Microwave-irradiated synthesis and antimicrobial activity of 2-phenyl-7-substitutedalkyl/arylaminoquinoline-4-carboxylic acid derivatives

Article abstract of DOI:10.1007/s00044-009-9198-4

This report focuses on the synthesis of 2-phenyl-7-substitutedquinoline-4- carboxylic acid derivatives through both conventional and microwave-irradiated methods. Intermediate 7-chloro-2-phenyl-quinoline-4-carboxylic acid was synthesized by condensation a

Full text of DOI:10.1007/s00044-009-9198-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2010) 19:392–402
DOI 10.1007/s00044-009-9198-4
ORIGINAL RESEARCH
Microwave-irradiated synthesis and antimicrobial
activity of 2-phenyl-7-substitutedalkyl/
arylaminoquinoline-4-carboxylic acid derivatives
Hardik G. Bhatt Æ Yadvendra K. Agrawal
Received: 30 January 2009 / Accepted: 17 March 2009 / Published online: 29 April 2009
¨
Ó Birkhauser Boston 2009
Abstract This report focuses on the synthesis of 2-phenyl-7-substitutedquinoline-
4-carboxylic acid derivatives through both conventional and microwave-irradiated
methods. Intermediate 7-chloro-2-phenyl-quinoline-4-carboxylic acid was synthe-
sized by condensation and cyclization of benzaldehyde, pyruvic acid, and m-chlo-
roaniline in the presence of absolute ethanol and further substituted with aromatic,
aliphatic, and alicyclic amines to obtain the desired 2-phenyl-7-substitutedaryl/
alkylamino-quinoline-4-carboxylic acid derivatives under the influence of micro-
wave irradiation, with output power ranging from 160 to 480 W, yield ranging from
90% to 95%, and a shorter reaction time than with the conventional method. All the
synthesized compounds were screened for in vitro antimicrobial activity against six
gram-positive and four gram-negative organisms. All synthesized compounds are
active against a broad spectrum of microorganisms, with prominent results for
Streptococcus pyrogenes and Pseudomonas aeruginosa. Compounds 7c and 7h
showed a minimum inhibitory concentration of less than 10 lg.
Keywords Doebner reaction Á In vitro antimicrobial activity Á MIC Á
Microwave irradiation Á Quinoline-4-carboxylic acid
Introduction
In past few years, the use of microwave irradiation for both the organic reaction and
synthesis of pharmaceutical compounds is rapidly increasing due to the short duration
of reaction and high yield with purity (Mitra et al., 1999). Use of the domestic
microwave oven is now a well-established procedure for microwave-induced organic
H. G. Bhatt (&) Á Y. K. Agrawal
Institute of Pharmacy, Nirma University of Science and Technology,
S. G. Highway, Chharodi, Ahmedabad 382 481, India
e-mail: hardikbhatt23@hotmail.com

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393
reaction enhancement (MORE) chemistry (Bose et al., 1990, 1991). The lack of a
wide spectrum of biologic data is an important obstacle preventing efficient molecular
design.
Quinoline derivatives are known to exhibit a variety of biologic effects (Musiol
et al., 2007). A novel and highly convergent synthesis leading to 2-phenyl-
quinolines has already been developed (Yan et al., 2005).
Quinoline-4-carboxylic acids and their salts are useful as immunosuppressive
agents, as neurokinin receptor antagonists, as a mosquito repellant, and as antiviral
agents, to name a few (Batt et al., 1996; Belenkaya et al., 1981; Carling et al., 2006;
Gualtieri et al., 1973). The antimicrobial activity of quinoline-4-carboxylic acid
derivatives against gram-positive and gram-negative organisms is reported (Dinak-
aran et al., 2008; Metwally et al., 2006; Strigacova et al. 2000). Newer quinoline-4-
carboxylic acid derivatives also have been synthesized by the microwave-irradiated
method (Duvelleroy et al., 2005; Ivachtchenko et al., 2004; Tu et al., 2006).
This report describes the microwave-irradiated synthesis and in vitro antimicro-
bial activity of 2-phenyl-7-substitutedaryl/alkylamino-quinoline-4-carboxylic acid
derivatives for the first time.
Materials and methods
Chemistry
The synthesis of 2-phenyl-7-substitutedaryl/alkylamino-quinoline-4-carboxylic acid
follows the doebner pyruvic acid synthesis (Atwell et al., 1989). In the presence of
benzaldehyde 1, pyruvic acid 2, and absolute ethanol 3, m-chloroaniline 4
condensed and cyclized to form intermediate 7-chloro-2-phenyl-quinoline-4-
carboxylic acid 5 after 5–6 h of heating in a steam bath. This intermediate moiety
was further substituted with different aromatic, aliphatic, or alicyclic amines 6 to
synthesize the final product, 2-phenyl-7-substitutedaryl/alkylamino-quinoline-4-
carboxylic acid (7a–7l), in presence of potassium carbonate, copper acetate, and
N,N-dimethyl formamide (Koga et al., 1980; Wolf et al., 2006) after it had been
heated on heating metal for 4–5 h (Scheme 1).
The aforementioned conventional synthesis has three major disadvantages,
namely, a longer reaction time, a large amount of required solvents that are not eco-
friendly, and poor yield. Hence, we report the rapid synthesis of 2-phenyl-7-
substitutedaryl/alkylamino-quinoline-4-carboxylic acid derivatives under micro-
wave irradiation in a domestic microwave oven in the absence of solvent. The
output power range varies from 160 to 480 W, and the reaction time varies from 30
to 200 s for a 90% to 95% yield.
The comparison of the results from both the conventional and microwave-
irradiated methods are summarized in Table 1. The time required for completion of
the reaction under the influence of microwave irradiation is drastically shorter than
with the conventional method. The yield of the microwave-irradiated reaction also
is greater than with the conventional method. Reactions performed in such
conditions are faster and cleaner due to less thermal decomposition of products. All

