Synthesis, ABTS-Radical Scavenging Activity, and Antiproliferative and Molecular Docking Studies of Novel Pyrrolo[1,2-a]quinoline Derivatives

Article abstract of DOI:10.1080/00397911.2015.1085572

A new 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)-radical scavenging and antiproliferative agents of pyrrolo[1,2-a]quinoline derivatives have been synthesized. An efficient method for the synthesis of 14 novel diversified pyrrolo[1,2-a]q

Full text of DOI:10.1080/00397911.2015.1085572

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis, ABTS-Radical Scavenging Activity, and
Antiproliferative and Molecular Docking Studies of
Novel Pyrrolo[1,2-a]quinoline Derivatives
Chandrika Nanjappa, Suresha Kumara T. Hanumanthappa, Nagendrappa
Gopalpur, Sujan Ganapathy, Shruthi S. D., Sunil More, Gilish Jose, Sowmya H.
B. V. & Rashmi S. Kulkarni
To cite this article: Chandrika Nanjappa, Suresha Kumara T. Hanumanthappa, Nagendrappa
Gopalpur, Sujan Ganapathy, Shruthi S. D., Sunil More, Gilish Jose, Sowmya H. B. V. &
Rashmi S. Kulkarni (2015): Synthesis, ABTS-Radical Scavenging Activity, and Antiproliferative
and Molecular Docking Studies of Novel Pyrrolo[1,2-a]quinoline Derivatives, Synthetic
Communications, DOI: 10.1080/00397911.2015.1085572
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1085572
Accepted online: 02 Oct 2015.
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Date: 08 October 2015, At: 20:18

Synthesis, ABTS-Radical Scavenging Activity, and Antiproliferative and Molecular
Docking Studies of Novel Pyrrolo[1,2-a]quinoline Derivatives
1
1,2
1
Chandrika Nanjappa , Suresha Kumara T. Hanumanthappa , Nagendrappa Gopalpur ,
3
4
5
1
1
Sujan Ganapathy , Shruthi S. D. , Sunil More , Gilish Jose , Sowmya H. B. V. , Rashmi
1
S. Kulkarni
1
P.G. Dept. of Chemistry, Jain University, Hebbal, Bangalore, Karnataka, India,
2
Department of Chemistry, U.B.D.T. College of Engineering (VTU), Davanagere,
3
Karnataka, India, Centre for Advanced Studies in Biosciences, Jain University, Hebbal,
Bangalore, Karnataka, India, Microbiology and Cell Biology Department, Indian
Institute of Science, Bangalore, Karnataka, India, P.G. Department of Biochemistry,
4
5
C.P.G.S., Jain University, Bangalore, India
Corresponding Author: Suresha Kumara T.H. Department of Chemistry, U.B.D.T.
College of Engineering (VTU), Davanagere, Karnataka 577004, India.
E-mail: suresha.kumara@gmail.com
Abstract
A new ABTS-radical scavenging and antiproliferative agents of pyrrolo[1,2-a]quinoline
derivatives have been synthesized. An efficient method for the synthesis of fourteen
novel diversified pyrrolo[1,2-a]quinoline derivatives has been described using 4-(1,3-
dioxolan-2-yl)quinoline and different phenacyl bromides in acetone and followed by
reacting with different acetylenes in DMF/K
2
3
CO . The structure of the newly synthesized
1
13
compounds was determined by IR, H NMR, C NMR, mass spectrometry and elemental
analysis. The in vitro antioxidant activity revealed that, among all the tested compounds
5
n has exhibited maximum scavenging activity with ABTS. The compound 5b has
showed good antiproliferative activity as good inhibitor of EGFR tyrosine kinase.
1

KEYWORDS: Pyrrolo[1,2-a]quinoline, quinoline 4-carbaldehyde, 1,3-dipolar
cycloaddition, antiproliferative activity, ABTS-radical scavenging activity, molecular
docking
1
. INTRODUCTION
Reactive oxygen species (ROS) play a critical role in cardiovascular diseases,
inflammatory diseases, neurodegenerative disorders, cancer and aging [1]. Antioxidants
are compounds that detoxify ROS and prevent their damage through multimechanisms
[2]. Cancer is one of the highest impacting disease worldwide with significant morbidity
and mortality rates. A key regulator of tissue homeostasis is the apoptosis or programmed
cell death and the imbalances between cell death and proliferation which may result in
tumor formation [3]. To induce apoptosis-related signaling in cancer cells while
disrupting their proliferation were the objective of using anticancer agents [4]. The time
has come where synthesis of a newer class of anticancer agents is in very much need.
The chemistry of N-bridged heterocyclic compounds like indolizines [5], azaindolizines
[6] and benzoindolizines [7] has certainty due to their important biological and physical
applications. Among these, the pyrrolo[1,2-a]quinoline derivatives are significant due to
their potential biological activities including antitumor [8], gastric (H+/K+)–ATPase
inhibitor [9], antineoplastic [10] anti-inflammatory [11], antimalarial [12], antiasthmatic
[
13], antidiabetic [14], antibacterial [15], in vitro antifungal [16], immunosuppressive
17], HIV-1 integrase inhibitory [18], anti-breast cancer [19] and antiproliferative
[
activities [20]. Additionally, Tokuyama et al., have reported the isolation, total synthesis
2

