An operational transformation of 3-carboxy-4-quinolones into 3-nitro-4-quinolones via ipso-nitration using polysaccharide supported copper nanoparticles: Synthesis of 3-tetrazolyl bioisosteres of 3-carboxy-4-quinolones as antibacterial agents

Article abstract of DOI:10.1039/c5ra26909a

Chitosan supported Cu nano-particles have been synthesized, and utilized for the synthesis of 3-nitro-4-quinolones from 3-carboxy-4-quinolones via ipso nitration. The synthesized 3-nitro derivatives of 4-quinolones were successfully converted into their 3-tetrazolyl bioisosteres which showed increased antibacterial activity as compared to the standard ciprofloxacin.

Full text of DOI:10.1039/c5ra26909a

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: A. K. Narula and
C. S. Azad, RSC Adv., 2016, DOI: 10.1039/C5RA26909A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Please do not adjust margins
RSC Advances
Page 1 of 9
View Article Online
DOI: 10.1039/C5RA26909A
Journal Name
COMMUNICATION
An operational transformation of 3-carboxy-4-quinolones into 3-
nitro-4-quinolones via ipso-nitration using polysaccharide
supported copper nanoparticles: synthesis of 3-tetrazolyl
bioisosteres of 3-carboxy-4-quinolones as antibacterial agents
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Chandra S Azad and Anudeep K Narula*
Chitosan supported Cu nano-particles have been synthesized, use in heterogeneous catalysis.8 A copolymer of
β(1→4)ꢀ2ꢀ
and utilized for the synthesis of 3-nitro-4-quinolones from the 3- aminoꢀdeoxyꢀDꢀglucopyranose and 2ꢀacetamidoꢀ2ꢀdeoxyꢀDꢀ
carboxy-4-quinolones via ipso nitration. The synthesized 3-nitro glucopyranose, chitosan prepared from deacetylation of chitin,
derivatives of 4-quinolones were successfully converted into its which is second most abundant biopolymer after cellulose
3-tetrazolyl bioisosteres which showed increased antibacterial (Scheme 1
).9
activity as compared to the standard ciprofloxacin.
Major concerns have been raised about environmental impacts,
remarkable exertions are being made towards the development
of new environmental friendly chemical processes with
minimum pollutants.1 Heterogeneous catalysis offers promising
approach for the reduction of waste products, low
contamination of the products with the active catalytic species,
separation (removal and recovery) and recycling of catalyst.2
The immobilization of catalyst on solid support is an
advantageous method to improve the efficiency and ease of
separation. Several successful examples are available for such
kind of catalytic applications.3 The important reported solid
supports are inorganic materials (e.g. SiO2, Al2O3, ZrO2, TiO2,
MgF2), zeolite, charcoal, magnetic materials (Fe3O4 and Co)
and polymers.4 The search for more environmental friendly
solid support is being shifted towards biological materials.5
There is ever increasing interest in exploration of natural
polymers, and in particular polysaccharides, to generate
Scheme 1 Chemical structure of Chitin (1a) and Chitosan (1b
)
Chitosan has excellent stabilization strength for metal
nanoparticles due to the biꢀfunctionality of hydroxyl and amine
groups in its molecular structure. This polymer has shown
potential in the field of catalysis. One of the authors recently
reported the copper mediated conversions of 3ꢀcarboxyꢀ4ꢀ
quinolones into 3ꢀnitroꢀ4ꢀquinolones via ipsoꢀnitration.10 As
high stoichiometric ratio of copper is required in the previous
study, the authors focused on immobilizing the copper on
polysaccharides and study the effect of operability of the
reaction in the synthesis of 3ꢀnitroꢀ4ꢀquinolones. The ipso
nitration especially decarboxylative nitration appeared to be a
significant synthetic approach in the synthesis of nitro
compounds in high regioselectivity.11 Recently, Konwar and
coꢀworker reported the cellulose supported CuꢀNP (Copper
nanoparticle) catalysed decarboxylative nitration of aromatic
α, βꢀunsaturated carboxylic acids.12 The scope of the reaction
limited to the aromatic α, βꢀunsaturated carboxylic acids.
Nevertheless, to the best of the knowledge, no work on
chitosanꢀCuꢀNP catalyst for the decarboxylative nitration of 3ꢀ
carboxyꢀ4ꢀquinolones has been reported. The synthesis of 3ꢀ
nitro quinolone was our prime concern as these molecules are
less explored as compared to other quinolone derivatives. Haiꢀ
efficient
and
environmentally
friendly
catalysts.
