to rotate during docking. The grid map was
centered at particular residues of the proteins which was predicted
from the ligplot and were generated with AutoGrid. The Lamarck-
ian genetic algorithm and the pseudo-Solis and Wets methods
were applied for minimization, using default parameters [71].
Bond lengths are in normal ranges [74] (Table 2a). In the crystal,
weak C7AH7ꢃ ꢃ ꢃN1 intermolecular interactions (Table 3) link the
molecules into tetramers and influence the crystal packing (Fig. 2).
Symmetry transformations used to generate equivalent atoms:
(i) 1 ꢁ x, ꢁ1/2 + y, 1/2 ꢁ z; (ii) 1 ꢁ x, ꢁy, 1 ꢁ z.
(2-Chloro-6-methylquinolin-3-yl)methyl acetate (6e)
In C13H12ClNO2, two independent molecules [A and B] crystal-
lize in the asymmetric unit. The dihedral angle between the mean
planes of the 2-chloro-6-methylquinolin-3-yl and the carboxylate
group is 10.9(3)°[A] and 7.0(9)° [B] (Fig. 3).
Bond lengths are in normal ranges [74] (Table 2b). The chlorine
atoms in [A] and [B] are slightly deviated from the mean planes of
the 2-chloro-6-methylquinolin-3-ylrings by 2.9(9)° and 2.8(8)°,
respectively. In the crystal, weak C7BAH7Bꢃ ꢃ ꢃO1A intermolecular
interactions (Table 3) link the molecules into dimers along [100]
(Fig. 4).
Results and discussion
For synthesis
In addition Cg1ACg1p—p intermolecular interactions are
Synthesis of the derivatives (6a–i) was carried out as depicted
in Scheme 1. Quinoline carbaldehydes (4a–c) were synthesized
through traditional Vilsmeier–Haack cyclization [35–46] of acetan-
ilides (3a–c) [72]. These compounds were then reduced using
NaBH4 in methanol to yield (2-chloroquinolin-3-yl)methanol
derivatives (5a–c). The analytical data of the compounds 4a–c
and 5a–c was compared with the reports available in the literature
[44–59]. The strategy employed for the synthesis of compounds
(6a–i) is almost similar to that reported earlier [73]. Various quin-
oline ester derivatives (6a–i) were prepared by coupling alcohols
(5a–c) with various acid chlorides in the presence of K2CO3 in
DMF (Table 1). The IR spectra of compounds (6a–i) showed a peak
around at 1750 cmꢁ1 due to C@O stretching. The 1H NMR spectra of
compound 6a showed a shift at d = 3.92 (s, 3H) for the protons
CH3CO. The LC–MS m/z value of [M]2+ was obtained at 236.1.
Finally the 13C NMR spectra of the compound 6a showed a signal
at nearly d = 170 ppm for the carbonyl group. The detailed proce-
dure and the analytical data for all the derivatives (6a–i) are placed
in experimental section. The crystal structures of the compounds
6a and 6e were also determined. Further, supporting data for all
the final derivatives 6a–i, i.e. scanned copies of 1H NMR, 13C
NMR and LC–MS spectra are enclosed.
observed and contribute to crystal packing (Cg1—Cg1 =
3.8029(13) Å; 2 ꢁ x, ꢁy, 1 ꢁ z; Cg1 = N1A/C4A/C3A/C11A/C10A/
C5A).
For ABTS radical-scavenging activity and antimicrobial activity
The ABTS radical-scavenging activityof the compounds (6a–i)
revealed that amongst all the tested compounds, 6a and 6g exhib-
ited maximum scavenging activity with ABTS. Compounds 6d–f
and 6h, exhibited similar activity (Table 4).
Antimicrobial studies
The synthesized compounds were effective in controlling the
growth of clinical strains tested (Table 5). The study revealed that
the antibacterial activity of compound 6i was highest with zone of
inhibition in the range of 32.24 0.18 to 18.67 0.69. The lowest
inhibition values were recorded by compound 6g (13.87 0.28 to
5.53 0.24). The rest of the compounds i.e., 6a–f and 6h showed
moderate activity. Staphylococcus aureus was the most susceptible
and Klebsiellapneumoniae, the least amongst all the bacterial strains
investigated in the present work. Streptomycin which was used as
positive experimental control against strains assayed, produced a
zone of inhibition of 45.33 0.63 to 28.53 0.17, while no inhibi-
tory effect could be observed for DMSO used as negative control.
