Nickel nanoparticles: A highly efficient and retrievable catalyst for the solventless Friedlander annulation of quinolines and their in silico molecular docking studies as histone deacetylase inhibitors

Article abstract of DOI:10.1039/c5ra06593c

The present work explores a highly efficient, environmental friendly, green, solvent-free protocol for the preparation of polysubstituted quinolines via Friedlander annulation using nickel nanoparticles (80-100 nm) biofabricated from Aegle Marmelos Correa

Full text of DOI:10.1039/c5ra06593c

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Nickel nanoparticles: A highly efficient and retrievable catalyst for the
solventless friedlander annulation of quinolines and their in-silico molecular
docking studies as histone deacetylase inhibitors.
*
Gangadhara Angajala, R. Subashini
Chemistry Research Laboratory, Organic Chemistry Division. School of Advanced Sciences, VIT University, Vellore
-
632014.
*
Corresponding author:
Tel.: +91 94435 41305, +91 0416 2202352.
Email address: dr.subashini.r@gmail.com (Dr. R. Subashini)
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Nickel nanoparticles: A highly efficient and retrievable catalyst for the solventless
Friedlander annulation of quinolines and their in-silico molecular docking studies
as histone deacetylase inhibitors
5
Gangadhara Angajala, R. Subashini*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The present work explores a highly efficient, environmental friendly, green, solventꢀfree protocol for the preparation of polysubstituted
quinolines via Friedlander annulation using nickel nanoparticles (80ꢀ100 nm) biofabricated from Aegle Marmelos Correa aqueous leaf
extract. These nickel nano materials exhibit high catalytic efficacy to achieve the target molecules in excellent yields ranging from 85ꢀ96
1
1
2
0
5
0
%
mainly due to their diverse properties and high surface area to volume ratio. The synthesized polysubstituted quinolines were
1
13
successfully characterized by FTꢀIR, H NMR, C NMR, and GCꢀMS. The effect of various solvents and catalyst concentration on the
synthesis of quinolines has been investigated where under solventless conditions at10 mol % of the nickel nano catalyst high yields of the
product were obtained. Reusability of the catalyst up to five cycles under solventꢀfree conditions within shorter reaction time, without
any significant loss in the yields of the product are the unique features of this heterogenous solid catalysis. Furthermore safer reaction
profiles, high selectivity, greater yields, reliable cost efficiency, simple workup conditions are some of the noteworthy highlights of this
green ecofriendly process. In-silico molecular docking studies for anticancer efficacy of the quinoline derivatives as histone deacetylase
inhibitors (HDIs) were carried out. The results showed that compounds 3h (ꢀ7.3), 3n (ꢀ7.1), 3l (ꢀ6.5) and 3b (ꢀ6.7), are having better
binding affinity showing docking score which is greater than that of standard Vorinostat (ꢀ6.4) and comparable to that of standard
Panobinostat (ꢀ7.9).
3
3ꢀ35
the development of new quinolineꢀbased structures
different newer methods for their construction
and
. Over the past
decades various chemical methods such as Doebnerꢀvon Miller,
Quinolines and their derivatives are considered as important 55 Skraup, Friedlander and Combes reactions have been developed
3
6,37
1
Introduction
38ꢀ41
2
3
3
4
4
5
0
5
0
5
scaffolds in medicinal chemistry because of their wide spectrum
for the synthesis of quinolines
. Among the various
1
ꢀ4
of biological activities . Annually nearly 2000 tons of quinoline
are produced from all over the world indicating its biological
preparation methods of quinolines reported so far in literature,
Friedlander annulation of quinolines is one of the most straight
forward and simplest method for the synthesis of quinoline
5ꢀ7
importance . It is an important heterocyclic intermediate with
wide range of applications especially in metallurgical process, 60 derivatives. It usually starts with the reaction of 2ꢀamino aryl
8
polymer industry, agro chemical production and in dye industry .
Quinoline moiety also has significant role in the formation of
conjugated molecules and polymers that combine enhanced
nonlinear optical, optoelectronic properties with excellent
ketones and a second carbonyl compound possessing a reactive αꢀ
methylene group which is catalysed by both acids and bases.