and various biological studies of a natural alkaloid called gephyrotoxin enclosing
pyrrolo[1,2-a]quinoline skeleton [21] (Fig 1). Since, 1,3-dipolar cycloadditions were
widely used for the versatile synthesis of highly functionalized N-bridged heterocyclic
compounds including pyrroloquinolines from the readily available substrates [22] and
after going through above such several descriptions related to significant biological
activities of pyrrolo[1,2-a]quinolines, we in this, reported the 1,3-dipolar assisted
synthesis, antioxidant and antiproliferative activity and docking study of various novel
pyrrolo[1,2-a]quinoline derivatives.
In view of the biological importance of these compounds, it was planned to synthesize a
new series of its derivatives and was further evaluated for its in vitro antioxidant and
antiproliferative activity against cervical carcinoma cell line HeLa using MTT (3-[4,5-
dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) assay. In addition, the in silico
analysis was carried out with the synthesized derivatives in order to understand the mode
of interaction with SOD (superoxide dismutase) and EGFR (epidermal growth factor
receptor) tyrosine kinase using docking protocols.
2
. RESULTS AND DISCUSSION
2
.1. Chemistry
Synthesis of the targeted derivatives (5a–n) was carried out as depicted in Schemes 1
and 2. Usually, the synthesis of pyrrolo[1,2-a]quinolines by 1,3-dipolar cycloaddition of
the quinolinium N-ylides implies the preparation and separation of quinolinium salts
which in the second step by reaction with a suitable base afford the corresponding
3

quinolinium N-ylides. In presence of the suitable base and alkynes, the pyrrolo[1,2-
a]quinolines are obtained by 1,3-dipolar cycloaddition reaction. First step of the reaction
is the quaternization and isolation of 4-(1,3-dioxolan-2-yl)quinoline (2) with 2-
bromoacetophenone (3) into quinolinum bromide (4). Subsequently, the quinolinium
bromide (4) was treated with different symmetrical alkynes (ethylpropiolate, dimethyl
acetylenedicarboxylate and diethyl acetylenedicarboxylate) in the presence of activated
K
2
CO
3
as base in DMF. In this protocol, first the deprotonation of quinolinium bromides
(
4a-e) occurs by the action of the base. Subsequently, the 1,3-dipolar cycloaddition
between an intermediate N-ylide (7a-n) and symmetrical alkynes (ethyl propiolate,
dimethyl acetylenedicarboxylate and diethyl acetylenedicarboxylate) has led to
construction of pyrrolo[1,2-a]quinolines (5a-n) [23].
Our aim in this work was to develop a simple and mild procedure for the synthesis of
pyrrolo[1,2-a]quinoline derivatives from substituted quinoline. The materials for the
synthesis of pyrrolo[1,2-a]quinolines (5a-n) were 4-formyl quinoline (1), substituted 2-
bromoacephenones (3a-e) and substituted alkynes.
1
13
The structures of the new compounds (5a-n) were assigned on the basis of H NMR, C
1
NMR, mass spectra and elemental analysis. H NMR spectrum of 5a showed a triplet at
δ 1.31 (3H) and a quartet at δ 4.30 (2H) ppm corresponds to an ethyl ester group at
position C-2 and the multiplet at δ 4.13 (4H) ppm corresponds to the presence of dioxalan
1
3
2 3
ring. C NMR spectrum of 5a has showed peaks at δ 162.9 (COO-CH -CH ), 59.9 (O-
CH
2
), 14.21 (CH
3
), 64.95 (O-CH
2
), and 184.3 (CO-Ar) ppm corresponds to ethyl ester,
4

dioxalan ring and carbonyl group in the COAr respectively. IR spectrum of 5a revealed
-1
that the appearance of the characteristic band at 1632 and 1748 cm corresponds to
carbonyl group in the COAr and for ethyl ester C=O stretch respectively. Additionally,
the LC-MS has supported through a peak at 415 corresponding to the molecular weight of
the compound 5a. Finally, the elemental analysis also supported for the compound 5a.
Similarly, the remaining compounds (5b-n), Table 1 and 2 were confirmed. These
compounds were then tested for antioxidant, antiproliferative and molecular docking
studies.
2
.2. In Vitro Antioxidant Activity
ABTS [2, 2’-Azinobis-(3-Ethylbenzothiazoline-6-Sulfonic Acid)] Radical Cation
Scavenging Method: [24]
Principle
The pre-formed radical monocation of 2, 2’-azinobis-(3-ethylbenzothiazoline-6-sulfonic
acid) is generated by oxidation of ABTS 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
Soution I: ABTS (2, 2’-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (2 mM solution
isprepared using distilled water).
Solution II: Potassium persulfate (17 mM solution is prepared using distilled water).
5

