Synthesis of new 3-heteroaryl-2-phenylquinolines and their pharmacological activity as antimicrobial agents

Article abstract of DOI:10.2174/1570178611310020005

Some new unfused tricyclic aromatic systems containing various heterocyclic cores were synthesized. These compounds were prepared in good yields via appropriate routes using 6-methyl-2-phenylquinoline-3-carbaldehyde as a key intermediate. The antibacterial activity of the prepared compounds was evaluated against: Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia and Salmonella thipymurium using the disk-diffusion method. The minimum inhibitory concentration (MIC) was determined for the tested compounds.

Full text of DOI:10.2174/1570178611310020005

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94
Letters in Organic Chemistry, 2013, 10, 94-99
Synthesis of New 3-heteroaryl-2-phenylquinolines and their Pharmaco-
logical Activity as Antimicrobial Agents
Saida Benzerka,a Abdelmalek Bouraiou,a Sofiane Bouacida,b Thierry Roisnel,c Chafia Bentchouala,d
Farida Smati,d Bertrand Carbonie and Ali Belfaitaha,*
aLaboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique, Université Mentouri-Constantine1,
25000, Algéria
bUnité de Recherche de Chimie de l’Environnement et Moléculaire Structurale, Université Mentouri-Constantine1,
25000, Algéria
cCentre de Diffractométrie X, UMR 6226 CNRS Unité Sciences Chimiques de Rennes, Université de Rennes I, 35042
Rennes CEDEX, France
dLaboratoire de Microbiologie, Centre Hospitalier Universitaire Dr Ben Badis, Constantine, 25000, Algéria
eUniversité de Rennes 1, Sciences Chimiques de Rennes, UMR 6226 CNRS, 35042 Rennes CEDEX, France
Received September 18, 2012: Revised January 23, 2013: Accepted February 12, 2013
Abstract: Some new unfused tricyclic aromatic systems containing various heterocyclic cores were synthesized. These
compounds were prepared in good yields via appropriate routes using 6-methyl-2-phenylquinoline-3-carbaldehyde as a
key intermediate. The antibacterial activity of the prepared compounds was evaluated against: Escherichia coli, Staphylo-
coccus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia and Salmonella thipymurium using the disk-diffusion
method. The minimum inhibitory concentration (MIC) was determined for the tested compounds.
Keywords: 2-Phenylquinoline, heterocycles, crystal structure, antimicrobial activity, minimum inhibitory concentration.
On the other hand, Denny et al. have demonstrated the
efficacy of unfused tricyclic aromatic systems such as phen-
ylquinolines and benzimidazoles as 'minimal intercalators'
that have moderate binding affinity with DNA [13]. Other
studies have showed that the presence of aryl ring at 2nd
position of quinoline moiety gives a very good pharmacol-
ogical activity to the target molecule [14]. The coupling of
heterocyles entities with 2-phenylquinoline moiety might as
well be envisioned to bring with some biological activities.
Heterocyclic compounds have so far been synthesized
mainly due to the wide range of biological activities. Much
attention has been paid to the synthesis of heterocyclic com-
pounds bearing nitrogen and oxygen containing ring system,
like pyrazole, oxazole, coumarine, and pyrrole derivatives
mainly due to their higher pharmacological activity [1]. At
present, the role of heterocyclic compounds has become in-
creasingly important in designing new class of structural
entities of medicinal importance [2].
Following of our previous works related to the use of
substituted 2-chloro-3-formylquinolines as precursors of
different quinoline-containing heterocycles [15], we have
recently reported preparations and antibacterial screening of
series of compounds carrying diverse functionalities such as
an amine, amide or ester group linked to the 2-
phenylquinoline entity [16]. We wish to report herein our
preliminary results concerning the synthesis of new 3-
heteroaryl-2-phenylquinoline hybrids. The synthetic path-
ways adopted for the preparation of 2-phenylquinoline com-
pounds linked to the heterocyclic nucleus are outlined in
schemes 1–4.
Quinoline derivatives have considerable interest since
many years due to the presence of this skeleton in a large
number of bioactive compounds and natural products [3].
Thus, a large variety of quinoline derivatives exhibit useful
biological activities like antimalarial [4], anti-inflammatory
[5], anticancer [6], antibiotic [7], antihypertensive [8], ty-
rokinase PDGF-RTK inhibiting agents [9], and anti HIV
[10]. To improve the pharmacological profile of the quino-
line moiety, a number of investigations have been carried out
which involved there coupling with some various heterocyc-
lic core [11]. The introduction of the quinoline nucleus has
already been used successfully in a number of other cases
[12].