All the compounds exhibited different antifungal activity
in vitro against the tested fungal strains (Table 5). Of these fungal
strains, Candida albicans was more resistant to the synthesized
compounds than Aspergillus niger. All the compounds produced
the inhibitory zones; the most active compound being 6i with
X-ray crystal structure analysis
(2-Chloroquinolin-3-yl)methyl acetate (6a)
In C12H10NO2Cl, the dihedral angle between the mean planes of
the
2-chloroquinolin-3-yl
and
the
carboxylate
group
(C10nO1nC11nO2) is 12.8(5)° (Fig. 1).
Scheme 1. Preparation of 2-chloroquinolin-3-yl ester derivatives (6a–i).
Please cite this article in press as: S. Tabassum et al., J. Mol. Struct. (2014), http://dx.doi.org/10.1016/j.molstruc.2014.04.009

6
S. Tabassum et al. / Journal of Molecular Structure xxx (2014) xxx–xxx
Table 2b
Selected crystal bond lengths (Å), bond angles (°), and torsion angles (°) for
C13H12ClNO2.
Cl(1A)AC(4A)
O(1A)AC(1A)
O(2A)AC(1A)
N(1A)AC(4A)
C(1A)AC(13A)
C(8A)AC(9A)
Cl(1B)AC(4B)
O(1B)AC(1B)
1.754(3)
1.195(4)
1.337(3)
1.289(3)
1.491(4)
1.364(4)
1.750(3)
1.196(3)
1.442(3)
1.375(4)
1.498(4)
115.7(2)
117.1(2)
122.9(3)
111.4(3)
124.1(2)
115.2(2)
115.83(19)
127.2(2)
114.7(2)
117.0(2)
123.5(3)
111.3(2)
124.9(2)
115.3(2)
115.97(19)
127.1(2)
171.9(2)
172.6(2)
ꢁ177.6(2)
ꢁ177.3(2)
ꢁ1.6(3)
O(2B)AC(2B)
N(1B)AC(5B)
C(1B)AC(13B)
C(1A)AO(2A)AC(2A)
C(4A)AN(1A)AC(5A)
O(1A)AC(1A)AO(2A)
O(2A)AC(1A)AC(13A)
C(11A)AC(3A)AC(2A)
C(11A)AC(3A)AC(4A)
N(1A)AC(4A)ACl(1A)
N(1A)AC(4A)AC(3A)
C(1B)AO(2B)AC(2B)
C(4B)AN(1B)AC(5B)
O(1B)AC(1B)AO(2B)
O(2B)AC(1B)AC(13B)
C(11B)AC(3B)AC(2B)
C(11B)AC(3B)AC(4B)
N(1B)AC(4B)ACl(1B)
N(1B)AC(4B)AC(3B)
O(2A)AC(2A)AC(3A)AC(4A)
O(2B)AC(2B)AC(3B)AC(4B)
N(1A)AC(5A)AC(6A)AC(7A)
N(1B)AC(5B)AC(6B)AC(7B)
N(1A)AC(5A)AC(10A)AC(11A)
N(1B)AC(5B)AC(10B)AC(11B)
C(1A)AO(2A)AC(2A)AC(3A)
C(1B)AO(2B)AC(2B)AC(3B)
Fig. 1. Molecular structure of C12H10NO2Cl showing the atom labeling scheme and
50% probability displacement ellipsoids.
Table 2a
Selected crystal bond lengths (Å), bond angles (°), and torsion angles (°) for
C
12H10NO2Cl.
C(l1)AC(1)
C(1)AC(2)
O(1)AC(10)
C(2)AC(10)
O(2)AC(11)
C(5)AC(6)
N(1)AC(1)
C(11)AC(12)
1.7468(13)
1.4181(16)
1.4356(15)
1.5018(17)
1.1953(18)
1.3702(19)
1.2987(16)
1.492(2)
ꢁ1.3(4)
ꢁ167.1(2)
ꢁ173.6(2)
C(11)AO(1)AC(10)
C(1)AN(1)AC(9)
N(1)AC(1)ACl(1)
N(1)AC(1)AC(2)
C(2)AC(1)ACl(1)
C(3)AC(2)AC(1)
117.29(10)
117.13(11)
115.66(9)
126.70(12)
117.63(9)
116.05(11)
121.62(11)
119.11(12)
110.51(12)
123.07(13)
126.41(13)
106.56(10)
178.47(9)
ꢁ1.86(15)
ꢁ0.17(18)
179.50(11)
0.58(17)
Table 3
Non-bonded interactions and possible hydrogen bonds in C12H10NO2Cl and C13H12-
ClNO2 (Å, °). (D-donor; A-acceptor; H-hydrogen).