Bronsted acids such as hydrochloric acid, sulfamic acid, sulphuric
acid, pꢀtoluene sulfonic acid and polyphosphoric acid were
9
ꢀ14
42
pharmacological activities . Synthesis of quinoline derivatives 65 widely employed as catalysts in the synthesis of quinolines .
and its analogues has been an attractive goal for the synthetic
organic chemists due to their pharmacological role as
substructures in the wide variety of designer and natural products
However most of these methods require very harsh conditions
and lead to several side unwanted reactions. In the presence of
base catalysts at high temperature, 2ꢀaminobenzophenone fails to
react with simple ketones such as cyclohexanone and βꢀketo
15ꢀ19
.
Quinoline scaffold is present in many medicinal plant
43
alkaloids and with the advancements in the phytochemistry 70 esters .
isolation of quinine prompted the development of wide variety of
2
0ꢀ23
synthetic antimalarials
.
In medicinal chemistry quinolines
Further extensive work on quinoline derivatives showed that acid
catalysts are more effective than base catalysts for the Friedlander
annulation of quinoline. Lewis acids such as SnCl , ZnCl ,
have wide variety of biological applications such as antiꢀ
2
4
25
26
27
inflammatory , antibacterial , antimalarial , antifungal ,
2
2
2
8
29
30
31
antiprotozoal , analgesic , antiviral , antineoplastic
and 75 Mg(ClO ) , Sodium fluoride, FeCl , silverphosphotungstate and
4
2
3
3
2
cardiovascular activity . Development of polysubstituted
quinolines can achieve hierchical selfꢀassembly into meso and
nano structures with enhanced electronics and photonic
properties.
NaAuCl .2H O have been proved to be effective for the synthesis
4 2
44ꢀ48
of quinolines
. Most of the reported methods for the synthesis
of quinolines suffer from the usage of harmful organic solvents,
high reaction temperature, prolonged reaction times with low
yields, tedious work up procedures and use of relative expensive
reagents. Therefore in order to avoid limitations associated with
normal chemical synthesis there is an effective need to develop
easy practical approaches to a variety of quinoline derivatives
80
5
0
In the recent years significant efforts continued to be directed in
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with useful pharmacophores. Different researches from all over 65 lead to higher chemical reactivity. Moreover, as the surface area
the world have made use of new catalysts in several well
established new methodologies. Besides an array of new and
innovative strategies have been developed which has rendered the
synthesis of quinoline core a much simpler process than earlier.
increases the dominance behaviour of the atoms increases on its
outer surface rather than the interior of the particle. Collectively
the surface functional hydroxyl groups, highly active Lewis acid
sites and other effects play a major role in the Friedlander heteroꢀ
annulation of quinolines (Fig.1).
5
0
5
0
5
0
5
0
70
Now a day there is huge demand in assembling quinoline systems
by nano catalysts for selective, cheap, ecofriendly, low cost
Hence keeping all these facts of nickel, it is considered
worthwhile to explore the catalytic applications of biofabricated
NiNPs in Friedlander annulation of quinolines. Initially, the
4
9
protocols for their synthesis . In literature various metal oxide
nanoparticles have been used for the Friedlander annulation of
1
1
2
2
3
3
4
50,51
quinolines
. Nano catalysis is currently the subject of 75 reaction was monitored under different solvents and without
considerable attention for synthetic chemists to develop some
ecofriendly, environmentally benign techniques because these
heterogenous organic reactions have several advantages such as
safe handling, ease of disposal, minimum execution time and
solvent. The most important property of solvent molecules is the
response to the changes associated with charges and their
corresponding distribution during the process of a reaction. In
order to accommodate the distribution of charges dielectric
5
2,53
waste minimization
. The use of metal nanoparticles in 80 constant of the solvent is considered as a good indicator. It
catalysis is crucial as they mimic metal surface activation and
catalysis at the nanoscale and thereby bring selectivity and
efficiency to heterogeneous catalysis. Metal nanoparticles have
tremendous catalytic applications in organic synthesis mainly due
reduces the field strength of the electric field surrounding the
charged particle immersed in the solvent. In general, protic
solvents gave better yields because of their participation in
hydrogen bonding that forms a powerful intermolecular force
5
4ꢀ57
to their small size and large surface area
. Recently nickel 85 with the reactants efficiently. On the other hand aprotic solvents
nanoparticles are widely employed as catalysts which offer great
opportunities for wide range of organic reactions and chemical
result in lower yields because of lack of OꢀH and NꢀH bonds and
cannot form hydrogen bond with the reactants. When compared
to the yields in different solvents, nickel nano catalyst under
solventless condition has been found to give quinoline in a high
90 yields (96 %) (Table 1), the two component cyclization reaction
carried out effectively with high selectivity using reflux condition
without solvent has been chosen for further study.