Polysaccharides have many structural advantages viz. present in
abundance, suitable functionality for the chelation of metallic
species, numerous stereoꢀcentre and chemically stability with
biodegradable nature.6 Recently the polysaccharides like starch,
cellulose and chitosan are being used as solid supports in
heterogeneous catalytic systems.7 The presence of readily
functionalizable amino group and insolubility in most of the
organic solvent and water favour the chitosan over chitin for
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 2 of 9
View Article Online
DOI: 10.1039/C5RA26909A
COMMUNICATION
Journal Name
Hong Li et al has also shown that 3ꢀnitro quinolone is the Diffraction (XRD), Energy Dispersive Xꢀray Fluorescence
potent inhibitor of EGFR (epidermal growth factor receptor).13 (EDXRF), Scanning Electron Microscope (SEM) and IR
Other 3ꢀnitro quinolones derivatives were also screened for analysis. As shown in figure 1, the nanoparticle exhibited high
their antihistaminic, antiprotozoal and antimalarial activities.14 crystalline nature. The diffraction peak at 2θ =43.5, 50.6, and
Recently one of the author explored the potential of 3ꢀ 74.3 can be indexed as the [111], [200] and [220] planes of
nitroquinole as inhibitor of Brugia malayi thymidylate kinase.10 copper with face centered cubic
(fcc) symmetry. The
In the continuation to develop the novel methodologies for the spectrograph showed no sign of impurities like CuO and Cu2O.
synthesis of biological important scaffold, the synthesized nitro The results are in good agreement with those reported for Cuꢀ
derivatives were further functionalized and screened for their NP prepared by different methods.18 To know the morphology
antibacterial activity.10,15 Hence a mild, cost effective and of the prepared chitosan supported copper catalyst, SEM study
environmental benign method for the synthesis of 3ꢀnitro at an accelerating voltage of 20 kV is employed. The SEM
quinolone has been developed using chitosanꢀCuꢀNP and its images of the catalyst taken before and after five times of use in
efficacy further equated with celluloseꢀCuꢀNP and StarchꢀCuꢀ the reaction (Figures
2 and 3) show no noteworthy change in
NP. The results of this study are reported in this manuscript. the morphology indicating extensive retention of the catalytic
The required 4ꢀquinoloneꢀ3ꢀcarboxylic acids were activity after five recycling. The size of nanoparticle was found
synthesized according to the reported method,16 starting from 3ꢀ to be in the order of 266 nm. The EDXRF analysis confirmed
chloroꢀ4ꢀfluoro aniline (
malonate (EMME) ( ), which on condensation followed by the 8.682% composition (Figure
thermal cyclization in diphenyl ether yielded ester ( ) via determine the molecular interaction(s) between the chitosan and
The N alkylation of
with alkyl halide by K2CO3 in DMF and the synthesized NP.19
NaH in DMF (for cycloꢀprop) yielded the Nꢀalkylated
derivatives ( ). The Nꢀalkylated derivatives thus treated with
2N HCl to afford acids by hydrolysis (Scheme ). After
2
) and diethyl 2ꢀ(ethoxymethylene) the presence of copper in synthesised heterogeneous catalyst at
3
4
). The IR analysis was steered to
5
4.
5
6
7
2
getting 4ꢀquinoloneꢀ3ꢀcarboxylic acids experiment began with
the intention of optimizing the reaction parameter for
decarboxylative nitration.
Scheme 2 Synthetic route for the synthesis of 4ꢀquinoloneꢀ3ꢀ
carboxylic acids by ChitꢀCuꢀNP and NO2BF4.
Fig. 2 SEM Image of ChitꢀCuꢀNP synthesized.
Fig. 1 XRD pattern of the ChitꢀCuꢀNP synthesized (red) and
ChitꢀCuꢀNP after fifth cycle (black).
The polysacꢀCuꢀNPs were synthesized by the chemical
reduction method17 and characterization was done using Xꢀray
Fig. 3 SEM Image of ChitꢀCuꢀNP after fifth cycle.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 3 of 9
View Article Online
DOI: 10.1039/C5RA26909A
Journal Name
COMMUNICATION
and
transformation (88% yield, Table
that NO2BF4 was operative only in the presence of chitꢀCuꢀNP
(Table , entry 21). Evidently, both NO2BF4 and chitꢀCuꢀNP
5
mol% found to be essential for the effective
1
, entries 18 20). It is notable
ꢀ
1
are important for the reaction
Table 1 Condition screened.a
b
entry cat.