0
.3 mL of solution II was added to 50 mL of solution. The reaction mixture was left to
stand atroom temperature overnight in dark before use.
Preparation of Test Solution
1
mg of each of the drug samples accurately weighedseparately and dissolved in 1 mL of
DMSO.
Method
1
mL of distilled DMSO was added to 0.2 mL of the drug samples orstandard, and 0.16
mL of ABTS solution was added to make a final volume of 1.36 mL. Absorbance was
measured spectrophotometrically, after 7 min at 734 nm. Blank was maintained without
ABTS. The radical scavenging activity (%) is calculated by the following formula.
Absorbance of control – Absorbance of sample
100
Absorbance of control
ABTS radical scavenging capacity assay is an electron transfer based assaywhich
measures the capacity of an antioxidant toreduce an oxidant, which changes color when
reduced. Thedegree of color change is correlated with the sample’s
antioxidantconcentration.
ABTS assay which is applicable for both lipophilic and hydrophilic antioxidants, showed
various radical scavenging activity between the derivatives. According to Table 3 values
ranged from 27.14 to 92.88 %, compound 5n possessed the highest ABTS radical
scavenging activity (92.88 %) followed by the 5i and 5l derivatives (89.02 % and 87.44
%) respectively, for derivative 5e, 5m, 5h, 5b, 5d, 5j, 5g, 5c, 5f (85.72, 81.43, 75.71,
6

7
2.10, 68.57, 65.77, 57.86, 48.54, 35.78 %), and 5a (32.86%), the 5k derivative showed
the lowest antioxidant capacity (27.14 %) after 7 minute.
2
.3. Antiproliferative Activity:
Cell culture:
HeLa cell line was maintained in DMEM medium (GIBCO) supplemented with 10%
(v/v) heat-inactivated fetal bovine serum (FBS) and 1% antibiotic solution (penicillin
−1
−1
◦
1
00Uml and streptomycin 100µgml ) at 37 C in a humidified atmosphere of 95%
air/5% CO
2
. The medium was changed every second day, and cells were subcultured
when confluency reach to 95% by 0.25% trypsin containing 0.02% ethylene-
◦
diaminetetraacetic acid (EDTA) in PBS for 3min at 37 C.
MTT Assay:
The MTT assay was carried out as described previously to measure cell viability [25].
Ten thousand cells in 100μL of DMEM media were seeded in the wells of a 96-well
plate. After 24 h, existing media was removed and 100 μL of various concentrations of
complexes was added and incubated for 48 h at 37°C in a CO
were supplemented with 0.05% DMSO vehicle. At the 48th hour of incubation, MTT (3-
4,5-dimethylthaizol-2-yl)-2,5-diphenyltetrazolium bromide- supplied from Sigma, 10μL
2
incubator. Control cells
(
of 5 mg/mL) was added to the plate. The contents of the plate were pipetted out carefully,
the formazan crystals formed were dissolved in 100μL of DMSO, and the absorbance
was measured at 550 nm in a micro plate reader (Tecan, infinite F200 Pro). Experiments
were performed in triplicate, and the results were expressed as mean of percentage
7

inhibition. A graph of the concentration versus percentage growth inhibition was plotted,
and the concentration at which 50% cell death occurred was considered as the IC50
value. Before adding MTT, bright field images (Olympus 1X81, cell Sens Dimension
software) were taken for visualizing the cell death.
The values obtained demonstrated that all the compounds presented cytotoxic effects in a
dose dependent manner. The set of compounds showed excellent inhibitory activity. The
results of which are shown in Fig. 2. Microscopy images representing the cell death
caused by the compounds are as seen in Fig 3. HeLa cells have been reported to contain
human papilloma virus 18 (HPV-18) sequences, a low expression of p53 and normal
expression of pRB (retinoblastoma suppressor) [26]. But the epidermal growth factor
receptor is the first identified member of the type I receptor tyrosine kinase family and is
a major regulator of several distinct, diverse cellular pathways. Selective compounds
have been developed that target either the extracellular ligand-binding region of the
EGFR or the intracellular tyrosine kinase region. This results in interference with the
signalling pathways that modulate mitogenic and other cancer-promoting responses like
cell motility, cell adhesion, invasion, angiogenesis etc [27]. It is important to correlate the
structure of these compounds with their biological effect, which will be valuable to
propose new lead compounds with better cytotoxic potential.
2
.4. Molecular Docking Studies
The three dimensional structure of target protein superoxide dismutase (SOD)and EGFR
tyrosine kinase having keyword 1CB4 and 2J5F was downloaded from PDB
8

