New 2-phenylquinoline derivatives: Synthesis and preliminary evaluation as antimicrobial agents

Article abstract of DOI:10.2174/157017812801264647

A number of new 2-phenylquinoline derivatives have been synthesized. All the synthesized compounds were evaluated for their antibacterial activity. Most of them showed a good activity against Escherichia coli and Staphylococcus aureus. The minimum inhibit

Full text of DOI:10.2174/157017812801264647

Letters in Organic Chemistry, 2012, 9, 309-313
309
New 2-Phenylquinoline Derivatives: Synthesis and Preliminary Evaluation
as Antimicrobial Agents
Saida Benzerkaa, Abdelmalek Bouraioua, Sofiane Bouacidab, Thierry Roisnelc, Chafia Bentchoualad,
Farida Smatid and Ali Belfaitah*,a
aLaboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique, Université Mentouri-Constantine,
25000, Algérie
bUnité de Recherche de Chimie de l’Environnement et Moléculaire Structurale, Université Mentouri-Constantine,
25000, Algérie
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 de Constantine, Constantine 25000,
Algérie
Received September 08, 2011: Revised March 11, 2012: Accepted March 26, 2012
Abstract: A number of new 2-phenylquinoline derivatives have been synthesized. All the synthesized compounds were
evaluated for their antibacterial activity. Most of them showed a good activity against Escherichia coli and
Staphylococcus aureus. The minimum inhibitory concentration (MIC) was determined for tested compounds.
Keywords: 2-Phenylquinoline, antibacterial activity, minimum inhibitory concentration, suzuki coupling.
INTRODUCTION
antihypertensive [10], tyrokinase PDGF-RTK inhibiting
agents [11], and anti HIV [12]. In addition to the medicinal
importance, multi-substituted quinolines are valuable
synthons used for the preparation of nano- and meso-
structures with enhanced electronic and photonic properties
[13].
The dramatically rising prevalence of multi-drug resistant
microbial infections in the past few decades has become a
serious health care problem. In particular, the emergence of
multi-drug resistant strains of Gram-positive bacteria
pathogens such as methicillin-resistant Staphylococcus
aureus and Staphylococcus epidermis and vancomycin-
resistant Enterococcus is a problem of ever-increasing
significance [1-5]. One way to counterbalance this challenge
is the controlled use of the currently marketed antibiotics;
the other is the development of novel antimicrobial agents.
Consequently, the search for new antimicrobial agents will
always remain an important and challenging task for
medicinal chemists.
It has been well-established that presence of aryl ring at
second position of quinoline moiety gives a very good
antibacterial property to the target molecule and plays a
significant role in development of new antibacterials [14].
These derivatives were found to be useful biological targets,
and at present they attained much attention in the
development of new drugs [15]. In addition, they are ideally
suited for further modifications to obtain more efficacious
antibacterial and antituberculosis agents.
At present, the role of heterocyclic compounds has
become increasingly important in designing new class of
structural entities of medicinal importance. Among
pharmacologically important heterocyclic compounds,
quinoline derivatives are significant compounds in medicinal
chemistry.
In the course of our ongoing program related to the use of
substituted 2-chloro-3-formylquinolines 1as precursors of
different quinoline-containing heterocycles with diverse
functionalities [16], we wish to report herein our preliminary
results concerning the synthesis of new 2-phenylquinolines
and their evaluation as antibacterial agents.
Quinoline moiety is of great importance to chemists as
well as biologists as it is found in a large variety of naturally
occurring compounds and also chemically useful molecules
having diverse biological activities. A large variety of
quinoline derivatives have been used as antimalarial [6],
anti-inflammatory [7], anticancer [8], antibiotic [9],
First of all, as an initial attempts, three different series of
compounds carrying an amine (series A: 4a-e), amide (series
B: 7a-d) or ester group (series C: 8a-d) linked to the 2-
phenylquinoline nucleus were synthesized and investigated
for their antimicrobial activity. The synthetic pathways
adopted for the preparation of the new compounds (series A,
B and C) are outlined in schemes 1–3.
*Address correspondence to this author at the Laboratoire des Produits
Naturels d’Origine Végétale et de Synthèse Organique, Université
Mentouri-Constantine, 25000, Algérie; Tel/Fax: 0021331818862;
E-mail: abelbelfaitah@yahoo.fr
The key intermediates 6-methyl-2-phenylquinoline-3-
carbaldehyde 2 and 2-chloro-6-methylquinoline-3-carboxylic
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