mol %
MNO3
Yieldc
(%)
48
55
62
33
69
77
76
23
35
63
27
12
55
59
62
1
cellꢀCu
10
10
10
5
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
NaNO3
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
starchꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
chitꢀCu
ꢀꢀꢀꢀꢀꢀ
Fig. 4 EDXRF spectrum of ChitꢀCuꢀNP synthesized
At first, an assessment on the reaction parameter, including,
polysacꢀCuꢀNP, nitrating agent, and solvent, was conducted at
fixed temperature 100o C and reaction time (10 h), using 7ꢀ
chloroꢀ1ꢀethylꢀ6ꢀfluoroꢀ4ꢀquinoloneꢀ3ꢀcarboxylic acid (7a) as a
model. Initially, the significance of polysaccharide support was
ascertain using chitosanꢀCuꢀNP, celluloseꢀCuꢀNP and starchꢀ
CuꢀNP. In the first trial AgNO3 was used as a nitration agent
and water as a solvent. With chitꢀCuꢀNP (10 mol %) 62% nitro
derivative was formed with in 8 h, on the other hand cellꢀCuꢀ
NP and starchꢀCuꢀNP was found to less effective as they
yielded the desired nitro derivative in < 55 % yield in 10 h with
15
20
30
20
20
20
20
20
20
20
20
20
20
20
10
5
KNO3
Ni(NO3)2
Co(NO3)2
Zn(NO3)2
Ca(NO3)2
Cu(NO3)2
Pb(NO3)2
Fe(NO3)3
Bi(NO3)3
NO2BF4
NO2BF4
NO2BF4
NO2BF4
the recovery of substrate 7a (Table
% chitꢀCuꢀNP was found to be essential for an efficient
conversion producing 8a in 77 % yield within 10 h (Table
entries ). The high stoichiometric ratio of chitꢀCuꢀNP (30
mol %) does not bear any effect on the yield (Table , entry ).
1 entries 1ꢀ3). The 20 mol
71
78
84d
87d
88d
ꢀꢀꢀꢀꢀe
1,
4ꢀ6
1
7
After having product in 77% yield further screening with other
metal nitrates were carried. The nitrating agents (mono) like
NaNO3 and KNO3 produced the 8a in 23 and 33 % yield
ꢀꢀꢀꢀꢀ
a
Reaction conditions: 3ꢀcarboxyꢀ4ꢀqionolone (7a) (1mmol), CuꢀNP,
Nitrate (1.2 mmol), in water (5ml/mmol with respect to 7a) at 100oC.b
nitrates used in hydrated forms c Isolated yield.d Reaction performed in
respectively (Table
like Ni, Co, Zn, Ca, Cu, Pb, and Ni yield the product in < 63 %
(Table , entry 10 15). The triꢀnitrates found to be much
1, entry 8ꢀ9). Although use of di nitrates
.
ACN at reflux temperature.e Starting material recovered.
1
ꢀ
effective than any used nitrates as Fe and Bi nitrates resulted
the decarboxylation nitration in 71 and 78 % yield respectively.
The used nitrates generates NO2 in the reaction medium,
Table 2 Effect of solvent on the synthesis of 3ꢀnitroꢀ4ꢀ
quinolones.a
+
which is responsible for the nitration. Therefore it was
considered of interest that if nitronium ion is directly added to
the reaction medium it may lead to the increase in the yield.
The nitronium salts are excellently explored in the organic
synthesis and among all of them nitronium tetrafluoroborate
(NO2BF4) is the most important one.20 The NO2BF4 is a
crystalline solid, which in presence of water decomposes into
HF and HNO3, so while using NO2BF4 (1 equivalent) the
reaction was screened in acetonitrile at reflux temperature
which resulted in the formation of 8a in 84% yield. The
required stoichiometric quantity was further screened for
NO2BF4 and it was found that be 1.2 equivalent yielded 88% of
8a and higher equivalents do not have any effect on the yield.
The catalyst loading was also screened in the case of NO2BF4
Entry
Solvent
DMF
DMSO
CH3CNb
Diglyme
DCMb
Yield %
92
80
84
72
1
2
4
5
6
49
a
Reaction condition: ChitꢀCuꢀNP (5 mol%), 1.2 equivalent NO2BF4 at
100oC.b reflux condition.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 4 of 9
View Article Online
DOI: 10.1039/C5RA26909A
COMMUNICATION
Journal Name
After having 8a in 88 % yield the reaction was also and 6). The recyclability and nature (deformation if happened)
screened in different solvents. The NO2BF4 was used as a of the catalyst was further confirmed SEM, XRD, EDXRF and
nitrating agent and due to its highly polar nature, it was ipso nitration of 3ꢀcaboxyꢀquinolone (Figures and ). The
1
3
considered of interest to use anhydrous polar solvents. Among EDXRF analysis inveterate the decrease in percentage of
the used different solvents DMF was found to facilitate the copper in the catalyst after fifth cycle. (6.865%).
formation of 8a in excellent yield 92% (Table 2, entry 1).
These finding steered us to explore the scope and limitation
of this newly developed methodology. Therefore various
therapeutically significant diꢀhalo quinolones containing
assorted alky groups at Nꢀ1, were selected for the nitration
under optimised reaction condition to give corresponding 3ꢀ
nitro derivatives. The results are summarised in table 3. All the
reaction gave excellent yield within a reaction time of 8ꢀ14 h.