(www.rcsb.org/pdb) structural database. This file was then opened in SPDB viewer
edited by removing the heteroatoms, adding C terminal oxygen. The active pockets on
target protein molecule were found out using CASTp server [28]. The ligands were
drawn using ChemDraw Ultra 6.0 and assigned with proper 2D orientation (ChemOffice
package). 3D coordinates were prepared using PRODRG server [29] (Ghose and
Crippen, 1987). Autodock V3.0 was used to perform Automated Molecular Docking in
AMD Athlon (TM)2x2 215 at 2.70 GHz, with 1.75 GB of RAM. AutoDock 3.0 was
compiled and run under Microsoft Windows XP service pack 3. For docking, grid map is
required in AutoDock, the size of the grid box was set at 82, 82 and 100 Å (R, G, and B),
and grid center 16.191, 70.024, 15.326 for x, y, and z-coordinates for SOD while 102,
1
26 and 118 Å (R, G, and B), and grid center -58.865, -8.115, -24.556 for x, y, and z-
coordinates for EGFR tyrosine kinase. All torsions were allowed to rotate during
docking. The Lamarckian genetic algorithm and the pseudo-Solis and Wets methods were
applied for minimization, using default parameters [30]. The newly synthesized
compounds were taken as ligands and docked against target molecules.
To identify potential antioxidant lead among compounds 5a-n, docking calculations were
performed using Autodock v3. After docking the synthesized molecule with Superoxide
dismutase, the compounds bound exactly at the active site of Superoxide dismutase,
which was shown in Fig.4. A careful inspection of the binding pocket indicated that the
active site of SOD was similar in all synthesized compounds at the Cu-Zn domain of
SOD (Fig.5). Target information and docking details for the compounds were tabulated
in Table 4, which may provide useful information for in- depth understanding in binding
9

mechanism of the compound to the active site of the protein. Hydrogen bond formation
also makes important contributions to the interaction between ligand and the receptor. All
the fourteen molecules showed good binding energy and docking energy ranging from -
-1
-1
-1
-1
6
.27 kJmol to -10.28 kJmol and -8.87 kJmol to
-13.61 kJmol respectively.
Among the fourteen molecules, docking of SOD with compound 5i followed by
compound 5n revealed three hydrogen bonds and its binding energy and docking energy
-
1
-1
were -10.28, -9.88 kJmol and -13.61, -11.18, kJmol respectively, and these two
compounds may be considered as the lead molecules to increase the activity of
Superoxide dismutase and reduce oxidative stress. In in vitro studies also compound 5n
has emerged as an active molecule. Hence, from the study it has been proved that
molecule 5n to be one of the potent antioxidant molecules.
Based on the antiproliferative activity results, it was thought worthwhile to perform
docking studies for supportive coordination between in silico studies with the in vitro
results. The fourteen derivatives docked with EGFR tyrosine kinase domain revealed
that, our synthesized derivatives are having inhibitory potential and exhibiting
interactions with one or the other amino acids in the active pockets as shown in Fig. 6.
The docking results of synthesized derivatives are documented in Table 5. Derivatives
-
1
5
b, 5h and 5n showed -6.16, -5.93 and -6.11 kJmol binding energy with 3 hydrogen
-1
bonds respectively. Whereas derivative 5l showed -5.61 kJmol binding energy with two
hydrogen bonds with the target receptor, this indicates that among the nine derivatives 5l
is less efficient derivative. From the study it is evident that derivative 5b is more efficient
molecule for antiproliferative activity and good inhibitor of EGFR tyrosine kinase.
1
0

3
. EXPERIMENTAL SECTION
Chemicals were purchased from SD-fine, Sigma-Aldrich companies and were used
without further purification. All products were characterized by comparison of their IR,
1
13
HNMR and CNMR spectra. All yields refer to the isolated products. The purity
determination of the substrates, products and reaction monitoring were accomplished by
TLC on silica gel polygram SIL/UV 254 plates. IR spectra were recorded on an infrared
1
13
Fourier Transform spectrometer. H-NMR (400 MHz) and C-NMR (100 MHz) were
recorded on a BrukerAvance 400 instrument using TMS as an internal standard and
3 6
CDCl or DMSO-d as solvent. Melting points were recorded in open capillary tubes. LC-
MS analysis was performed on Agilent LC-1200 series coupled with 6140 single quad
mass spectrometer with ESI +ve and –ve mode, MS range 100-2000. Elemental analyses
were recorded using Perkin Elmer CHNS analyzer.
Experimental Procedure For The Synthesis Of Ethyl 1-(4-Chlorobenzoyl)-5-(1,3-
Dioxolan-2-Yl)Pyrrolo[1,2-A]Quinoline-2-Carboxylate (5d)
To a stirred solution of 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(1,3-dioxolan-2-
yl)quinoliniumbromide (4b) (100mg, 0.230mmol) in dry DMF, ethyl propiolate (0.03mL,
0
2 3
.230mmol) and K CO were added. Stirring was continued for 2h at room temperature.
Completion of reaction was monitored by TLC. The reaction mass was quenched by ice
cold water. Solids were separated out, filtered and dried under vacuum to afford (94mg,
0
.204mmol) of pale yellow solid of titled compound 5d. Similarly, other compounds of
the series 5a-n were prepared.
1
1