N(1)AC(9)AC(4)
N(1)AC(9)AC(8)
O(1)AC(11)AC(12)
O(2)AC(11)AO(1)
O(2)AC(11)AC(12)
O(1)AC(10)AC(2)
Cl(1)AC(1)AC(2)AC(3)
Cl(1)AC(1)AC(2)AC(10)
N(1)AC(1)AC(2)AC(3)
N(1)AC(1)AC(2)AC(10)
C(1)AN(1)AC(9)AC(4)
C(1)AN(1)AC(9)AC(8)
C(10)AO(1)AC(11)AO(2)
C(10)AO(1)AC(11)AC(12)
C(10)AC(2)AC(3)AC(4)
C(11)AO(1)AC(10)AC(2)
DAHꢃ ꢃ ꢃA
DAH
Hꢃ ꢃ ꢃA
2.59
2.55
Dꢃ ꢃ ꢃA
3.5030(17)
3.391(4)
DAHꢃ ꢃ ꢃA
167.1
150.5
C7AH7ꢃ ꢃ ꢃN1i
0.93
0.930(4)
C7BAH7Bꢃ ꢃ ꢃO1Aii
Symmetry transformations used to generate equivalent atoms: i) 1ꢁx, ꢁ1/2+y, 1/
2ꢁz; ii) 1ꢁx, ꢁy, 1ꢁz (D-donor; A-Acceptor; H-hydrogen).
ꢁ179.53(11)
ꢁ0.8(2)
178.40(11)
ꢁ178.66(11)
177.23(10)
maximum zone of inhibition in the range of 20.53 0.66 to
16.67 0.84 followed by the compounds 6f, 6b, 6h, 6d, 6a, 6c,
6e; and 6g exhibited minimum antifungal activity (6.67 0.16 to
4.87 0.22), when compared with Nystatin (29.53 0.33 to
24.73 0.57).
Hence, it is apparent that they have been found to be effective
antimicrobial substances against a wide range of microorganisms.
Their activity is probably due to their ability to react with extracel-
lular and soluble proteins and to complex with bacterial cell walls
[75]. From the results it can be concluded that 6i is more effective
than 6g and proved to be a better antimicrobial agent of the nine
compounds and can be used as a leading molecule in drug design
i.e., in inhibiting these medically important microbial strains. Such
screening of various compounds and identifying the active agents
Fig. 2. Packing diagram of C12H10NO2Clviewed along a-axis. Dashed lines indicate
weak C7AH7ꢃ ꢃ ꢃN1 intermolecular interactions link the molecules into tetramers
and influence the crystal packing. The remaining H atoms have been deleted for
clarity.
Please cite this article in press as: S. Tabassum et al., J. Mol. Struct. (2014), http://dx.doi.org/10.1016/j.molstruc.2014.04.009

S. Tabassum et al. / Journal of Molecular Structure xxx (2014) xxx–xxx
7
Fig. 3. Molecular structure of C13H12ClNO2 showing the atom labeling scheme with two molecules (A and b) in the asymmetric unit and 30% probability displacement
ellipsoids.
Table 4
ABTS radical-scavenging assay of (6a–i) derivatives.
Sl no.
Compound
Scavenging activity (%)
1
2
3
4
6
8
9
10
11
6a
6b
6c
6d
6e
6f
6g
6h
6i
99.88
96.33
80.7
99.08
99.08
99.08
99.88
99.08
81.65
Docking studies
The docking of 6a–i derivatives with Glutamine amido transfer-
ase domain reveals that, our synthesized molecule which are hav-
ing inhibitory capability are exhibiting the interactions with one or
the other amino acids in the active pockets which is showed in
Fig. 5.
The docking results for inhibitor compounds are documented in
Table 6.
Fig. 4. Packing diagram of ‘‘C13H12ClNO2’’ viewed along the b axis. Dashed lines
indicate weak C7BAH7Bꢃ ꢃ ꢃO1A intermolecular interactions link the molecules into
dimers along [100]. The remaining H atoms have been deleted for clarity.
Practically, all the nine molecules showed good binding energy
and docking energy ranging from ꢁ7.84 kJ molꢁ1 to ꢁ10.36 kJ molꢁ1
and ꢁ8.81 kJ molꢁ1 to ꢁ11.01 kJ molꢁ1 respectively. Amongst the
nine molecules, docking of GlcN-6-P synthase with 6i revealed five
hydrogen bonds and its binding energy and docking energy were
ꢁ9.71 kJ molꢁ1 and ꢁ10.98 kJ molꢁ1 respectively and it may be con-
sidered as good inhibitor of GlcN-6-P synthase. All the synthesized
molecules were completely enfolded in the entire active pocket of
is essential because the successful prediction of a lead molecule
and drug-like properties at the onset of drug design will pay off
later in drug development.