In order to widen the scope of this reaction the nitration of N1
Scheme 3 Synthesis of 3ꢀnitro Nꢀaryl quinolone (100oC, 12h).
benzylated quinolone
9 was carried out to see the effect of
nitration on the aromatic ring of the alkyl aryl (benzyl) and aryl
(3ꢀchloroꢀ4ꢀfluoroꢀphenyl) group. The 3ꢀnitro derivative 10a
was formed in 52% yield and some over nitrated product 10b
especially on benzylic part was noticed as observed by NMR
and Mass spectrometry (Scheme 3). The 3ꢀnitro derivative was
then successfully isolated from column chromatography using
10% CH3OH/CHCl3 as eluent.
Table 3 Scope of optimized method for the synthesis of 3ꢀnitroꢀ
4ꢀquinolones.
Fig. 5 (a) recovered ChitꢀCuꢀNP after reaction (blue) (b) Chitꢀ
CuꢀNP after regeneration by reduction (black).
Entry
R
R’, R”
Yield (%) Time
(h.)
7a.
7b.
7c.
7d.
7e.
7f.
Et
Isoprop
F/Cl
F/Cl
F/Cl
F/Cl
F/Cl
F/Cl
92
85
82
85
79
76
10
8
9
12
10
8
81
61
41
21
1
nꢀbutyl
secꢀbutyl
Me
cycloꢀ
prop
1
2
3
4
5
7g.
7h.
7i.
7j.
7k.
7l.
nꢀpropyl
secꢀbutyl
F/F
F/F
F/F
F/F
Cl/Cl
Cl/Cl
86
88
91
82
79
75
12
14
12
12
10
7
Run
n
n
ꢀpentyl
ꢀoctyl
Fig. 6 Reusability study of ChitꢀCuꢀNP catalyst.
Et
cycloꢀ
prop
A plausible reaction mechanism was suggested for the
copperꢀNPꢀmediated chelation of ꢀketo acid assisted
decarboxylative nitration of quinolone (Scheme ). Initially 3ꢀ
carboxy quinolone converted into Cu2+ having 7’ in the
presence of atmospheric oxygen. The two carbonyl group of
quinolones chelated through oxygen with Cu2+ ion. The
decarboxylative nitration takes place through a concerted
mechanism, in which NO2 from nitronium tetrafluoroborate
attack by the charge developed on the Cꢀ3 carbon and
decarboxylation takes place simultaneously, leading to
β
7m.
7n.
7o.
nꢀbutyl
Cl/Cl
Cl/Cl
Cl/Cl
89
79
89
9
8
10
4
secꢀbutyl
heptyl
After completion of the decarboxylation nitration reaction
the reaction mixture was dried in vacuum and extracted with
ethyl acetate after addition of water. The catalyst recovered
after the reaction (blue coloured) further activated by NaBH4
reduction (black coloured), which stored under nitrogen
atmosphere and could be reused up to five cycles with
+
formation of product
8. The blue coloured recovered catalyst
confirmed the presence of oxidised copper.
negligible loss of activity towards the ipso nitration (Figure
5
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 5 of 9
View Article Online
DOI: 10.1039/C5RA26909A
Journal Name
COMMUNICATION
O
O
The Cꢀ7 position of
8
was then substituted by piperazine in
DMSO at 120ꢀ130 oC to get 11 which on reduction with
anhydrous SnCl2 in HCl afford 4ꢀquinoloneꢀ3ꢀamine (12). The
amine (12) on treatment with triethyl orthoformate and sodium
azide in acetic acid yield the targeted molecule (13) in good to
excellent yield. The nonꢀpiperazyl derivatives (14) were also
Cu2+
Cu
-
H
O
O
O
O
O
R'
R'
O
O
R''
N
R
been synthesized by 3ꢀnitro derivative (
of reactions which were applied for synthesis of (13) (Scheme
). In the present manuscript the lower alkyl derivatives were
used for synthesis of targeted molecules due to their importance
in mode of action of quinolone as antibacterial agents.22 The
reaction was monitored by TLC, and after completion of the
reaction, the compounds were isolated and purified by the
column chromatography. These compounds were characterized
by their IR, NMR and mass spectra.
8) using same sequence
7'
R''
N
R
2+
Cu
7
5
O
NO2BF4
+
Cu2+
O
NO2
O
O
-CO2
R'
R'
NO2
O
Cu2+
R''
N
R
7''
R''
N
R
O
O
O
F
NO2
piperzine
8
F
NO2
F
NH2
O
O
N
SnCl2
HCl, 0oC-rt
HN
DMSO
120-130oC
Cl
N
R
R'
R''
N
N
R
8
N
N
R
11
O
12
HN
CH(OEt)3
NaN3/AcOH
Reflux
N
R
R= CH3, C2H5, cyclo-prop, sec-prop
N
O
N
N
N
N
O
N
F
N
F
N
Cl
N
R
N
N
R
13
Scheme 4 Probable reaction mechanism.
14
HN
Biological Evaluation
Scheme 5 Synthesis route for the synthesis of Prototype
molecule A.