58
manufacturing processes including reduction of aldehydes and
5
9
60
ketones , chemoselective oxidative coupling of thiols ,
6
1
62
63
hydrogenation of citral , styrene oxide , synthesis of thioesters
and quinoxalines .
64
From the past 100 years Friedlander annulation is a wellꢀknown
method for the synthesis of quinolines. To handle this particular
condensation in smooth manner, we have developed an 95 behaviour of various 2ꢀamino aryl ketones with acyclic, cyclic
inexpensive, safe, nonꢀvolatile, green nickel nano catalyst
biofabricated from Aegle Marmelos Correa aqueous leaf extract
under optimum reaction conditions nearly 96 % of yields have
been achieved. The increasing yields are due to large surface
The optimization of the reaction conditions and to investigate the
ketones and βꢀketo esters in the presence of catalytic amount of
NiNPs was carried over. The compound 3a was taken as
representative example which was synthesized by taking 2ꢀamino
benzophenone, 1a with cyclohexaneꢀ1,3ꢀdione, 2 in the presence
area, surface activity of the catalyst with the effect of reduced 100 of catalytic amount of nickel under solventless conditions. In
time to get the corresponding products in high yield. The purpose
of present study was to investigate the feasibility of nickel nano
catalyst in the Friedlander annulation of quinolines as an
ecofriendly, inexpensive, effective and smooth reaction
conditions.
order to evaluate scope and limitation of the reaction, the reaction
conditions and the concentration of the nickel nano catalyst was
varied and optimized as 10 mol %, where high yields of the
product 96 % have been achieved without any by products
105 (Table.2). On further increase in the concentration of the catalyst,
the raise in the yields of the product remains unaffected. However
in the absence of nickel nano catalyst the reaction did not proceed
even for longer reaction time.
2
Results and discussion
2
.1 Chemistry
1
1
1
1
10 The biofabricated nickel nano catalyst under solventless
conditions indeed displayed better activity both for cyclic as well
as acyclic ketones. The Lewis acid sites present in the nickel nano
catalyst effectively interacts with the carbonyl oxygen of ketone
through the formation of surface bound hydrogen bonded species
15 which further undergoes Intramolecular cyclization to generate
the target molecules in a good yield (Table.3).
45
50
55
60
Catalytic applications of various metal nanoparticles are always
advantageous in various organic transformations. The reason for
this high efficient catalytic ability was mainly due to its surface
area to volume ratio. High surface area to volume ratios have
interesting applications such as increased therapeutic and
catalytic applications . Nickel nanoparticles are special and
interesting mainly because, their physical and chemical properties
are totally different when compared to their macro counter parts.
Due to their small size nickel nanoparticles possess unique
properties, regardless of their chemical properties they generally
have high surface area to volume ratio. This automatically causes
their physical properties to be dominated by the effect of capping
agents and surface atoms on the surface of nickel nanoparticles.
6
5
2.2 Reusability of the catalyst
20 The catalyst was filtered off from the reaction mixture at the end
of the reaction. It was washed with hot ethanol and water, dried
and activated at 250 ˚C for 3 h. The catalyst was reused as such
for successive experiments up to five cycles (Fig.3) under similar
reaction conditions. It was observed that the morphology of the
25 nickel nano catalyst remains unaffected and moreover there was
only a slight difference in the yields of the product thereby
showing reusability and recyclability of the nano catalyst without
any considerable loss in the catalytic activity. The reusability of
the catalyst was examined on the reaction of 2ꢀamino
ꢀ
1
The broad band centered at ̴ 3400 cm in the FTꢀIR spectral
analysis of the nickel nanoparticles (80ꢀ100 nm) indicates the
presence of hydroxyl functional group (Fig.2). The high surface
areaꢀtoꢀvolume ratio of nickel nanocrystals can sometimes lead to
unexpected properties. Particles with high surface area possess
many reaction sites than a particle with low surface area and thus
2
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benzophenone with cyclohexaneꢀ1,3ꢀdione to afford quinolines in
6 to 92 %. A comparative study has been carried out on the
efficiency of various catalysts reported in literature along with
nickel nano catalyst in the synthesis of quinoline derivatives
through Friedlander hetero annulation (Table.4).
final 3D quinoline ligands possess various ionization states and
ring confirmations with broad chemical and structural diversity.