Table 5
Antimicrobial activity of synthesized compounds against microbial strains.
Compound
Bacterial strains
Fungal strains
Bacillus subtilis
Staphylococcus aureus
Escherichia coli
Klebsiella pneumoniae
Candida albicans
Aspergillus niger
Streptomycin
Nystatin
6a
6b
6c
6d
6e
6f
6g
32.66 0.33
–
45.33 0.63
–
30.68 0.22
–
28.53 0.17
–
–
–
24.73 0.57
10.67 0.59
12.00 0.04
8.33 0.16
11.00 0.92
7.67 0.25
12.77 0.30
4.87 0.22
11.47 0.16
16.67 0.84
29.53 0.33
14.00 1.19
16.00 0.27
11.07 0.50
14.67 0.58
10.00 0.92
16.67 0.63
6.67 0.16
15.33 0.40
20.53 0.66
16.00 0.56
18.73 0.19
13.53 0.28
17.33 0.29
12.67 0.53
19.53 0.01
10.60 0.23
18.00 0.63
24.27 0.30
20.20 0.14
23.27 0.55
18.20 0.14
21.87 0.28
17.67 0.69
24.53 0.17
13.87 0.28
22.73 0.20
32.24 0.18
14.00 0.15
15.67 0.33
11.33 0.32
14.67 0.58
10.33 0.32
16.00 0.56
7.67 0.25
15.00 0.36
20.87 0.30
11.67 0.33
13.73 0.10
10.67 0.34
12.00 0.66
9.87 0.18
14.67 0.51
5.53 0.24
12.33 0.19
18.67 0.69
6h
6i
The values are the mean of three experiments S.E.
Please cite this article in press as: S. Tabassum et al., J. Mol. Struct. (2014), http://dx.doi.org/10.1016/j.molstruc.2014.04.009

8
S. Tabassum et al. / Journal of Molecular Structure xxx (2014) xxx–xxx
6a
6b
6c
Streptomycin
6d
6e
Nystatin
6f
6g
6h
6i
Fig. 5. Enfolding of synthesized molecules in the active pocket.
GlcN-6-P synthase(Fig. 5). Thetopology ofthe active siteof GlcN-6-P
synthase was similar in all the synthesized molecules, which is lined
by interacting amino acids as predicted from the ligplot (Fig. 6).
In vitro studies reveals that 6i has emerged as an active mole-
cule against all the screened microorganisms, so it can be predicted
that the activity may be due to the inhibition of enzyme GlcN-6-P
Please cite this article in press as: S. Tabassum et al., J. Mol. Struct. (2014), http://dx.doi.org/10.1016/j.molstruc.2014.04.009

S. Tabassum et al. / Journal of Molecular Structure xxx (2014) xxx–xxx
9
Table 6
Molecular docking results with glucosamine-6-phosphate synthase.
Molecule
Binding energy
Docking energy
Inhibitory constant
Internal energy
H-bonds
4
Bonding
6a
ꢁ7.98
ꢁ8.87
1.41eꢁ006
ꢁ8.91
6a::DRG1:OAO:GPS:B:ARG217:HH22
6a::DRG1:NAG:GPS:A:GLU14:HN
6a::DRG1:OAO:GPS:B:ARG216:HH12
6a::DRG1:OAO:GPS:B:ARG216:HH22
6b
ꢁ10.0
ꢁ10.85
4.72eꢁ008
ꢁ11.24
4
6b::DRG1:OAL:GPS:B:LEU195:O
6b::DRG1:OAO:GPS:A:THR200:HG1
6b::DRG1:OAL:GPS:B:ARG201:HH22
6b::DRG1:OAO:GPS:A:ARG201:HN
6c
ꢁ8.78
ꢁ8.53
ꢁ10.13
ꢁ9.94
3.65–007
ꢁ10.03
ꢁ9.78
3
4
6c::DRG1:OAO:GPS:B:ARG217:HH22
6c::DRG1:OAO:GPS:B:ARG216:HH22
6c::DRG1:OAO:GPS:B:ARG216:HH12
6d
5.59eꢁ007
6d::DRG1:NAG:GPS:A:GLU14:HN
6d::DRG1:OAO:GPS:B:ARG217:HH22
6d::DRG1:OAO:GPS:B:ARG216:HH12
6d::DRG1:OAO:GPS:B:ARG216:HH22
6e
6f
ꢁ7.84
ꢁ8.81
1.8eꢁ006
ꢁ8.77
ꢁ11.6
3
4
6e::DRG1:OAP:GPS:B:GLN9:HN
6e::DRG1:OAP:GPS:B:ARG10:HN
6e::DRG1:NAH:GPS:A:GLU14:OE1
ꢁ10.36
ꢁ10.83
2.56eꢁ008
6f::DRG1:OAL:GPS:B:THR200:HG1
6f::DRG1:NAG:GPS:B:ARG202:HE
6f::DRG1:OAL:GPS:B: ARG201:HN
6f::DRG1:OAO:GPS:A:ARG201:HH22