310 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
Benzerka et al.
CHO
a
N
CHO
Cl
2
N
CO2H
Cl
1
b
N
3
Scheme 1. Reagents and conditions: (a) Pd(PPh3)4, PhB(OH)2, Na2CO3 (2M), DME, reflux, 4h; (b) CrO3 aq., H2SO4, acetone, 0°C to rt, 3h.
acid 3, required for the preparation of the target compounds
was obtained from the 2-chloro-3-formylquinoline 1 (scheme
1). The carboxylic acid derivative 3 was prepared by reacting
the parent compound 1 with Jones reagent in acetone at 5–
10°C. Thus Suzuki coupling of the 2-chloroquinoline-3-
carbaldehyde with phenylboronic acid gave the
corresponding 2-phenylquinoline derivative 2.
may have a considerable impact on the pharmacological
activities [21]. In this context, a new series of compounds
were prepared incorporating a nitro group on the quinoline
unit. The nitration at C-5 of amides 5a and 5b, followed by
Suzuki coupling and reduction reaction of the resulting 5-
nitroquinoline 10a and 10b with PMHS in presence of
Pd(OAc)2 gave the corresponding amino derivatives 11a and
11b respectively (Scheme 4).
The 2-phenylquinoline derivatives substituted on their C-
3 with an amino group (Series A: 4a-e; Table 1) were first
prepared by conversion of 6-methyl-2-phenylquinolin-3-
carbaldehyde 2 in the presence of appropriate amine in
MeOH into corresponding imine, followed by reduction by
using NaBH4 in methanol.
O
CO2H
a or b
Y
N
Cl
N
X
CHO
R
5a-d (Y=NHR, X=Cl)
6a-d (Y=OR, X=Cl)
N
a, b
H
3
N
c or d
N
7a-d (Y=NHR, X=Ph)
8a-d (Y=OR, X=Ph)
2
4a-e
Scheme 3. Reagents and conditions: (a) for amides (5): ethyl
chloroformate, Et3N, RNH2, CHCl3, 5-10°C; (b) for esters (6): (i)
SOCl2, reflux, overnight; (ii): ROH, Toluene, 0°C to reflux, 24h;
(c) for amides (7): Pd(PPh3)4, PhB(OH)2, Na2CO3 (2M), DME,
reflux, 4h; (d) for esters (8): Pd(OAc)2, PhB(OH)2, K2CO3 (2M),
PPh3, DME, reflux, 2h.
Scheme 2. Reagents and conditions: (a) RNH2, MeOH, 24h; (b)
NaBH4, MeOH, rt, 3h.
The carboxamide derivatives (Series B: 5a-d; Table 1)
were prepared by stirring 2-chloroquinolin-3-carboxylic acid
3 with ethyl chloroformate in the presence of triethylamine
in chloroform at 5–10°C, followed by addition of the
appropriate amine [17]. On the other hand, heating 3 with
thionyl chloride gave the 2-chloro-6-methylquinolin-3-
carbonyl chloride derivative which was pure enough (TLC)
for use in subsequent steps. The acyl chloride was stirred at
reflux with alcohol in toluene to give the corresponding 2-
chloro-6-methylquinolin-3-carboxylate (Series C: 6a-d;
Table 1) [18]. The palladium-catalysed cross coupling
between phenylboronic acid and halides 5 and 6 gave the
corresponding 2-phenylquinoline derivatives 7a–d and 8a-d
respectively (Scheme 3).
The X-ray crystallographic analysis of single crystals of
7b and 8c confirmed their respective structural assignments
(Fig. 1, 2).
Fig. (1). ORTEP plot of the X-ray crystal structure of 7b.
Displacement ellipsoids are drawn at the 50% probability level
[19].
Numerous studies have demonstrated that the nature of
substituents and substitution pattern on the quinoline unit