Ethyl 1-(4-Chlorobenzoyl)-5-(1,3-Dioxolan-2-Yl)Pyrrolo[1,2-A]Quinoline-3-
Carboxylate (5d)
0
1
Brownish yellow solid, mp. 150-155 C; H-NMR (400 MHz, DMSO-d
6
): δ = 1.31 (t,
3
H), 4.16-4.17 (m, 4H), 4.36-4.38 (m, 2H), 6.44 (s, 1H), 7.50-7.52 (m, 5H), 8.01-8.02
1
3
(
m, 3H), 8.19 (dd, J = 1.20, 8.00 Hz, 1H), 8.60 (s, 1H)ppm ; C-NMR (100 MHz,
DMSO-d ): δ = 14.47, 60.28, 65.43, 101.00, 108.76, 115.17, 120.43, 123.04, 125.52,
25.67, 126.20, 127.98, 128.55, 128.86, 129.02, 129.42, 131.46, 133.14, 134.84, 136.68,
6
1
1
6
+
39.40, 139.49, 163.84, 183.57ppm; m/z 449 [M+H] . Anal.calcd. for C25
5
H20ClNO : C,
6.74, H, 4.48, N, 3.11; Found: C, 66.76, H, 4.45, N, 3.09.
4
. CONCLUSIONS
The research work is focused on to develop a simple and mild procedure for the synthesis
of pyrrolo[1,2-a]quinoline derivatives from substituted quinoline. The reactions
performed are eco-friendly as they are carried out at room temperature. The structures
1
13
have been confirmed by spectroscopic techniques like H-NMR, C-NMR and mass.
Based on the results of in silico studies and the in vitro activity, derivative 5n showed
radical scavenging activity and 5b has been proved to be one of the potent
antiproliferative agents. Hence, 5n and 5b can be used as efficient antioxidant and
antiproliferative products.
SUPPLEMENTAL MATERIAL
1
13
Full experimental details, H and C NMR spectra, and LCMS spectra for this article can
be accessed on the publisher’s website.
1
2

ACKNOWLEDGMENTS
We are thankful to authorities of Jain University for the support and encouragement and
thanks to NMR research center, IISc, Bangaluru, for providing NMR spectra.
REFERENCES
1
.
Kai-Wei, L.; Chiung-Hui, L.; Huang-Yao, T.; HorngHuey, K.; Bai-Luh, W. Food
Chem. 2009, 115, 558-562.
Dehghan, G.; Shafiee, A.; Ghahremani, M.; Ardestani, S.; Abdollahi, M.
Pharma. Biol. 2007, 45, 1-9.
2
.
3
1
4
.
Sheng, X.; Sun, Y.; Yin, Y.; Chen, T.; Xu, Q. J. Pharm. Pharmacol. 2008, 60,
523–1529.
Hu, W.; Lee, S.K.; Jung, M.J.; Heo, S.I.; Hur, J.H.; Wang, M.H. Bioresour.
.
Technol. 2010, 101, 9366-9372.
(a) Mahon, J.; Mehta, L. K.; Middleton, R. W.; Parrick, J.; Rami, H. K. J. Chem.
Res. 1992, 362; (b) Troll, T.; Beckel, H.; Lettner-Bohm, C. Tetrahedron. 1997, 53, 81;
c) Cheng, Y.; Ma, B.; Wudl, F. J. Mater. Chem. 1999, 9, 2183; (d) Sonnenschein, H.;
5
.
(
Hennrich, G.; Resch-Genger, U.; Schulz, B. Dyes Pigments. 2000, 46, 23; (e) Vlahovici,
A.; Andrei, M.; Druţă, I. J. Lumin. 2002, 96, 279; (f) Rotaru, A.; Druţă, I.; Oeser, T.;
Muller, T. J. Helv. Chim. Acta. 2005, 88, 1798; (g) Vasilescu, M.; Bandula, R.;
Dumitaşcu, F.; Lemmetyinen, H. J. Fluoresc. 2006, 16, 631; (h) Furdui, B.; Dinică, R.;
Demeunynck, M.; Druţă, I.; Vlahovici, A. Rev. Roum. Chim. 2007, 52, 633; (i)
Georgescu, E.; Georgescu, F.; Filip, P.; Dumitrescu, D. G.; Dumitrascu, F. Rev. Chim.
(Bucharest), 2008, 59, 883; (j) Dumitraşcu, F.; Georgescu, E.; Georgescu, F.; Filip, P.;
1
3