The key intermediate 6-methyl-2-phenylquinoline-3-
carbaldehyde 2, required for the preparation of the target
compounds was obtained in two steps according to estab-
lished methods [17]: first 6-methyl-2-chloroquinolyl-3-
carbaldehyde 1 was prepared by condensation/cyclization of
the corresponding anilide with phosphoryl chloride and
DMF. Subsequent Suzuki-Miyaura reaction of 1 with phen-
*Address correspondence to this author at the Laboratoire des Produits
Naturels d’Origine Végétale et de Synthèse Organique,Université Mentouri-
Constantine1, 25000, Algéria; Tel: +(213) (0) 31 81 88 62; Fax: +(213) (0)
31 81 88 62; E-mail: abelbelfaitah@yahoo.fr
1875-6255/13 $58.00+.00
© 2013 Bentham Science Publishers

Synthesis of New 3-heteroaryl-2-phenylquinolines and their Pharmacological Activity
Me
Letters in Organic Chemistry, 2013, Vol. 10, No. 2
95
Me
CHO
Ph
Me
CHO
i
ii
O
N
N
N
Cl
H
2
1
Scheme 1. Reagents and conditions: (i) POCl3, DMF, 85°C, 18h; (ii) Pd(PPh3)4, PhB(OH)2, Na2CO3 (2M), DME, reflux, 4h.
O
O
Me
CHO
Ph
Me
Me
ii
i
78%
N
N
Ph
X
N
Ph
2
4
3a : X=NH2 84%
3b : X=Me 78%
Scheme 2. Reagents and conditions: (i) 2-methylacetophenone or 2-aminoacetophenone, NaOH, EtOH, rt; (ii) (a) MeI, Mg, Et2O; (b) PCC,
CH2Cl2, rt.
ylboronic acid affords the 6-methyl-2-phenyl-3-formylquino-
line 2 in 79% of yield (Scheme 1).
dihedral angle between the quinoline ring system and the
linked phenyl ring is 37.38 (8) and, this value is 41.05 (8)
between the quinoline entity and the second phenyl o-tolyl
ring. The crystal packing can be described by layers parallel
to (100) crystallographic plane. It is stabilized by C-H...O
and C-H...ꢂ interactions and ꢂ...ꢂ stacking interactions.
Chalcones derivatives 3a or 3b were easily prepared in
good yields by aldol condensation reaction of 6-methyl-2-
phenylquinoline-3-carbaldehyde
2
with 2-methylaceto-
phenone and 2-aminoacetophenone respectively which were
pure enough for use in subsequent steps. The reaction of 2
with methyl magnesium iodide afforded the secondary alco-
hol intermediate. Oxidation of this latter with pyridinium
chlorochromate gives the corresponding 1-(6-methyl-2-
In the title compound, 4, the quinoline ring system is ap-
proximately planar with a dihedral angle of 2.05 (5)° and
forms a dihedral angle of 65.32(6)° with the phenyl ring. The
crystal packing can be described as parallel layers to the
(010) plane. It features C-H···ꢀ interactions and strong ꢀ-ꢀ
stacking interactions. These interactions link the molecules
within the layers and also link the layers together, reinforc-
ing the cohesion of the structure.
phenylquinolin-3-yl)ethanone 4 (Scheme 2). Both 1H and 13
C
NMR spectra of compounds 3 and 4 were in full agreement
with the proposed structures.
The X-ray crystallographic analysis of single crystals of
3b and 4 confirmed their respective structural assignments
(Figs. 1, 2).
The pyrrole compound 5a was prepared by stirring chal-
cone 3b with TosMic in the presence of t-BuOK in THF at
room temperature [19]. The oxidation of 2'-aminochalcone
3a using FeCl3.6H2O in MeOH [20] gives the corresponding
4-methoxy-2-(6-methyl-2-phenylquinolin-3-yl) quinoline 5b
in good yields (Scheme 3).
The conversion of 2 into the corresponding bromide 6a
was accomplished via a reduction/ substitution sequence.
The reaction of 6a with 7-hydroxy-4-methylcoumarin in the
presence of cesium carbonate gave the quinoline 6b in 88%
of yields (Scheme 4).