The results (Table.5) obtained from the docking studies have
showed that the compounds 7ꢀchloroꢀ3,3ꢀdimethylꢀ9ꢀphenylꢀ
70 3,4ꢀdihydroacridinꢀ1(2H)ꢀone 3h (ꢀ7.3), 3,3, 9ꢀtrimethylꢀ3,4ꢀ
dihydroacridinꢀ1(2H)ꢀone (ꢀ7.1) 3n, 7ꢀchloroꢀ9ꢀphenylꢀ2,3ꢀ
dihydroꢀ1Hꢀcyclo penta [b] quinoline 3l (ꢀ6.5), 3,3ꢀdi methylꢀ9ꢀ
phenylꢀ3,4ꢀdihydro acridinꢀ1(2H)ꢀone 3b (ꢀ6.7), are having
better binding affinity showing docking score which is greater
9
5
2
.3 UV-Visible spectrum of nickel nano catalyst
The UVꢀVisible spectrum of nickel nano catalyst in water was
recorded against time of reaction by using UVꢀVisible 75 than that of standard Vorinostat (ꢀ6.4) and comparable to that of
1
1
2
0
5
0
spectrophotometer. The UVꢀVisible pattern of nickel nano
catalyst before and after the reaction was monitored in the range
of 200ꢀ800 nm where distinct broad bands were observed at 272
and 274 nm in the ultraviolet region which was very close to the
the standard Panobinostat (ꢀ7.9). The compound 7ꢀchloroꢀ3,3ꢀ
dimethylꢀ9ꢀphenylꢀ3,4ꢀdihydroacrid inꢀ1(2H)ꢀone, 3h posses
good lipophilic character mainly because of the presence of
halogen and two methyl groups as substituents. Ligand binding
calculated optical spectrum of various metal nanoparticles both in 80 induces confirmational changes in the protein, such as loop
water and in vacuum by Creighton and Eadon based on Mie’s
motions or domain reorientations. The affinity and specificity of
the binding interactions of the ligands were mainly determined by
the structural and physicochemical properties of the binding
partners. Moreover there is no significant change has been
85 observed in the final geometry of the synthesized ligands after
interaction with the receptor.
6
9
theory
. The results showed that the stability of the nickel
nanocatalyst remains unaffected after five cycles (Fig. 4A, 4B)
2.4 X-ray diffraction pattern of nickel nano catalyst
XRD analysis of recovered nickel nano catalyst showed three
intense peaks in the spectrum 2θ scale ranging from 10 to
Increase in lipophilic nature makes the molecule more polarized
and accordingly the London dispersion force increases which are
quite necessary for the lipophilic substances to interact within
themselves and other amino acid residues in the receptor. From
the results it can be understood that the compounds 3h, 3n, 3l, 3b
possess good anticancer efficacy as histone deacetylase inhibitors
8
0. The XRD pattern of recovered nickel nano catalyst agrees
9
0
2
3
3
4
4
5
5
6
6
5
0
5
0
5
0
5
0
5
well with the standard pure crystalline nickel structures published
by the Joint Committee on Powder Diffraction standards (File no:
0
4ꢀ0850) confirmed that the nickel nano catalyst are in crystalline
form with face centered cubic (FCC) structure. The presence of
nickel nano catalyst results in the formation of Bragg’s peaks at
2θ values of 44.18º, 50.92º and 74.16º can be indexed as (111),
(HDIs). Histone deacetylase inhibitors are cytostatic agents that
95
inhibit the proliferation of cells and arrest cell cycle there by
inducing apoptosis. In order to carry out gene expression
normally, the coiling and uncoiling of DNA around histones
should be primarily controlled. This process is accomplished with
the support of histone acetyl transferases (HAT), where the lysine
(220), (200) planes of FCC nickel (Fig.4D). Similarly the
presence of nickel nano catalyst (before reaction) results in the
formation of Bragg’s peaks at 2θ values of 44.39º, 51.26º and
7
4.68º can be indexed as (111), (220), (200) planes of FCC
1
1
1
00 residues in core histones are acetylated with the formation of less
compact, transcriptionally active chromatin where as histone
deacetylases (HDAC) leads to the formation of condensed and
transcriptionally silenced chromatin by effectively removing the
acetyl groups from the lysine residues. This reversible
05 mechanism is very vital for controlling and regulating the gene
expression and in remodelling the topology of chromatin
structure. The synthesized quinoline derivatives selectively block
the deacetylation of lysine residues which subsequently causes
hyperacetylation of histones with altered gene expression (Fig.7).