In the designing of new antimicrobial agent with reduced side
effect and enhanced activity, lead optimization is one of the
most important step. In this process the molecule with optimum
pharmacological profile cannot tuned or tailored because there
is chances of loss of desired biological activity. The major
concerns comprises insufficient oral bioavailability due to less
solubility, metabolic instability, toxicity caused by reactive
functional groups or nonselective binding. Bioisosteric
modification represents a significant approach for refining the
pharmacological profiles of lead candidates and involves
replacing undesirable structural features with bioisosteric
groups or molecular structures which are known to display the
same biological activities. Bioisosteres are not the exact
structural mimetics and are often more similar in biological
rather than physical properties. 21 Hereby the authors design the
The evaluation of antibacterial activities of compounds
(
13aꢀd) and (14a-d) against various strains of the bacteria, for
example, Staphylococcus aureus (ATCC 6538), Staphylococcus
aureus (ATCC 25632) (MRSA), Escherichia coli (ATCC
49416), Salmonella typhii (ATCC 49416) and Vibrio cholera
(ATCC 55868), was carried out according to microꢀdilution
method (using microtitre ELISA plate). These strains were
chosen based on their clinical and pharmacological
importance.23 Bacteria such as Staphylococcus have emerged
with resistance to six and more different antibiotics.24 The
minimum inhibitory concentration (MIC) of each compound
was determined against test isolates using this technique. The
MICs of standard antibacterial drug ciprofloxacin were
determined using MullerꢀHinton broth. The antibacterial
activity was compared with ciprofloxacin which was used as
positive control. In all tests, the MIC values are expressed
novel 3ꢀtetrazolyl bioisosteres (Figure
7) of 4ꢀquinoloneꢀ3ꢀ
carboxylic acids and the synthesis was successfully achieved by
developed methodology. All the synthesised compounds screed
for their antibacterial properties.
in ꢀM. The Compounds 14a-d had same activity when
compared with ciprofloxacin although these molecule lack the
important piperazyl substitution at Cꢀ7 position, which clearly
reveals that the designed molecule with 3ꢀtetrazolyl substitution
plays important role in the inhibition of gram positive as well as
gram negative bacteria. The piperazine substitution at Cꢀ7
position increase the activity as assumed as compared to
standard drug ciprofloxacin. The preꢀeminent inhibition showed
by the compound 13a-d against gram positive bacteria S.
aureus and the methicillin resistance S. aureus (MRSA) from
Fig. 7 Structure of prototype molecule
12.5 to 25
ꢀ
M. The norfloxacin and ciprofloxacin derivatives
M against
13b and 13c showed activity at 12.5 and 25
ꢀ
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 6 of 9
View Article Online
DOI: 10.1039/C5RA26909A
COMMUNICATION
Journal Name
bacterium S.typhi respectively, whether corresponding drugs the same with the protein amino acids (Figure
are active at 100 M. The designed molecules 13a-d also ciprofloxacin forms coordination bond with manganese ion by
showed excellent activity against bacteria V.chloera and E.coli the carbonyl and carboxylate group’s Oxygen with 1.8 Ǻ and
(Table ). The solubility of the synthesized compound are 2.1 Ǻ distance correspondingly while the coꢀcrystallized
8). The docked
ꢀ
4
promising as compared to parent drug which may enhance the ciprofloxacin form bond with manganese with 2.1 Ǻ with its
activity of the compounds. In the present manuscript it is carbonyl and carboxylate groups. Carboxylate group of the
evidenced that tertrazolyl substitution is a remarkable good docked ciprofloxacin form hydrogen bonded with the ꢀOH of
bioisostere of carboxylic acid which increased the activity of Ser1084 and the nitrogen atom of piperazine ring forms
corresponding drug molecule.
hydrogen bonding with the side chain carboxylate group of
Glu477
.
Table 4 The MIC (µM) data of the compounds against bacteria.
Sample
S.
S. aureus E.
S.
V.