Miu, B. and Dumitrescu, D. G. Rev. Roum. Chim. 2008, 53, 589; (k) Georgescu, E.;
Georgescu, F.; Draghici, C.; Filip, P.; Dumitrascu, F. Rev. Chim. (Bucharest), 2008, 59,
2
69; (l) Georgescu, E.; Georgescu, F.; Filip, P.; Popa, M. M.; Dumitrascu, F. Rev. Chim.
Bucharest), 2008, 59, 1224.
(a) Vasilescu, M.; Bandula, R.; Cramariuc, O.; Hukka, T.; Lemmetyinen, H.;
(
6
.
Rantala, T. T.; Dumitraşcu, F. J. Photoch. Photobiol. Chemistry A. 2008, 194, 308; (b)
Mitsumori, T.; Craig, I. M.; Martini, I. B.; Schwartz, B. J.; Wudl, F. Macromolecules.
2
005, 38, 4698; (c) Mitsumori, T.; Bendikov, M.; Sedó, J.; Wudl, F. Chem. Mater. 2003,
5, 3759; (d) Dumitraşcu, F.; Dumitrescu, D. G. ARKIVOC. 2008, 232-270; (e)
1
Dumitrascu, F.; Drăghici, C.; Miu, B.; Căproiu, M. T.; Barbu, L.; Dumitrescu, D. G. Rev.
Roum. Chim. 2008, 53, 261; (f) Dumitrascu, F.; Drăghici, C.; Miu, B.; Dumitrescu, D. G.;
Popa, M. M. Rev. Roum. Chim. 2008, 53, 509; (g) Caproiu, M. T.; Dumitrascu, F.; Caira,
M. R. Rev. Chim. (Bucharest), 2008, 59, 1242; (h) Dumitrascu, F.; Caira, M. R.;
Drăghici, B.; Căproiu, M. T.; Dumitrescu, D. G. Synlett. 2008, 813; (i) Dumitrascu, F.;
Caira, M. R.; Drăghici, C.; Căproiu, M. T.; Miu, B.; Barbu, L. ARKIVOC. 2008, (xii),
5
7
8
1.
.
El-Sayed I. I.; El-Sayed, H. E.-A. Adv. Heterocycl. Chem. 2003, 84, 83.
Marquez, V.E.; Cranston, J.W.; Ruddon, R.W.; Kier, L.B.; Burckhalter, J.H. J.
.
Med. Chem.1972, 15, 36-39.
9
4
1
8
.
Kang, S.K.; Park, S.S.; Kim, S.S.; Choi, J-K.; Yum, E.K. Tetrahedron Lett. 1999,
0, 4379-4382.
0.
Ferlin, M.G.; Gatto, B.; Chiarelotto, G.; Palumbo, M. Bioorg. Med. Chem. 2000,
, 1415-1422.
1
4

1
1
1.
2.
Testa, M.L.; Lamartina, L.; Mingoia, F. Tetrahedron. 2004, 60, 5873-5880.
Doube, D.; Blouin, M.; Brideau, C.; Chan, C.; Desmarais, D.; Ethier, J. P.;
Falgueyret, R. W.; Friesen, M.; Girard, Y.; Girard, J.; Guay, P.; Tagari, R.N. Bioorg.
Med. Chem. Lett. 1998, 8, 1255-1260.
1
1
1
3.
0, 1831-1834.
4. Kidwai, M.; Bhushan, K.R.; Sapra, P.; Saxena, R.K.; Gupta, R. Bioorg. Med.
Edmont, R.; Rocher, C.; Plisson, J.; Chenault, R. Bioorg. Med. Chem. Lett. 2000,
Chem. 2000, 8, 69-72.
5. Malendez Gomez, C.M.; Kouznestsov, V.V.; Sortino, M.A.; Alvarez, S.L.;
Zacchino, S.A. Bioorg. Med. Chem. 2008, 16, 7908-7920.
1
1
1
1
6.
7.
8.
Dillard, R.D.; Pavey, D.E.; Benslay, D.N. J. Med. Chem. 1973, 16, 251-253.
Narsinh, D.; Anamik, S. Ind. J. Pharm. Sci. 2001, 63, 211-213.
Batt, D.G.; Petraitis, J.J.; Sherk, S.R.; Copeland, R.A.; Dowling, R.L.; Taylor,
T.L.; Jones, E.A.; Magolda, R.L.; Jafee, B.D. Bioorg. Med. Chem. Lett. 1998, 8, 1745-
1
1
750.
9.
Sechi, M.; Rizzi, G.; Bacchi, A.; Carcelli, M.; Rogolino, D.; Pala, N.; Sanchez,
T.W.; Taheri, L.; Dayam, R.; Neamati, N. Bioorg. Med. Chem. 2009, 17, 2925-2935.
0. Shi, A.; Nguyen, T.A.; Battina, S.K.; Rana, S.; Takemoto, D.J.; Chiang, P.K.;
Hua, D.H. Bioorg. Med. Chem. Lett. 2008, 18, 3364-3368.
1. (a) Tokuyama, T.; Uenoyama, K.; Brown, G.; Daly, J. W.; Witkop, B. Helv.
Chim. Acta. 1974, 57, 2597; (b) Fujimoto, R.; Kishi, Y. J. Am. Chem. Soc.1980, 102,
156; (c) Pearson, W. H.; Fang, W. J. Org. Chem. 2000, 65, 7158; (d) Wei, L.-L.;
Hsung, R. P.; Sklenicka, H. M.; Gerasyuto, A. I. Angew. Chem. Int. Ed. 2001, 40, 1516;
2
2
7
1
5