Next, we expanded this work to the preparation of het-
erocycles containing two heteroatoms such as pyrazole and
oxazole coupled 2-phenylquinoline unit. The reaction of the
resulting enamine obtained from the condensation of 4 with
dimethylformamid dimethyl acetal, and hydrazine hydrate
gave 6-methyl-2-phenyl-3-(1H-pyrazol-3-yl)quinoline 7 in
good yields (65%) [21]. TosMic reacts with 6-methyl-2-
phenylquinolin-3-carbaldehyde 2 in the presence of potas-
sium carbonate in MeOH [22], giving the corresponding 6-
methyl-3-(oxazol-5-yl)-2-phenylquinoline 8a in 82% of
yields [23]. The Erlenmeyer-Plöchl azlactone synthesis [24]
of oxazolone 8b was achieved in good yield (75%) after pu-
rification by column chromatography using CH2Cl2 as
eluent, by addition of a slight excess of hippuric acid (N-
Fig. (1). ORTEP plot of the X-ray crystal structure of 3b. Dis-
placement ellipsoids are drawn at the 50% probability level [18].
Fig. (2). ORTEP plot of the X-ray crystal structure of 4. Displace-
ment ellipsoids are drawn at the 50% probability level [18].
The structure of 3b contains a quinoline unit linked to an
aryl ketone ꢀ,ꢁ-unsaturated at C3 and phenyl ring at C2. The
benzoylglycine)
to
6-methyl-2-phenylquinolin-3-
carbaldehyde 2 in presence of acetic anhydride and anhy-

96 Letters in Organic Chemistry, 2013, Vol. 10, No. 2
Benzerka et al.
O
X
Me
H
N
N
Ph
ii
i
OMe
3
72%
X=Me
Me
X=NH2
88%
Me
N
O
N
Ph
Me
N
Ph
5a
5b
Scheme 3. Reagents and conditions: (i) FeCl3.6H2O, MeOH, reflux; (ii) TosMIC, t-BuOK, THF, 0°C to rt.
Me
O
O
Me
Me
Me
O
O
H
Br
ii
i
N
Ph
N
Ph
N
Ph
2
6a
6b
Scheme 4. Reagents and conditions: (i) (a) NaBH4, MeOH, rt; (b) PBr3, CH2Cl2, rt; (ii) 7-hydroxy-4-methyl-2H-chromen-2-one, Cs2CO3,
acetone, rt.
N
O
NH
Me
Me
Me
O
N
ii
R
O
i
R=H
N
Ph
R=Me
N
Ph
N
Ph
7
8a
R=H
iii
N
Me
O
N
Ph
Ph
8b
Scheme 5. Reagents and conditions: (i) (a) Me2NCH(OMe)2, reflux; (b) H2NNH2.H2O, EtOH, reflux; (ii) TosMic, K2CO3, MeOH, reflux;
(iii) hippuric acid, AcONa, Ac2O, MW.
drous sodium acetate under microwave irradiation (Scheme
5).
In structure of 8a, quinoline ring form a dihedral angle of
37.44(4)° and 52.80(7)° with phenyl ring and heterocyclic
ring respectively. The crystal packing can be described as
parallel layers to the (013) plane. Intermolecular interactions
of C-H...ꢀ and ꢀ-ꢀ stacking connect the molecules together
reinforcing the cohesion between the layers of the structure.
Single crystals of 8a were grown by evaporation of a
CH2Cl2 solution and an X-ray crystallographic analysis con-
firmed the structural assignment (Fig. 3).
Numerous studies have demonstrated that the nature of
substituents and substitution pattern on the quinoline unit
may have a considerable impact on the pharmacological ac-
tivities [25]. In this context, the prepared tricyclic aromatic
systems containing various heterocyclic cores were evalu-
ated for their antibacterial activities.
Almost prepared compounds were submitted for prelimi-
nary evaluation of their in vitro activity against Escherichia
coli (ATTC-25922), Staphylococcus aureus (ATTC-25923),
Pseudomonas aeruginosa (ATCC-27853), Klebsiella pneu-
Fig. (3). ORTEP plot of the X-ray crystal structure of 8a. Dis-
placement ellipsoids are drawn at the 50% probability level [18].