aureus (MRSA)
coli
typhi cholera
e
CSA001
100
100
100
100
100+ 100+
100 100
100+ 100+
50
(
14a
CSA003
14b
CSA004
14c
CSA006
14d
)
100+
100
100+
100
100+
100
(
)
(
)
100+
12.5
12.5
12.5
12.5
100+
25
100+
12.5
12.5
25
(
)
CSA002
(13a)
CSA005
(13b)
CSA007
(13c)
CSA008
(13d)
25
12.5
12.5
25
12.5
12.5
12.5
100
25
12.5
12.5
100
Fig. 8 Docked ciprofloxacin with coꢀcrystalize ligand
12.5
100+
12.5
100
Ciprofloxa 100
cin
Docking Simulation
In order to explain the biological activity and SAR of the
synthesized molecules, the docking studies were carried out
using Molegro Virtual Docker (MVD) on windows based PC.25
The direct evidences regarding the interaction of quinolones
with DNA gyrase or DNA were accessible after the discovery
of coꢀcrystal structure of the DNA gyrase with ciprofloxacin
which provided insights about inhibitory function of
quinolones. The reported coꢀcrystalize structure of protein in
complex with ciprofloxacin (pdb id 2XCT) with 3.35 Å
resolution was used for current docking studies.26 The docking
protocol of MVD was validated by predicting the binding mode
of the crystallographic ligand ciprofloxacin. The proteinꢀligand
complex obtained from docking simulation revealed that the
docked ciprofloxacin was nearly superimposed on the native
Fig. 9 Docked confirmation of most active compound 11d with
ciprofloxacin
Compound 13d which is the most active compound showed
very similar binding mode compared to the coꢀcrystallized
ciprofloxacin (Figure 9). The tetrazole formed three hydrogen
bond with Ser1084 instead of one which is formed by the
native coꢀcrystalize ciprofloxacin. The bond length of three
hydrogen bonds were 1.9, 2.1 and 3.1 Ǻ. The nitrogen of the
piperazine formed the hydrogen bond with base pair DNA
backbone DT4. The moldock score (Kcal/mol) and Rerank
coꢀcrystallized one (yellow). Figure
MVD successfully predicted the binding mode of
crystallographic mode with rootꢀmean square (RMS)
8 noticeably shows that
a
deviation of 0.521 Å. The hydrogen bonds interactions between
the native Xꢀray ciprofloxacin and docked ciprofloxacin were
Score score was ꢀ123.54 and ꢀ74.67 respectively for 13d
Overall, compound 13d docked in the binding site of enzyme in
.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 7 of 9
View Article Online
DOI: 10.1039/C5RA26909A
Journal Name
COMMUNICATION
Piermatti, M. Nocchetti, M. Pica, F. Pizzo and L.
Vaccaro, J Mol Catal A-Chem, 2015, 401, 27ꢀ34; (f) A.
a similar manner to ciprofloxacin with additional hydrogen
bonds related to the 3ꢀ tetrazole scaffold, supporting the
Dhakshinamoorthy and H. Garcia, Chem. Soc. Rev.
,
molecular design of compound
A prototype (Figure 7).
2012, 41, 5262ꢀ5284; (g) I. X. Green, W. Tang, M.
Neurock and J. T. Yates, Science, 2011, 333, 736ꢀ739;
(h) D. Tsukamoto, Y. Shiraishi, Y. Sugano, S.
Ichikawa, S. Tanaka and T. Hirai, J. Am. Chem. Soc.
,
Conclusions
2012, 134, 6309ꢀ6315; (i) M. Pietrowski, M. Zieliński
and M. Wojciechowska, ChemCatChem, 2011, 3, 835ꢀ
838; (j) M. Zieliński and M. Wojciechowska, Cat.
Commun., 2012, 18, 1ꢀ4; (k) D. Azarifar and F.
Soleimanei, RSC Advan., 2014, 4, 12119ꢀ12126; (l) B.
H. Lipshutz, D. M. Nihan, E. Vinogradova, B. R. Taft
and Z. V. Boskovic, Org. lett., 2008, 10, 4279ꢀ4282;
(m) B. H. Lipshutz, J. B. Unger and B. R. Taft, Org.
lett., 2007, 9, 1089ꢀ1092; (n) M. B. Gawande, Y.
To conclude, through the oneꢀstep reduction in aq. NaBH4,
chitosan supported Cu nanoparticles were prepared and
characterized by state of art techniques. The synthesized
heterogeneous catalysts led to decarboxylative nitration of 3ꢀ
carboxyꢀ4ꢀquinolone in single step. The ChitꢀCuꢀNP can be
recycled for catalytic purpose which is conferenced up to five
cycles. The synthesized 3ꢀnitro derivatives successfully
transformed into the 3ꢀtetrazolyl bioisosteres possessing high
antimicrobial activity without significant loss of activity of
corresponding drugs. This noticeable in vitro efficacy of these
compounds against gram positive as well as gram negative
bacteria indicative of the potential utility of this compound in
the therapy of bacterial infection and methicillin resistance S.
aureus infection.
Monga, R. Zboril and R. Sharma, Coordin. Chem. Rev.
,
2015, 288, 118ꢀ143; (o) R. N. Baig, M. N. Nadagouda
and R. S. Varma, Coordin. Chem. Rev., 2015, 287, 137ꢀ
156.
(a) M. G. Dekamin, M. Azimoshan and L. Ramezani,
Green Chem., 2013, 15, 811ꢀ820; (b) A. Primo, T.
Marino, A. Corma, R. Molinari and H. Garcia, , J. Am.
Chem. Soc., 2011, 133, 6930ꢀ6933; (c) J. Sun, J. Wang,
W. Cheng, J. Zhang, X. Li, S. Zhang and Y. She, Green
Chem., 2012, 14, 654ꢀ660.