6g
6h
ꢁ9.25
ꢁ9.07
ꢁ11.01
ꢁ9.9
1.65eꢁ007
2.24Eꢁ007
ꢁ10.5
2
4
6g::DRG1:OAL:GPS:B:GLY183:O
6g::DRG1:OAO:GPS:B:ARG202:HH22
ꢁ10.32
6h::DRG1:OAO:GPS:B:ARG217:HH22
6h::DRG1:OAQ:GPS:B:MET184:O
6h::DRG1:OAQ:GPS:A:ARG10:HH11
6h::DRG1:OAO:GPS:B:ARG216:HH12
6i
ꢁ9.71
ꢁ10.98
7.64eꢁ008
1.56
5
6i::DRG1:OAX:GPS:B: MET184:O
6i::DRG1:OAX:GPS:A:ARG10:HH11
6i::DRG1:OAO:GPS:B:ARG216:HH22
6i::DRG1:OAO:GPS:B:ARG216:HH12
6i::DRG1:OAO:GPS:B:ARG217:HH22
Streptomycin
Nystatin
ꢁ1.54
ꢁ5.72
0.07
0
ꢁ4.34
4
8
SM::DRG1:H67:GPS:A:ALA8:O
SM::DRG1:H42:GPS:A:THR67:OG1
SM::DRG1:OBH:GPS:A:ARG217:HE
SM::DRG1:H7B:GPS:B:ASP11:OD2
2400
2410
2400
NY:: DRG1:OCE:GPS:B:ARG10:HH11
NY:: DRG1:OCK:GPS:A:ARG216:HH21
NY:: DRG1:OCE:GPS:A:MET184:HN
NY:: DRG1:OAF:GPS:A:ARG202:HH12
NY:: DRG1:HCS:GPS:B:GLU14:OE2
NY:: DRG1:OCH:GPS:A:THR200:HG1
NY:: DRG1:OBY:GPS:A:ARG216:HH11
NY:: DRG1:OCK:GPS:A:ARG217:HH22
synthase, which catalyzes a complex reaction involving ammonia
transfer from -glutamine to Fru-6-P, followed by isomerization
bonds. Additionally the supramolecular assembly is consolidated
by special type of Cg–Cg ( -ring) interaction. The structure analysis
L
p
of the formed fructosamine-6-phosphate to glucosamine-6-phos-
phate. Hence, this study has provedthat molecule 6i to be one of
the potent antibacterial and antifungal agent.
of these compounds provides an insight into the correlation
between molecular structures and intermolecular interactions in
compounds for drug development. Some of these derivatives were
found effective against tested organisms. This provides further
scope for evaluation of this class of compounds for other biological
activities and also in particular with data pertaining to structure–
activity relationships. It is also expected that the drugs synthesized
using the above would pave a new way for the planning, designing
and synthesis of next generation drugs.
Conclusion
Starting from aniline, novel substituted quinoline derivatives
(6a–i) were synthesized with moderate to excellent yields. The
obtained products were thoroughly characterized by spectral tech-
niques. The crystal and molecular structure of the two compounds
(6a and 6e) have been determined. Weak interactions and supra-
molecular assembly, involving several hydrogen bonding interac-
tions of different functional groups have been demonstrated. It is
observed that the crystal structure of the two compounds is stabi-
lized by strong intermolecular CAHꢃ ꢃ ꢃN and CAHꢃ ꢃ ꢃO hydrogen
Acknowledgements
JPJ acknowledges the NSF-MRI program (Grant No. CHE-
1039027) for funds to purchase the X-ray diffractometer. THS
Please cite this article in press as: S. Tabassum et al., J. Mol. Struct. (2014), http://dx.doi.org/10.1016/j.molstruc.2014.04.009

10
S. Tabassum et al. / Journal of Molecular Structure xxx (2014) xxx–xxx
Fig. 6. Interacting amino acids as predicted from the ligplot.
acknowledges the NMRC, IISc, Bangalore for providing 1H NMR and
13C NMR spectra.