(e) Santarem, M.; Vanucci-Bacqué, C.; Lhommet, G. J. Org. Chem. 2008, 73, 6466–
6
2
469.
2.
Cameron, R.; Smith. Eric, M.; Bunnelle. Allison, J.; Rhodes.; Richmond
Sarpong.; Org. Lett. 2007, 9, 1169-1171.
3. Mino R. Caira.; Georgescu, E.; Georgescu, F.; Marcel M. Popa.; Dumitraşcu, F.
ARKIVOC. 2009, (xii) 242-253
2
2
1
2
2
2
1
2
2
3
2
3
4.
Sithisarn, P.; Supabhol, R.; Gritsanapan, W. J. Ethnopharmacol. 2005, 99, 109-
12.
5.
Wajapeyee, N.; Britto, R.; Ravishankar, H. M.; Somasundaram, K. J. Biol. Chem.
006, 281, 16207−16219.
6.
Scheffner, M.; Munger, K.; Byrne, J. C.; Howley, P. M. P Natl. Acad. Sci. USA,
991, 88, 5523-5527.
7.
Raymond, E.; Faivre, S.; Armand, J.P. Drugs.2000, 60, 15-23
8.
Binkowski, T.A.; Naghibzadeg, S.; Liang, J. Nucleic Acid Res. 2003, 31, 3352–
355.
9.
Ghose, A.K.; Crippen, G.M. J. Chem Inf Comput Sci. 1987, 27, 21–35.
0.
Morris, G. M.; Goodsell, D. S; Halliday, R.S.; Huey, R.; Hart, W. E; Belew, R.
K.; Olson, A. J. J. Comput Chem. 1999, 19, 1639-1662.
1
6

Table 1: Synthesis of quinolinium bromides (4a-e)
Entry
Compound
Ar
Yield (%)
1
2
3
4
5
4a
4b
4c
4d
4e
H
96
94
93
94
92
4-Cl
4-Br
4-F
4-CH
3
1
7

Table. 2. Pyrrolo[1,2-a]quinoline derivatives (5a–n)
o
Compound
R
1
R
2
Yield (%)
92
M.p ( C)
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
COOC
2
H
5
H
142-146
225-227
160-162
150-155
201-204
218-220
140-145
203-205
152-155
155-158
220-223
165-169
148-151
210-212
COOCH
3
COOCH
3
93
COOC
COOC
2
2
H
H
5
5
COOC
H
2
H
5
5
5
5
90
91
COOCH
3
COOCH
3
92
COOC
COOC
2
2
H
H
5
5
COOC
H
2
H
93
g
h
i
89
COOCH
3
COOCH
3
90
COOC
COOC
2
2
H
H
5
5
COOC
H
2
H
91
j
90
k
l
COOCH
3
COOCH
3
92
COOC
COOC
2
2
H
H
5
5
COOC
H
2
H
91
m
n
91
COOCH
3
COOCH
3
93
1
8

Table 3: % Antioxidant activity of compound 5a-n
Sl. No.
Compound
Antioxidant activity (%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
32.86
72.10
48.54
68.57
85.72
35.78
57.86
75.71
89.02
65.77
27.14
87.44
81.43
92.88
5g
5h
5i
1
1
1
1
1
0
1
2
3
4
5j
5k
5l
5m
5n
1
9

Table 4: Molecular docking results with Superoxide dismutase
Molecules
Binding
energy
-6.67
Docking
energy
-8.87
Inhibitory
constant
Intermol
energy
-8.54
H-
Bonding
bonds
3
5
a
1.29e-005
5a::DRG1:OAZ:SOD:A:ALA1:HN2
5
5
a::DRG1:OAO:SOD:B:GLY106:HN
a::DRG1:OBC:SOD:B:ILE111:O
5
b
-8.31
-7.87
-10.29
-11.33
8.17-007
-10.48
-10.67
3
3
5b::DRG1:OBG:SOD:A:VAL7:O
5
5
b::DRG1:OBB:SOD:B:VAL146:HN
b::DRG1:OAR:SOD:B:LYS9:O
5
c
1.71e-006
5c::DRG1:OBC:SOD:B:ASP11:HN
5
5
c::DRG1:OAZ:SOD:B:THR56:HN
c::DRG1:OAZ:SOD:B:THR56:HG1
5
5
d
e
-8.83
-9.01
-10.55
-11.46
3.35e-007
2.47e-007
-10.7
2
3
5d::DRG1:OAR:SOD:B:LYS9:O
d::DRG1:OAZ:SOD:B:LYS9:HZ3
5e::DRG1:OAO:SOD:A:ASN51:HD22
5
-11.19
2
0