5
Acknowledgement
6
7
(a) S. Dumitriu inPolysaccharides: Structural Diversity
and Functional Versatility, Marcel Dekker, New York,
2005 ;(b) M. Yalpani, Polysaccharides: syntheses,
CSA acknowledges GGS Indraprastha University, New Delhi
for financial assistance and TRC Lab for providing analytical
data. We are also thankful to BioGenics, Karnataka for
providing antibacterial activity on payment basis.
modifications
and
structure/property
relations
,
Elsevier, 2013.
(a) A. KhalafiꢀNezhad and F. Panahi, Green Chem.
2011, 13, 2408ꢀ2415; (b) A. KhalafiꢀNezhad and F.
Panahi, J. Organomet. Chem., 2012, 717, 141ꢀ146; (c)
D. Baruah, R. N. Das, S. Hazarika and D. Konwar, Cat.
Commun., 2015, 72, 73ꢀ80; (d) B. Jia, Y. Mei, L.
,
References
Cheng, J. Zhou and L. Zhang, ACS Appl. Mater Inter,
2012, 4, 2897ꢀ2902; (e) P. Cotugno, M. Casiello, A.
Nacci, P. Mastrorilli, M. M. Dell’Anna and A.
Monopoli, J. Organomet. Chem., 2014, 752, 1ꢀ5.
8
9
(a) R. N. Baig and R. S. Varma, Green Chem., 2013,
15, 1839ꢀ1843; (b) R. N. Baig, M. N. Nadagouda and R.
S. Varma, Green Chem., 2014, 16, 2122ꢀ2127; (c) Y.
1
2
(a) 1.P. Anastas and N. Eghbali, Chem. Soc. Rev., 2010,
39, 301ꢀ312; (b) C.ꢀJ. Li and B. M. Trost, P. Nat. Acad.
Sci, 2008, 105, 13197ꢀ13202.
(a) R. A. Sheldon and H. Van Bekkum, Fine chemicals
through heterogeneous catalysis, John Wiley & Sons,
2008; (b) ; (b) J. M. Thomas and W. J. Thomas,
Qin, W. Zhao, L. Yang, X. Zhang and Y. Cui, Chirality
2012, 24, 640.
,
(a) R. A. Muzzarelli, Chitin, Elsevier, 2013; (b) J.
Zikakis, Chitin, chitosan, and related enzymes, Elsevier,
2012.
Principles and practice of heterogeneous catalysis
,
John Wiley & Sons, 2014; (c) D. Astruc, F. Lu and J. R.
Aranzaes, Angew. Chem. Int. Edit., 2005, 44, 7852ꢀ
7872; (d) N. Mizuno and M. Misono, Chem. Rev., 1998,
98, 199ꢀ218.
(a) J. Lu and P. H. Toy, Chem. Rev., 2009, 109, 815ꢀ
838; (b) J. H. Clark and C. N. Rhodes, Clean synthesis
using porous inorganic solid catalysts and supported
reagents, Royal Society of Chemistry, 2000.
(a) X.ꢀZ. Shu, S. C. Nguyen, Y. He, F. Oba, Q. Zhang,
C. Canlas, G. A. Somorjai, A. P. Alivisatos and F. D.
Toste, J. Am. Chem. Soc., 2015, 137, 7083ꢀ7086; (b) G.
Zhu, C. Wang, Y. Zhang, N. Guo, Y. Zhao, R. Wang, S.
Qiu, Y. Wei and R. H. Baughman, Chem-Eur. J., 2004,
10, 4750ꢀ4754; (c) J. H. Clark, M. G. Dekamin and F.
M. Moghaddam, Green Chem., 2002, 4, 366ꢀ368; (d) G.
Zhu, C. Wang, Y. Zhang, N. Guo, Y. Zhao, R. Wang, S.
Qiu, Y. Wei and R. H. Baughman, Chem-Eur J., 2004,
10, 4750ꢀ4754; (e) C. Petrucci, M. Cappelletti, O.
10 C. S. Azad, V. M. Balaramnavar, I. A. Khan, P. K.
Doharey, J. K. Saxena and A. K. Saxena, RSC Advan.
2015, 5, 82208ꢀ82214.
,
11 (a) G. Prakash and T. Mathew, Angew. Chem. Int. Edit.
,
3
4
2010, 49, 1726ꢀ1728, (b) S. Manna, S. Jana, T. Saboo,
A. Maji and D. Maiti, Chem. Commun., 2013, 49, 5286ꢀ
5288., (c) K. Ramesh, S. Shylaja, K. Rajanna, P.
Giridhar Reddy and P. Saiprakash, Adv. Phy. Chem.
2013, Article ID 146585, doi:10.1155/2013/146585 (d)
S. Maity, T. Naveen, U. Sharma and D. Maiti, Org. let.
,
,
2013, 15, 3384ꢀ3387, (e) T. Naveen, S. Maity, U.