10
nickel. (Fig.4C). The results revealed that the morphology of the
nickel nano catalyst remains the same after five cycles.
2
.5. EDAX pattern of nickel nano catalyst
Energy dispersive Xꢀray (EDAX) analysis on various regions
confirms the presence of nickel nano catalyst with energy bands
centered at 7.5 and 8.3 keV [K lines] and 0.8 keV [L lines]. The
oxygen and carbon peaks are negligible in EDAX pattern of
nickel nano catalyst (before reaction) whereas the oxygen and
carbon peaks detected in EDAX pattern of the recovered catalyst
was mainly attributed to partial oxidation of the catalyst during
handling and due to the interaction with solvent during the
workup process (Fig.5A, 5B)
3
3
Experimental
.1 Materials and methods
Solvents and reagents were commercially sourced and used
without further purification. Thin layered chromatography (TLC)
15 was performed on preparative plates of silica gel and
visualization was made with iodine chamber. Column
chromatography was performed by using silica gel (100ꢀ200
mesh). Melting points were measured on Elchem Microprocessor
based DT apparatus using an open capillary tube and are
20 corrected with standard benzoic acid. The NMR spectra were
recorded on a Bruker Avance III – 400 MHz spectrometer using
TMS as internal standard (chemical shifts δ in ppm). GCꢀMS was
recorded on Perkin Elmer: clarus 680/600.
In-silico molecular docking studies
1
1
1
The proteinꢀligand based interaction plays a significant role in
structural based drug design. The most stable docking structure of
synthesized quinoline derivatives complexed with histone
deacetylase receptor as shown in (Fig .6) clearly indicate that the
synthesized ligands are having stronger binding interactions with
the receptor which was compared to that of standards Vorinostat
and Panobinostat. Ligprep is a versatile conversion program that
can be configured to generate ligand libraries with desired
structural and chemical features can significantly streamline the
entire in-silico drug discovery process. It also applies filters to
eliminate ligand that does not meet the user specified criteria,
allowing the generation of customized library. By using Ligprep
accurate, energy minimized 3D molecular structures of poly
substituted quinoline [ligand] derivatives were generated. The
25 3.1.1 Biofabrication of nickel nano catalyst
The biosynthesis of nickel nano catalyst from Aegle Mearmelos
70
Correa aqueous leaf extract was reported in our previous work
.
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created around the reference ligand (3ꢀCyclopentylꢀNꢀ
65 Hydroxypropanamide) of histone deacetylase. The structures of
the ligands were drawn using Maestro 8.5. The ligands were
prepared using Ligprep utility of Schrodinger software where
hydrogen atoms addition option was enabled, unwanted
molecules such as water and small ions are filtered out based on
3
.1.2 Characterization of nickel nano catalyst
The surface morphology of the synthesized nickel nano catalyst
was studied by using SEM analysis. The results obtained from
SEM showed that the nanoparticles are crystalline in nature with
5
0
5
0
traingle shape having an average particle size of 80ꢀ100 nm. 70 the properties of the ligands. Charge groups are neutralized and
(
Fig.8A, 8B)
ionization states were created by using Epik option. Finally the
geometries of the ligands were optimized by generating low
energy ring confirmations. The ligands did not show any signs
for the formation of isomers or tautomers after Ligprep. The
1
1
2
The metal nanoparticles are generally unstable, and exploration
of their stability is a key factor in their successful and wide
applications in heterogenous catalysis. In order to observe the 75 ligands docking were carried out with Xtra precision mode (XP)
characteristic weight loss of biosynthesized NiNPs with rise in
temperature thermogravimetric analysis were carried out by using
Shimadzu DTꢀ50 thermal analyser at a heating rate of 10 °C/min
was applied to NiNPs. The thermal analysis curve of the Nickel
option employed in Glide (5.5) module implemented in
Shrodinger LLC. In the present version both the receptor as well
as ligand kept fixed and for each derivative various confirmations
have been screened at different poses within the receptor. Finally
NPs showed a steady weight loss in the temperature of 100ꢀ800 80 the most stable confirmations were selected and subjected to
°C (Fig.8C).