5
5
e::DRG1:OBG:SOD:A:VAL146:HN
e::DRG1:OAO:SOD:A:LYS9:O
5
f
-7.58
-10.76
2.77e-006
-10.38
3
5f::DRG1:OBD:SOD:B:CYS144:O
5
5
f::DRG1:OAR:SOD:B:ASP11:HN
f::DRG1:OAO:SOD:B:CYS55:HN
5
5
g
h
-8.47
-8.99
-10.04
-11.11
6.16e-007
2.57e-007
-10.34
-11.17
2
3
5g::DRG1:OAR:SOD:A:ASN51:HD22
g::DRG1:OBD:SOD:A:VAL146:HN
5h::DRG1:OAR:SOD:B:ASN51:O
5
5
5
h::DRG1:OBG:SOD:B:VAL146:HN
h::DRG1:OBD:SOD:A:VAL146:HN
5
5
i
j
-10.28
-8.28
-13.61
-9.63
2.91e-008
8.57e-007
-13.08
-10.14
3
3
5i::DRG1:OAR:SOD:B:LYS9:O
5
5
i::DRG1:OBH:SOD:B:VAL146:HN
i::DRG1:OBC:SOD:A:VAL146:HN
5j::DRG1:OAO:SOD:A:VAL146:O
j::DRG1:OAR:SOD:B:ASN51:HN
5
2
1

5
j::DRG1:OBD:SOD:B:ASN51:O
5
5
k
l
-6.27
-9.65
-9.02
2.54e-005
8.42e-008
-8.45
3
3
5k::DRG1:OAZ:SOD:A:SER109:HG
5
5
k::DRG1:OBG:SOD:B:ALA1:HN1
k::DRG1:OBD:SOD:A:GLY106:O
-13.23
-12.45
5l::DRG1:OBH:SOD:B:VAL146:HN
5
5
l::DRG1:OAR:SOD:B:GLY54:HN
l::DRG1:OAR:SOD:B:ASN51:O
5
5
m
n
-9.02
-9.88
-11.18
-11.18
2.44e-007
5.72e-008
-10.89
-12.06
2
3
5m::DRG1:OAR:SOD:B:CYS144:O
m::DRG1:OBD:SOD:A:VAL146:HN
5n::DRG1:OBG:SOD:B:VAL146:HN
5
5
5
n::DRG1:OBC:SOD:A:VAL146:HN
n::DRG1:OAR:SOD:A:ASN51:HD22
2
2

Table 5: The docking results of synthesized molecules with EGFR tyrosine kinase
Molecule
Binding
energy
-6.55
Docking
energy
-8.67
Inhibitory
constant
Intermol
energy
-9.35
H-
Bonding
bonds
2
5
5
a
1.59e-005
5a::DRG:O:TK:A:LEU703:HN
5
a::DRG:OBF:TK:A:ARG776:HE
b
-6.16
-8.72
3.05e-005
-8.34
3
5b::DRG:OAZ:TK:A:ASP837:OD2
5
5
b::DRG:OAY:TK:A:LYS745:HZ1
b::DRG:O:TK:A:ARG841:HH11
5
5
5
5
c
-7.47
-7.66
-5.96
-5.93
-9.76
-9.51
-8.86
-8.57
3.33e-006
2.41e-006
4.31e-005
4.48e-005
-9.65
-9.53
-8.76
-8.11
2
2
2
3
5c::DRG:OBC:TK:A:ASP855:OD2
c::DRG:OBF:TK:A:MET793:HN
5d::DRG:OBC:TK:A:ARG841:HE
d::DRG:OAO:TK:A:LYS879:HZ3
5e::DRG:OAQ:TK:A:LEU703:HN
e::DRG:OBH:TK:A:ARG776:HH22
5h::DRG:OAR:TK:A:ASP770:OD2
5
d
e
5
5
h
2
3

5
5
h::DRG:OBD:TK:A:ASP770:OD1
h::DRG:OBC:TK:A:ARG776:HH12
5
5
5
i
-5.89
-5.61
-6.11
-8.73
-9.29
-8.55
4.82e-005
7.72e-005
3.32e-005
-8.69
-8.41
-8.29
2
2
3
5i::DRG:OAR:TK:A:ASP770:O
i::DRG:OAR:TK:A:ASN771:HD21
5l::DRG:OBH:TK:A:ARG836:HH11
l::DRG:OBH:TK:A:ARG836:HH21
5n::DRG:OBC:TK:A:ARG803:HH21
5
l
5
n
5
5
n::DRG:OBH:TK:A:ARG841:HE
n::DRG:OAO:TK:A:LYS879:HZ3
2
4

Scheme 1: Synthesis of pyrrolo[1,2-a]quinoline derivatives (5a-n)
2
5

Scheme 2: Proposed mechanism for synthesis of substituted pyrrolo[1,2-a]quinoline
derivatives
2
6

Figure 1. A few examples of pyrrolo[1,2-a]quinoline-containing natural products and
pharmaceuticals
2
7

Figure 2. Percentage inhibition of cell growth at different concentrations of compounds
a; 5b; 5c; 5d, 5e, 5h, 5i, 5l, 5n. Data are Mean±SE (n=3).
5
2
8

Figure 3: Anticancer activity of compounds showing cell death, A-control; B-treated.
2
9