New 2-Phenylquinoline Derivatives
Letters in Organic Chemistry, 2012, Vol. 9, No. 5
311
Most of the compounds tested were found to have good
antibacterial activities against Staphylococcus aureus and
Escherichia coli, however, in most case, no or moderate
activities were observed against Pseudomonas aeruginosa.
The compounds of the library C (8a-d) don’t show any
inhibitory activity against Pseudomonas aeruginosa and
Escherichia coli but have significant inhibition effect on the
growth of bacteria like Staphylococcus aureus, Salmonella
typhimurium and Klebsiella pneumoniae. The best results
were observed with amidoquinolines (series B) which were
showed the broadest antibacterial activity.
The data (Table 1) indicate that the introduction of the
nitro (compounds 10a-b) or amine group (compounds 11a-
b) on the quinoline ring affect the antimicrobial activity.
Comparison of biological activities of 10 and 11 with the
corresponding no substituted ones 7a-b show that these
substitutions reduce the antibacterial activity.
Fig. (2). ORTEP plot of the X-ray crystal structure of 8c.
Displacement ellipsoids are drawn at the 50% probability level
[20].
To confirm the antibacterial activities of the synthesized
compounds, the MICs tests were carried out. Bacterial
inoculums were prepared by dilution of an overnight broth
culture to give the equivalent of 106 cell/mL approximately.
The MICs values (µg/mL) of each compound after 1 day of
exposure are shown in Table 1.
Compounds of series (4, 7, 8, 10, 11) has been tested for
their antimicrobial activity against Escherichia coli (ATTC-
25922), Staphylococcus aureus (ATTC-25923), Pseudomo-
nas aeruginosa (ATCC-27853), Klebsiella pneumoniae
(ATCC-700603) and Salmonella thipymurium (ATCC-
07095) using the disk-diffusion method [22].
In conclusion, new series of 2-phenylquinoline with
diverse functionalities were synthesized using an appropriate
synthetic routes. All the target compounds were evaluated
for their in vitro antimicrobial activity against Escherichia
coli, Staphylococcus aureus, Pseudomonas aeruginosa,
Klebsiella pneumoniae and Salmonella typhimurium. These
prepared quinoline derivatives have shown moderate to
significant antibacterial activities. The minimum inhibitory
concentration (MIC) was determined for the tested
compounds.
The disk-diffusion method was performed as follows: the
bacterial suspension was spread on the surface of a Mueller-
Hinton agar. Paper disks (6mm) were charged with 50µg of
the tested compounds (4a-11b) and were placed on the agar
surface. Two standard drugs were used for comparison
(Gentamicin and Chloramphenicol). After overnight
incubation at 37°C, inhibition zones were measured with a
ruler and the zones were recorded in millimeter. The results
of the antibacterial screening of the tested compounds are
summarized in Table 1.
NO2
O
NO2
O
R
R
N
N
a
H
H
5a-b
b
N
N
Cl
9a-b
10a-b
c
NH2
O
R
N
H
N
11a-b
Scheme 4. Reagents and conditions: (a) H2SO4, HNO3, 5-10°C to rt 1h; (b) Pd(PPh3)4, PhB(OH)2, Na2CO3 (2M), DME, reflux, 4h; (c)
Pd(OAC)2, PMHS, KF, H2O, THF, rt, 3h.

312 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
Benzerka et al.
Table 1. In Vitro Antibacterial Activity of Compounds 4, 7, 8, 10, 11
Yielda
(%)
Compounds
R
MIC(µg/ml) (zones of inhibition in mm)
Escherichia
coli
Staphylococcus
Pseudomonas
Aeruginosa
Klebsiella
pneumoniae
Salmonella
Typhimurium
aureus
4a
Isopropyl
Pentyl
79
84
73
61
70
83
84
75
79
78
76
86
68
75
84
80
85
200 (8)
>200 (8)
50 (32)
>200 (17)
50 (16)
>200 (10)
No inhibition
200 (08)
>200 (8)
>200 (08)
200 (13)
No inhibition
No inhibition
>200 (10)
4b
4c
Cyclohexyl
Benzyl
100 (13)
4d
No inhibition
100 (16)
>200 (12)
100 (15)
100 (22)
200 (18)
50 (18)
No inhibition
>200 (10)
No inhibition
>200 (10)
No inhibition
>200 (08)
No inhibition
200 (08)
No inhibition
>200 (12)
4e
Tolyl
7a
Butyl
>200 (12)
100 (10)
No inhibition
No inhibition
>200 (12)
No inhibition
No inhibition
100 (18)
7b
Isopropyl
Benzyl
7c
100 (14)
7d
Pentyl
200 (08)
200 (14)
200 (13)
100 (10)
200 (16)
100 (13)
200 (16)
200 (16)
100 (14)
100 (13)
< 4 (21)
< 8 (18)
200 (08)
200 (No inhibition)
>200 (15)
8a
Ethyl
No inhibition
No inhibition
No inhibition
No inhibition
200 (08)
No inhibition
No inhibition
No inhibition
No inhibition
No inhibition
No inhibition
No inhibition
>200 (08)
>200 (12)
>200 (08)
>200 (08)
100 (12)
8b
Hexyl
200 (No inhibition)
>200 (10)
8c
Cyclohexyl
Cyclopentyl
Butyl
8d
>200 (08)
10a
10b
No inhibition
No inhibition
No inhibition
>200 (10)
< 4 (15)
No inhibition
No inhibition
No inhibition
No inhibition
< 4 (20)
Isopropyl
Butyl
200 (08)
11a
200 (10)
11b
Isopropyl
>200 (10)
< 4 (25)
Gentamicin
Chloramphenicol
< 4 (25)
< 8 (30)
ND
< 8 (20)
< 8 (25)
a: Yield of isolated product.
ND: Not determined.
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CONFLICT OF INTEREST
Declared none.
ACKOWLEDGEMENTS
We thank MESRS (Ministère de l’Enseignement
Supérieur et de la Recherche Scientifique), and ANDRU
(Agence Nationale pour le Développement de la Recherche
Universitaire), Algeria, for the financial support.
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