glide virtual simulation with optimization option using Tripos
force field and applying GasteigerꢀHuckel charges. The
rototranstional area in to which the ligand is allowed to move
3.1.3 Synthesis of quinoline derivatives
˚
freely around the active sphere is restricted to 10 A . The
85
derivatives of the final compounds were docked with the receptor
and the interactions of ligands with the receptor were shown.
The synthetic strategy leading to the key precursors and target
compounds was illustrated in (Scheme.1). The compounds were
prepared by the reaction of 2ꢀaminoaryl ketone with enolisable
ketone in the presence of NiNPs as a catalyst under solventꢀfree
conditions.
25
Conclusions
A costꢀeffective, ecofriendly protocol has been developed for the
synthesis of polysubstituted quinoline derivatives through
Friedlander annulation. This one pot nickel nano catalysed
synthesis of quinoline derivatives is unique alternative route for
rapid generation of structurally diversified quinoline derivatives
with high yields under solvent free conditions with shorter
reaction time. The remarkable reusability, selectivity and
environmental compatibility are among the other added
advantages to make this approach an efficient route for the
production of the target molecules. From the in-silico molecular
docking studies it can be concluded that the synthesized
quinolines possess excellent anticancer properties as histone
3
.1.4 General procedure for the synthesis of quinoline
9
0
derivatives
30
35
40
45
In a round bottom flask 2ꢀaminoaryl ketone (1 mmol) and
enolisable ketone (1 mmol) and catalytic amount of NiNPs was
added under stirring at room temperature for 10 min. Later the
reaction was carried out in an oil bath at 75 ˚C. The progress of
the reaction was monitored under TLC and after completion the
reaction mass was cooled to room temperature and extracted by
using ethylacetate as solvent. The catalyst was seperated from the
crude reaction mixture by normal filtration. The organic layer
containing crude reaction mass was separated and dried over
anhydrous sodium sulphate, then concentrated under reduced
pressure. Further purification of the reaction was done by column
chromatography in 100ꢀ200 mesh silica gel using petroleum ether
95
1
1
1
00 deacetylase inhibitors and in future research has to be carried out
in exploring the anticancer properties of the quinoline derivatives
in in-vivo models.
Ackowledgements
:
ethyl acetate (10 : 1 v/v) as the eluting solvent system. Further
05
characterization of the products was carried by spectral analysis
using FTꢀIR, H NMR, C NMR and GCꢀMS.
1
13
The authors sincerely thank the management of VIT University,
Vellore, Tamil Nadu, India for their constant encouragement and
support and providing all the necessary facilities for carrying out
this study. The authors also thank DSTꢀVITꢀFIST, SIFꢀVIT for
10 carrying out NMR analysis.
3
.1.5 In-silico molecular docking studies
The docking analysis of final quinoline derivatives 3a-s,
reference ligand and standards Vorinostat, Panobinostat was
carried out using Schrodinger molecular docking software. The
Xꢀray crystal structure of histone deacetylase receptor (IDꢀ1ZZ3)
was taken from protein data bank . The active site of histone
deacetylase receptor was well established with hydrophobic
50
55
60
Notes and references
7
7
a
Organic Chemistry Division, School of Advanced Sciences, VIT
University, Vellore 632014, Tamilnadu, India. Fax: 91-416 224 3092;
active site containing irreversible inhibitor. In order to distinguish 115 Tel: 0416 220 2352; E-mail: dr.subashini.r@gmail.com;.
the basic ligandꢀreceptor interactions molecular docking
1
.
R.D. Larsen, E.G. Corley, A.O. King, J.D. Carrol, P. Davis, T.R.