Synthesis of New 3-heteroaryl-2-phenylquinolines and their Pharmacological Activity
Letters in Organic Chemistry, 2013, Vol. 10, No. 2
97
Table 1. In vitro Antibacterial Activity and MIC of Compounds
Yielda
MIC(μg/ml)
Compounds
(%)
(Zones of Inhibition in mm)*
Escherichia
coli
Staphylococcus
aureus
Pseudomonas
aeruginosa
Klebsiella
Salmonella
pneumoniae
typhimurium
5a
72
88
88
65
82
75
100 (08)
<25 (16)
50 (16)
50 (14)
50 (10)
<25 (15)
< 4 (25)
< 8 (30)
50 (12)
<25 (32)
<25 (20)
<25 (18)
50 (15)
No inhibition
100 (12)
200 (08)
100 (10)
>200 (08)
200 (10)
< 4 (25)
ND
>200 (10)
200 (ND)
100 (08)
100 (10)
>200 (10)
200 (ND)
< 4 (15)
>200 (08)
No inhibition
>200 (08)
5b
6b
7
No inhibition
No inhibition
No inhibition
< 4 (20)
8a
8b
50 (17)
Gentamicin
Chloramphenicol
< 4 (21)
< 8 (18)
< 8 (20)
< 8 (25)
*Charge of disk 50μg.
a Isolated pure product
ND : Not determined
moniae (ATCC-700603) and Salmonella typhimurium
(ATCC-07095) E using the disk-diffusion method [26]. Pa-
per disks (6mm) were charged with 50μg of tested com-
pounds (5a-8b). To confirm the antibacterial activities of
synthesized compounds, the MICs tests were carried out.
Bacterial inoculums were prepared by dilution of an over-
night broth culture to give the equivalent of 106 cell/mL ap-
proximately. The MICs values (μg/mL) of each compound
after 1 day of exposure are shown in Table 1. Gentamicin
and Chloramphenicol were chosen as standard drugs. The
results of the antibacterial screening of the tested compounds
are summarized in Table 1.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flicts of interest.
ACKOWLEDGEMENTS
We thank MESRS (Ministère de l’Enseignement Supé-
rieur et de la Recherche Scientifique) and ATRST (Agence
Thématique pour la Recherche en Sciences et Technologies)
Algeria, for financial support. Authors thank Dr Fabienne
Berrée, Institut des Sciences Chimiques de Rennes, UMR
6226 CNRS-Université de Rennes 1, France, for his techni-
cal assistance.
Most of the tested compounds were found active against
Staphylococcus aureus and Escherichia coli, however, in
most cases, moderate activities were observed against Pseu-
domonas aeruginosa or Klebsiella pneumoniae. The com-
pounds 5b, 7, 8a and 8b don’t show any inhibitory activity
against Salmonella typhimurium. The best results were ob-
served with compounds 5b, 6b, 8a and 8b which have shown
a significant inhibition effect (MIC< 25 μg/mL) in the
growth of Gram positive bacteria like Staphylococcus aureus
(compounds 5b, 6b and 7) and Escherichia coli as Gram
negative bacteria (5b and 8b). Compounds 5a and 6b
showed a moderate to good activity with broad antibac-
terial spectrum, and the quinoline compound 5b is the
most promising antibacterial agent.
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[11]
[18]
Crystal structure analysis for 3b: C26H21NO, Mr = 363.44 g mol-1,
mp. 198 °C, orthorhombic, space group P 21nb, a = 7.4462(2) Å, b
= 14.6709(5) Å, c = 17.7923(5) Å, V = 1943.67(10) Å3, Z= 4.
Crystal structure analysis for 4: C18H15NO, Mr = 261.31 g mol-1,
mp. 175 °C, monoclinic, space group P21/n, a = 5.9353(2) Å, b =
12.2766(7) Å, c = 19.0972(8) Å, ꢁ = 91.926(2)°, V = 1390.74(11)
Å3, Z= 4. Crystal structure analysis for 8a: C19H14N2O, Mr =
286.32 g mol-1, mp. 182 °C, orthorhombic, space group P 21nb, a =
5.656(5) Å, b = 14.110(4) Å, c = 18.390(5) Å, V = 1467.6(14) Å3,
Z=4. The structures were solved by direct methods and refined by
full-matrix least squares analysis on F2 using SHELXL. Hydrogen
atoms were refined on the riding model with isotropic thermal pa-
rameters set twenty percent greater than those of their bonding
partners. All other atoms were refined anisotropically. Crystallo-
graphic data (excluding structure factors) for compounds 3b, 4 and
8a have been deposited at the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC 861478 for
3b, CCDC 861479 for 4 and CCDC 861480 for 8a. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif./cif.