Sharma and D. Maiti, J. Org. Chem., 2013, 78, 5949ꢀ
5954, (f) B. V. Rokade and K. R. Prabhu, J. Org.
Chem., 2014, 79, 8110ꢀ8117.
12 D. Baruah, P. Pahari and D. Konwar, Tetrahedron Lett.
2015, 56, 2418ꢀ2421.
,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 8 of 9
View Article Online
DOI: 10.1039/C5RA26909A
COMMUNICATION
Journal Name
13 Li, H. H.; Huang, H.; Zhang, X. H.; Luo, X. M.; Lin, L.
P.; Jiang, H. L.; Ding, J.; Chen, K. and Liu, H.; Acta
Pharm Sinic, 2008, 29, 1529
14 (a) Glushkov, R. G. and Davydova, N. K., KhimFarm
Zh, 1992, 26, 43; (b) Davydova,N. K.; Marchenko, N.
B.; Glushkov, R. G.; Peters,V. V. and Padeiskaya, E.
N., Pharm Chem Jour, 1991, 25, 730; (c) Surrey, A. R.
and Cutler, R. A., J Am Chem Soc, 1951, 73, 2413.
15 (a) C. S. Azad and A. K. Saxena, Org. Chem.Front.
,
2015, 2, 665ꢀ669: (b) C. S. Azad, S. S. Bhunia, A.
Krishna, P. K. Shukla and A. K. Saxena, Chem. Bio.
Drug Des., 2015, 86, 440ꢀ446; (c) C. S. Azad and A. K.
Saxena, Tetrahedron, 2013, 69, 2608ꢀ2612; (d) C. S.
Azad and A. K. Narula, RSC Advan., 2015, 5, 100223ꢀ
100227.
16 Koga, H.; Itoh A.; Murayama, S.; Suzue S. and Irikura
T., J. Med. Chem.; 1980, 23, 1358.
17 X. Cheng, X. Zhang, H. Yin, A. Wang and Y. Xu, App.
Sur. Sci., 2006, 253, 2727ꢀ2732.
18 (a) D. Mott, J. Galkowski, L. Wang, J. Luo and C.ꢀJ.
Zhong, Langmuir
, 2007, 23, 5740ꢀ5745; (b) S.
Panigrahi, S. Kundu, S. K. Ghosh, S. Nath, S. Praharaj,
S. Basu and T. Pal, Polyhedron, 2006, 25, 1263ꢀ1269.
19 M. S. Usman, N. A. Ibrahim, K. Shameli, N. Zainuddin
and W. M. Z. W. Yunus, Molecules, 2012, 17, 14928ꢀ
14936.
20 a) P. Natarajan, R. Chaudhary and P. Venugopalan, The
J. Org. Chem., 2015, 80,10498–10504 ; (bG. A. Olah,
G. K. S. Prakash, Q. Wang and X.ꢀy. Li, in
Encyclopedia of Reagents for Organic Synthesis, John
Wiley
&
Sons,
Ltd,
2001,
DOI:
10.1002/047084289X.rn043.
21 (a) D. J. Wood, J. d. Vlieg, M. Wagener and T.
Ritschel, J. Chem. Inform. Model., 2012, 52, 2031ꢀ2043
22 Y. Asahina, T. Ishizaki and S. Suzue, Prog. Drug Res
1992, 38, 57ꢀ106.
,
23 A. W. McCracken and R. A. Cawson, Hemisphere
Publishing Corporation, WASHINGTON, DC(USA).
1983. p 512.
24 F. D. Lowy, J. Clin. Inves., 2003, 111, 1265.
25 R. Thomsen and M. H. Christensen, J. Med. Chem.
2006, 49, 3315ꢀ3321.
,
26 B. D. Bax, P. F. Chan, D. S. Eggleston, A. Fosberry, D.
R. Gentry, F. Gorrec, I. Giordano, M. M. Hann, A.
Hennessy and M. Hibbs, Nature, 2010, 466, 935ꢀ940.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 9
RSC Advances
View Article Online
DOI: 10.1039/C5RA26909A
An operational transformation of 3-carboxy-4-quinolones into 3-nitro-4-
quinolones via ipso-nitration using polysaccharide supported copper
nanoparticles: synthesis of 3-tetrazolyl bioisosteres of 3-carboxy-4-quinolones
as antibacterial agents
Chandra S Azad and Anudeep K Narula*
Chitosan supported Cu nano-particles have been synthesized, and utilized for the synthesis of
3-nitro-4-quinolones from the 3-carboxy-4-quinolones via ipso nitration. The synthesized 3-nitro
derivatives of 4-quinolones were successfully converted into its 3-tetrazolyl bioisosteres which
showed increased antibacterial activity as compared to the standard ciprofloxacin.