Verhoeven, P.J. Reider, M. Labelle, J.Y. Gauthier, Y.B. Xiang and
R.J. Zamboni, J. Org. Chem.,1996, 61, 3398–3405.
simulations were carried out and protein was prepared by protein
preparation wizard where it is preprocessed by simultaneously
deleting the substrate cofactors as well as crystallographically
depicted water molecules and optimizing hydrogen bonds. Finally
after assigning charge and protonation state energy minimization
with root mean square deviation (RMSD) of 0.35 A˚ was done
using OPLS2005 force field. Receptor grid was prepared with
1
20 2. Y.L. Chen, K.C.Fang, J.Y. Sheu, S.L.Hsu and C.C.Tzeng, J. Med.
Chem., 2001, 44, 2374–2377.
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.
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G. Roma, M.D. Braccio, G. Grossi, F. Mattioli and M. Ghia, Eur. J
Med. Chem., 2000, 35:1021–1035
P.M.S. Chauhan and S.K. Srivastava, Curr. Med. Chem., 2001, 8,
1535ꢀ1542.
default parameters without having any constraints and sites were 125
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5
6
.
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FIGURE CAPTIONS
Fig.1 Plausible reaction mechanism for the synthesis of polysubstituted quinolines using nickel nanoparticles.
Fig.2 FTꢀIR spectrum of nickel nanoparticles (80ꢀ100 nm).
Fig.3 Reusability of the nickel nano catalyst (80ꢀ100 nm) for the synthesis of 9ꢀphenylꢀ3, 4ꢀdihydroacridinꢀ1(2H)ꢀone (3a).
Fig.4 [A] UVꢀVisible analysis of nickel nano catalyst (before reaction) [B] UVꢀVisible analysis of nickel nano catalyst [after
recovery] [C] XRD analysis of nickel nano catalyst (before reaction) [D] XRD analysis of nickel nano catalyst (after
recovery).
Fig.5 [A] EDAX pattern for nickel nano catalyst (before reaction) [B] EDAX pattern for nickel nano catalyst (after
recovery).
Fig.6 In silico molecular docking studies of quinoline derivatives as histone deacetylase inhibitors (HDIs). [A] The binding
interaction of 7ꢀchloroꢀ3, 3ꢀdimethylꢀ9ꢀphenylꢀ3, 4ꢀdihydroacridinꢀ1(2H)ꢀone 3h with histone deacetylase receptor. [B] The
binding interaction of 3, 3, 9ꢀtrimethylꢀ3, 4ꢀdihydroacridinꢀ1(2H)ꢀone 3n with histone deacetylase receptor. [C] The binding
interaction of 7ꢀchloroꢀ9ꢀphenylꢀ2, 3ꢀdihydroꢀ1Hꢀcyclopenta[b]quinoline 3l with histone deacetylase receptor. [D] The
binding interaction of 3, 3ꢀdimethylꢀ9ꢀphenylꢀ3, 4ꢀdihydro acridinꢀ1(2H)ꢀone 3b with histone deacetylase receptor.
Fig.7 Mechanism of action for anticancer efficacy of synthesized quinoline derivatives.
Fig.8 [A] SEM pattern for nickel nano catalyst (Magnification at 13700x) [B] SEM pattern for nickel nano catalyst
(
Magnification at 24600x) [C] Thermogravimetric analysis of nickel nano catalyst.
Scheme.1 Synthesis of polysubstituted quinolines using nickel nanoparticles.
1
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List of tables
a
Table.1 Effect of solvent in the synthesis of 9ꢀphenylꢀ3, 4ꢀdihydroacridinꢀ1(2H)ꢀone (3a)
b
Entry
Solvent
Catalyst (mol %)
Yield (%)
1
2
3
4
5
6
Acetonitrile
Tetrahydrofuran
Acetone
Acetic acid
Ethanol
10
10
10
10
10
10
55
62
76
84
92
96
Solventless
a
Reaction conditions : 2ꢀamino benzophenone, 1a (1 mmol), Cyclohexane1,3ꢀdione (1 mmol), NiNPs (80ꢀ100 nm), 75 ºC.
Isolated yield.
b
a
Table.2 Effect of catalyst concentration in the synthesis of 9ꢀphenylꢀ3, 4ꢀdihydroacridinꢀ1(2H)ꢀone (3a)
b
Entry
Catalyst (mol %)
Time (min)
Yield (%)
1
2
3
4
5
6
2.5
5.0
7.5
10.0
12.5
15.0
220
220
140
50
50
50
53
65
81
96
96
96
a
Reaction conditions : 2ꢀamino benzophenone, 1a (1 mmol), Cyclohexane1,3ꢀdione (1 mmol), NiNPs (80ꢀ100 nm)
Solventless, 75 ºC.
b
Isolated yield.