[14] M. Singh, M.P. Singh, S.Y. Ablordeppey, Drug Dev. Ind. Pharm. 22 (1996) 377–
381.
[15] L. Dassonneville, A. Lansiaux, A. Wattelet, N. Wattez, C. Mahieu, S. Van Miert, L.
Pieters, C. Bailly, Eur. J. Pharmacol. 409 (2000) 9–18.
[16] L. Dassonneville, K. Bonjean, M.C. De Pauw-Gillet, P. Colson, C. Houssier, J.
Quetin-Leclercq, L. Angenot, S.Y. Ablordeppey, Bioorg. Med. Chem. 10 (2002)
1337–1346.
Appendix A. Supplementary material
[17] C. Bailly, Biochemistry 38 (1999) 7719–7726.
CCDC 972576 and 972577 contains the supplementary crystal-
lographic data for C12H10NO2Cl and C13H12ClNO2. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/conts/
retrieving.html, or from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223
336 033; or email: deposit@ccdc.cam.ac.uk. Supplementary data
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.molstruc.2014.04.009.
[18] C. Bailly, W. Laine, B. Baldeyrou, M.C. De Pauw-Gillet, P. Colson, C. Houssier, K.
Cimanga, S.V. Miert, A.J. Vlietinck, L. Pieters, Anti-Cancer Drug Des. 15 (2000)
191–201.
[19] B. Kunze, G. Hofle, H. Reichenbach, J. Antibiot. 40 (1987) 258–265.
[20] J. Adams, C. Giam, Environ. Sci. Technol. 18 (1984) 391–394.
[21] N.M. Shavaleev, H. Adams, J. Best, R. Edge, S. Navaratnam, J.A. Weinstein, Inorg.
Chem. 45 (2006) 9410–9415.
[22] P.J. Bindu, K.M. Mahadevan, N.D. Satyanarayan, T.R. RavikumarNaik, Bioorg.
Med. Chem. Lett. 22 (2012) 898–900.
[23] Charnsak Thongsornkleeb, Charnsak Thongsornkleeb, Somsak Ruchirawata,
Tanita Gettongsonga, Org. Biomol. Chem. 11 (2013) 1463.
[24] Norio Sakai, Kosuke Tamura, Kazuyori Shimamura, Reiko Ikeda, Takeo
Konakahara, Org. Lett. 14 (2012) 836–839.
References
[25] Younes Laras, Vincent Hugues, Yogesh Chandrasekaran, Mireille Blanchard
Desce, Francine C. Acher, Nicolas Pietrancosta, J. Org. Chem. 77 (2012) 8294–
8302.
[26] Ram Shankar Upadhayaya, Popat Shinde, A. SandipKadam, N. AmitBawane, Y.
Aftab, Sayyed, A. RamakantKardile, N. Pallavi, Gitay, V. Santosh, Lahore, S.
Shailesh Dixit, Andras Foldesi, Jyoti Chattopadhyaya, Eur. J. Med. Chem. 46
(2011) 1306–1324.
[27] Neha Sharma, Mrityunjaya Asthana, Durgesh Nandini, R.P. Singh, M.
RadheySingh, Tetrahedron 69 (2013) 1822–1829.
[28] V. Krishnakumar, Fazlur-Rahman Nawaz Khan, Badal Kumar Mandal, Sukanya
Mitta, Ramu Dhasamandha, Vindhya NanuGovindan, Res. Chem. Intermed. 38
(2012) 1819–1826.
[1] M. Foley, L. Tilley, Pharmacol. Ther. 79 (1998) 55–87.
[2] V.K. Gupta, A. Mittal, V. Gajbe, J. Colloid Interface Sci. 284 (2005) 89–98.
[3] H.M. Grandin, S.M. Tadayyon, W.N. Lennard, K. Griffiths, L.L. Coatsworth, P.R.
Norton, Z.D. Popovic, H. Aziz, N.X. Hu, Org. Electron. 4 (2003). pp. 19–14.
[4] X. Zhao, X. Zhan, Chem. Soc. Rev. 40 (2011) 3728–3743.
[5] O. Bilker, V. Lindo, M. Panico, A.E. Etiene, T. Paxton, A. Dell, M. Rogers, R.E.
Sinden, H.R. Morris, Nature 392 (1998) 289–292.