[12]

Synthesis of New 3-heteroaryl-2-phenylquinolines and their Pharmacological Activity
Letters in Organic Chemistry, 2013, Vol. 10, No. 2
99
[19]
Procedure for the synthesis of 5a: To a solution of chalcone 3b
(1mmol) and tosylmethyl isocyanide (1mmol) in distilled tetrahy-
drofuran (5mL), was added t-BuOK (2 mmol) at 0°C. The reaction
mixture was then stirred at room temperature for 2h. After removal
of the solvent the residue was poured into water and extracted with
CH2Cl2 (10 mL). The aqueous phase was further extracted with
CH2Cl2 (2x10mL). The organic phases were combined, dried
(MgSO4), filtered and the filtrate was concentrated. The crude
product was then purified by column chromatography on silica gel
using Et2O/PE as eluent. Selected data for 5a: 1H NMR (300 MHz,
CDCl3): ꢀ 9.15 (br, 1H), 7.99 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.50
(s, 1H), 7.45-7.38 (m, 2H), 7.14-7.10 (m, 5H), 7.01 (d, J=7.4 Hz,
1H), 6.93 (t, J=7.4 Hz, 1H), 6.67-6.60 (m, 2H), 6.45-6.42 (m, 1H),
2.46 (s, 3H), 1.98 (s, 3H). 13C NMR (75 MHz, CDCl3): ꢀ 192.3,
158.7, 145.6, 141.3, 140.1, 136.6, 136.1, 135.9, 131.4, 130.4,
129.9, 129.2, 2x128.8, 2x128.0, 127.9, 127.5, 127.4, 127.2, 126.1,
124.5, 2x124.3, 119.9, 117.9, 21.6, 19.4. Anal. Calcd. For
C28H22N2O: C, 83.63; H, 5.25; N, 6.72; Found: C, 83.56; H, 5.51;
N, 6.96.
Aldehydes with Tosylmethyl Isocyanide, Chem. Pharm. Bull. 1979,
27, 793-796.
[23]
Procedure for the synthesis of 8a: To a mixture of 6-methyl-2-
phenylquinoline-3-carbaldehyde 2 (1 mmol) and tosylmethyl iso-
cyanide (1 mmol) in 10 mL of MeOH was added K2CO3 (1 mmol).
The solution was refluxed for 2 h and the solvent was removed un-
der reduced pressure. The residue was poured into ice-water and
extracted with ether (20 mL). The organic layer was washed with
saturated sodium hydrogen carbonate solution (10 mL) and dried
over anhydrous MgSO4. After filtration and evaporation of the sol-
vent, the product is purified by column chromatography on silica
1
gel using Et2O/PE as eluent. Selected data for 8a: H NMR (300
MHz, CDCl3): ꢀ 8.27 (s, 1H), 7.88 (d, J= 8.6 Hz, 1H), 7.71 (s, 1H),
7.44 (s, 1H), 7.42 (dd, J=8.6, 1.7 Hz, 1H), 7.35-7.30 (m, 5H), 6.18
(s, 1H), 2.41 (s, 3H);13C NMR (75 MHz, CDCl3): ꢀ 156.2, 150.5,
149.1, 145.7, 140.5, 137.3, 133.9, 132.8, 129.1, 2x128.8, 2x128.7,
128.5, 126.7, 126.5, 125.4, 120.7, 21.6. Anal. Calcd. For
C26H18N2O2 : C, 79.70; H, 4.93; N, 9.78; Found: C, 79.55; H, 4.91;
N, 9.43.
[20]
[21]
Kumar, K. H.; Perumal, P. T. A novel one-pot oxidative cyclization
of 2ꢁ-amino and 2ꢁ-hydroxy chalcones employing FeCl3·6H2O-
methanol. Synthesis of 4-alkoxy-2-aryl-quinolines and flavones.
Tetrahedron, 2007, 63, 9531-9535.
Borioni, A.; Mustazza, C ; Sestilli, I.; Sbraccia, M.; Turchetto, L.;
Del Gludice, M. R. Synthesis of New 4-Heteroaryl-2-
Phenylquinolines and Their Pharmacological Activity as NK-
2/NK-3 Receptor Ligands. Arch. Pharm. Chem. Life Sci. 2007, 340,
17-25.
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Paul, S.; Nanda, P.; Gupta, R.; Loupy, A. Calcium acetate cata-
lyzed synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones under
solvent-free conditions. Tetrahedron Lett. 2004, 45, 425-427.
Metwally, K. A.; Abdel-Aziz, L. M.; Lashine, E. M.; Husseiny, M.
I.; Badawya, R. H. Hydrazones of 2-arylquinoline-4-carboxylic
acid hydrazides: Synthesis and preliminary evaluation as antimi-
crobial agents. Bioorg. Med. Chem. 2006, 14, 8675-8282.
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Saikachi, H.; Kitagawa, T.; Sasaki, H.; van Leusen, A. M. Synthe-
sis of Furan Derivatives. LXXXV. Condensation of Heteroaromatic