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a
Table.3 Synthesis of quinolines and polysubstituted quinolines using NiNPs (80ꢀ100 nm)
b
Entry
1
Amino Ketone
1a
Enolisable Ketone
Product
Time (min)
Yield (%)
5
0
96
2
3
4
1a
1a
1a
5
0
95
92
94
89
5
5
6
6
5
8
5
6
1a
1a
5
5
2
9
95
92
7
1b
1b
8
9
5
7
6
0
6
1
94
96
1b
1b
1
1
0
1
92
89
1b
57
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Table.3 (Continued)
b
Entry
Amino Ketone
1b
Enolisable Ketone
Product
Time (min)
Yield (%)
12
6
5
0
0
95
92
13
1c
14
15
16
17
18
1c
1c
1c
1c
1d
5
0
6
95
90
5
7
5
2
0
94
92
6
0
87
93
19
1d
50
a
Reaction conditions : Amino ketone (1 mmol) Ketone (1 mmol) and NiNPs (10 mol %), Solventless, 75 ºC.
Isolated yield.
b
Table.4 Comparison of efficiency of various catalysts in the Friedlander annulation of quinoline synthesis.
Entry
Catalyst
KSF clay
ZnO NPs
Time (min)
Yield (%)
66
1
1
2
2
3
4
5
5
6
7
360
180
60
300
300
240
180
300
210
50
75
75
75
80
82
83
86
88
92
67
68
69
70
71
72
73
74
Yb[OTf]
Cu(CF SO
SbCl
Y(OTf)
3
3
3
)
2
3
3
Bi (OTf)
CuO NPs
3
ZrO
NiNPs
2
96
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Table.5 In silico molecular docking results of synthesized quinoline derivatives, reference ligand and standards.
Entry
Ligand
Glide Score [XP] Lipophilicity
Hydrophobicity
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
ꢀ4.5
ꢀ6.7
ꢀ5.3
ꢀ4.8
ꢀ5.6
ꢀ4.0
ꢀ6.3
ꢀ7.3
ꢀ6.2
ꢀ5.9
ꢀ5.6
ꢀ6.5
ꢀ6.0
ꢀ7.1
ꢀ4.8
ꢀ5.3
ꢀ5.9
ꢀ5.4
ꢀ5.8
ꢀ8.5
ꢀ6.4
ꢀ7.9
ꢀ2.5
ꢀ3.9
ꢀ3.2
ꢀ2.3
ꢀ3.4
ꢀ2.4
ꢀ4.0
ꢀ4.3
ꢀ3.6
ꢀ3.4
ꢀ3.1
ꢀ3.8
ꢀ3.5
ꢀ3.3
ꢀ2.7
ꢀ3.0
ꢀ3.2
ꢀ2.1
ꢀ3.2
ꢀ4.8
ꢀ3.9
ꢀ4.5
ꢀ0.5
ꢀ1.4
ꢀ0.8
ꢀ0.5
ꢀ1.1
ꢀ0.9
ꢀ0.7
ꢀ0.4
ꢀ1.2
ꢀ0.5
ꢀ1.0
ꢀ0.4
ꢀ0.8
ꢀ1.5
ꢀ1.1
ꢀ0.5
ꢀ0.2
ꢀ0.9
ꢀ0.4
ꢀ1.2
ꢀ0.3
ꢀ0.5
10
11
12
13
14
15
16
17
18
19
20
21
22
3q
3r
3s
a
Reference Ligand
b
Stdc
Std
a
b
c
3
ꢀCyclopentylꢀNꢀHydroxypropanamide; Vorinostat; Panobinostat.
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Fig.1
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Fig.2
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Fig.3
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Fig.4
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Fig.5
1
0
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Fig.6
1
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Fig. 7
1
2
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Fig. 8
1
3
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Scheme.1
R1
O
R1
N
O
R
NiNPs
Solventless, 75 o
C
R
O
+
NH2
O
1
2
3
a-s
R = H, Cl, NO2
R1 = CH , C H
6 5
3
1
4
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