[6] G. Roma, M.D. Braccio, G. Grossi, F. Mattioli, H. Ghia, Eur. J. Med. Chem. 35
(2000) 1021–1035.
[7] Y.L. Chen, K.C. Fang, J.Y. Sheu, S.L. Hsu, C.C. Tzeng, J. Med. Chem. 44 (2000)
2374–2377.
[8] K.C. Fang, Y.L. Chen, J.Y. Sheu, T.C. Wang, C.C. Tzeng, J. Med. Chem. 43 (2000)
3809–3812.
[9] J. Chevalier, S. Atifi, A. Eyraud, A. Mahamoud, J. Barbe, J. Med. Chem. 44 (2001)
4023–4026.
[10] L.T. Phan, T. Jian, Z. Chen, Y.Q. Qiu, Z. Wang, T. Beach, A. Polemeropoulos, J.
Med. Chem. 47 (2004) 2965–2968.
[29] Ulrich Abel, Angela Hansen, Falko Ernst Wolter, Bioern Krueger, Valerians
Kauss, Jevgenijs Rozhkovs, Valentina Semenihina, Irena Piskunova, Juris Pelss,
PCT Int. Appl. (2012) 2012164085.
[30] M. SimonaCeccarelli, Aurelia Conte, Holger Kuehne, Bernd Kuhn, Werner
Neidhart, Sander Ulrike Obst, Markus Rudolph, PCT Int. Appl. (2013)
2013064465.
[11] S.J. Benkovic, S.J. Baker, M.R.K. Alley, Y.H. Woo, Y.K. Zhang, T. Akama, W. Mao, J.
Baboval, P.T.R. Rajagopalan, M. Wall, L.S. Kahng, A. Tavassoli, L. Shapiro, J. Med.
Chem. 48 (2005) 7468–7476.
[12] K. MajerzManiecka, B. Oleksyn, R. Musiol, B. Podeszwa, Polanski, J. Abstracts
Papers (2005) 20–23.
[31] W. Donald Landry, Shixian Deng, Ottavio Aranico, Joie Fiorito, Andrew
Wasmuth, PCT Int. Appl. (2013) 2013109738.
[32] Jae In Lee, Bull. Korean Chem. Soc. 33 (2012) 1375–1378.
[33] Wu Yiran, Zheng Chen, Ying Liu, Yu Lanlan, Lu Zhou, Suijia Yang, Luhua Lai,
Bioorg. Med. Chem. 19 (2011) 3361–3366.
[13] L.Y. Vargas, M.V. Castelli, V.V. Kouznetsov, J.M. Urbina, S.N. Lopez, M. Sortino,
R.D. Enriz, J.C. Ribas, S. Zacchino, Bioorg. Med. Chem. 11 (2003) 1531–1550.
[34] M.J. Davis, O.D. Iancu, F. Acher, B.M. Stewart, M.A. Eiwaz, R.M. Duvoisin, J.
Raber, J. Org. Chem. 77 (2012) 8294–8302.
Please cite this article in press as: S. Tabassum et al., J. Mol. Struct. (2014), http://dx.doi.org/10.1016/j.molstruc.2014.04.009

S. Tabassum et al. / Journal of Molecular Structure xxx (2014) xxx–xxx
11
[35] K. Pong, Exp. Opin. Biol. Therapy. 3 (2003) 127–139.
[36] B. Sandhya, S. Manoharan, G. SirishaLavanya, Ch. RatnaManmohan, Indian J.
Sci. Technol. 3 (2010) 83–86.
[37] D. Anderson, Mutation Res. 350 (1999) 103–108.
[38] K. Balakumar, S. RamanathanKumaresan, R. Suresh, Indian J. Sci. Technol. 3
(2010) 322–327.
[55] M.M. Ali, S. Sana, R.K.C. Tasneem, P.K. Saiprakash, Synth. Commun. 32 (2002)
1351.
[56] S.M. Roopan, F.R.N. Khan, Arkivoc (2009) 161–169.
[57] B. Zeynizadeh, T. Behyar, Chem. Soc. Jpn. 78 (2005) 307.
[58] N.S. Narashimhan, N.M. Sunder, R. Ammanamanchi, B.D. Bonde, J. Am. Chem.
Soc. 112 (1990) 4431.
[39] M.A. Anagnostopoulou, P. Kefalas, V.P. Papageorgiou, A.N. Assimepoulou, D.
Boskou, Food Chem. 94 (2006) 19–25.
[40] U. Carounanidy, R. Satyanarayanan, A. Velmurugan, Indian J. Dent. Res. 18
(2007) 152–156.
[59] B. Bhat, A.P. Bhaduri, Indian J. Chem. 23B (1984) 33.
[60] O.V. Dolomanov, L.J. Bourhis, R.J. Gildea, J.A.K. Howard, H. Puschmann, J. Appl.
Cryst. 42 (2009) 339.
[61] Superflip, J. Appl. Cryst. 40 (2007) 786.
[41] M.L. Cohen, Science 257 (1992) 1050–1055.
[42] G.F. NascimentoGislene, L. Juliana, C.F. Paulo, L.S. Giuliana, Braz. J. Microbiol.
31 (2000) 247–256.
[62] G.M. Shelxl, Sheldrick, Acta Cryst. A64 (2008) 112.
[63] P. Sithisarn, R. Supabphol, W. Gritsanapan, J. Ethnopharmacol. 99 (2005) 109–
112.
[43] W.M. Rockey, A.H. Elcock, J. Med. Chem. 48 (2005) 4138–4152.
[44] E. Ramesh, T.K. SreeVidhya, R. Raghunathan, Tetrahedron Lett. 49 (2008) 2810.
[45] M. Kidwai, N. Negi, Monatsh. Chem. 128 (1997) 85.
[46] B.W. Cohen, D.E. Polyansky, R. Zong, H. Zhou, T. Ouk, D.E. Cabelli, R.P.
Thummel, E. Fujita, Inorg. Chem. 49 (2010) 8034.
[47] P. Rajakumar, R. Raja, Tetrahedron Lett. 51 (2010) 4365.
[48] P. Venkatesan, S.J. Sumathi, Heterocycl. Chem. 47 (2010) 81.
[49] A. Srivastava, R.M. Singh, Indian J. Chem. 44B (2005) 1868.
[50] M. Nyerges, A. Pinter, A. Viranyi, B. Gabor, L. To ke, Tetrahedron 61 (2005)
8199.
[51] V.S.H. Krishnan, P.K. Dubey, S.S. Rao, V. Aparna, Indian J. Heterocycl. Chem. 13
(2003) 11.
[52] V.S.H. Krishnan, P.K. Dubey, S.S. Rao, P.V.P. Reddy, Indian J. Heterocycl. Chem.
13 (2003) 5.
[53] P.K. Dubey, S.S. Rao, P.V.P. Reddy, Indian J. Heterocycl. Chem. 9 (2003) 411.
[54] K. Mogilaiah, N.V. Reddy, R.B. Rao, Indian J. Heterocycl. Chem. 11 (2002)
253.
[64] R. Nair, T. Kalariya, S. Chanda, Turkish J. Biol. 29 (2005) 1–47.
[65] C.H. Collins, P.M. Lyne, J.M. Grange, Microbiol. Methods, 6th ed. (1989) 410.
[66] M.S. Ali-Shtayeh, R.
M Yaghmour, Y.R. Faidi, K. Salem, M.A. Al-Nuri, J.
Ethnopharmacol. 60 (1998) 265–271.
[67] R.K. Pundir, P. Jain, J. Pharm. Res. 3 (2010) 506–510.
[68] A.K. Ghose, G.M. Crippen, J. Chem. Inf. Comput. Sci. 27 (1987) 21–35.
[69] T.A. Binkowski, S. Naghibzadeg, J. Liang, Nucleic Acid Res. 31 (2003) 3352–
3355.
[70] J. Gasteiger, M. Marsili, Tetrahedron 36 (1980) 3219–3288.
[71] G.M. Morris, D.S. Goodsell, R.S. Halliday, R. Huey, W.E. Hart, R.K. Belew, A.J.
Olson, J. Comput. Chem. 19 (1998) 1639–1662.
[72] S.S. Praveen Kumar Darsi, K.S. Nagamani, B. Rama Devi, A. Naidu, P.K. Dubey,
Der. Pharma. Chem. 3 (2011) 35–38.
[73] F. Korodi, Z. Szabo, Heterocycl. Commun. 1 (1995) 297–306.
[74] F.H. Allen, O. Kennard, D.G. Watson, L. Brammer, A.G. Orpen, R. Taylor, J. Chem.
Soc. Perkin Trans. 2 (1987). pp. S1–19.
[75] M.M. Cowan, Clin. Microbiol. Rev. 12 (2002) 564–582.
Please cite this article in press as: S. Tabassum et al., J. Mol. Struct. (2014), http://dx.doi.org/10.1016/j.molstruc.2014.04.009