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Med Chem Res (2010) 19:392–402
HO
O
CH
3
COCOOH
2
O
Abs Ethanol
Cl
NH
2
Cl
N
3
1
4
5
R-NH
6
Copper Acetate
DMF
K
2
CO3
HO
O
R-HN
N
7a-7l
Scheme 1 Synthesis of 2-phenyl-7-substitutedaryl/alkylamino-quinoline-4-carboxylic acid: R–NH=7a:
–NH–C6H4–CH3, 7b: –NH–C6H4–NO2, 7c: –NH–C6H5, 7d: piperazine, 7e: –NH–C6H4–SO2NH2,
7f: –NH–CO–NH2, 7g: –NH–CS–NH2, 7h: 2-aminothiazole, 7i: –NH–C6H4–OCH3, 7j: –NH–CH2–
COOH, 7k: 4-amino-1,2,4-triazole, 7l: 4-aminopyridine
Table 1 Comparison of the conventional method and the microwave-irradiated method
Compound no. Molecular formula Conventional method
Microwave-irradiated method
Time (h)
Yield (%)
Time (s) Output (W) Yield (%)
5
C16H10O2NCl
C23H18O2N2
C22H15O4N3
C22H16O2N2
C20H19O2N3
C22H17O4N3S
C17H13O3N3
C17H13O2N3S
C19H13O2N3S
C23H18O3N2
C18H13O4N2
C18H13O2N5
C21H15O2N3
6
72
65
60
55
58
75
60
61
62
54
67
53
61
60
160
120
60
160
320
160
480
320
320
320
160
320
320
320
320
160
95
93
95
94
91
95
92
94
93
91
93
91
91
7a
7b
7c
7d
7e
7f
7g
7h
7i
4.5
4.5
4
4
60
5
60
5
60
5
100
35
4.5
5
50
7j
7k
7l
4.5
5
160
130
90
5
1
the synthesized derivatives were characterized by FT-IR, H NMR, and mass and
elemental analysis.
Results and discussion
All the synthesized compounds were screened for their antimicrobial activity
against six gram-positive microbial organisms and four gram-negative microbial

Med Chem Res (2010) 19:392–402
395
organisms by the agar well-diffusion method. A minimum inhibitory concentration
(MIC) study was performed by the agar-dilution method (Butler et al., 2007; Goksu
et al., 2005). A 10-lg/well concentration of all the synthesized compounds was
evaluated.
The results of the antimicrobial activity with respect to zone of inhibition in
millimeters are shown in Table 2. All the compounds showed good results for a
wide range of microbial organisms, indicating broad-spectrum efficacy of the
designed series. Specifically, compounds 7b, 7c, 7f, 7g, and 7h showed promising
results for all microbial organisms compared with the standard drugs ofloxacin and
gentamicin. Compounds 7c and 7h showed good activity against Streptococcus
pyrogenes and Pseudomonas aeruginosa. The MICs of these two compounds are
summarized in Table 3.
Table 2 Antimicrobial activity of standard and synthesized compounds against gram-positive and gram-
negative organisms (zone of inhibition diameter in millimeters)
Compound
no.
Concentration
in lg/wella
S.A. B.S. B.C. B.P. S.P. K.P. E.C. E.F. P.A. P.O.
5
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
–
5
5
6
4
6
8
9
4
7
3
3
7
8
7
9
2
3
6
8
7a
7b
7
5
9
11
5
2
–
12
10
10
8
3
–
8
7c
8
9
10
5
7
5
9
4
12
11
11
9
7d
4
2
5
7
6
7
4
7e
9
5
5
2
5
–
5
4
7f
9
9
10
5
6
9
6
7
6
9
7g
9
–
3
5
–
5
9
12
15
8
7
7h
10
2
9
13
4
12
3
13
5
5
7
12
8
13
5
7i
4
3
3
7j
–
–
4
2
5
5
2
7
4
8
7k
2
–
3
2
–
4
3
3
–
4
7l
3
5
5
6
–
4
4
7
5
4
Ofloxacin
Gentamicin
16
16
17
19
16
17
17
17
17
17
19
16
17
16
16
18
16
19
17
19
S.A., Staphylococcus aureus; B.S., Bacillus subtilis; B.C., Bacillus cereus; B.P., Bacillus pumilus; S.P.,
Streptococcus pyrogenes; K.P., Klebsiella pneumoniae; E.C., Escherichia coli; E.F., Enterococcus fae-
calis; P.A., Pseudomonas aeruginosa; P.O., Pseudomonas oleovorans; –, no zone of inhibition
a
Vehicle DMSO (as control) produced no zone of inhibition
Table 3 Minimum inhibitory concentrations (MICs in lg)
Comp. no.
S.P.
P.A.
7c
7
5
9
3
7h
Comp., compound; S.P., Streptococcus pyrogenes; P.A., Pseudomonas aeruginosa

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Structure–activity relationship study
The agar well-diffusion method was used to evaluate the antimicrobial activity of
synthesized derivatives, and the agar-dilution method was used for the MIC study.
The results of antimicrobial activity showed that incorporation of the substituted
alkyl/arylamino group at C-7 of quinoline-4-carboxylic acid has a comparative
effect on the various six gram-positive and four gram-negative microbial
organisms. The concentration of compounds used for the current study was
10 lg/well, and effectiveness was evaluated by measuring the zone of inhibition
in millimeters.
Compared with C-7–substituted compounds, 7-chloro-2-phenylquinoline-4-
carboxylic acid (5) showed less activity, indicating the effectiveness of the
alkyl/arylamino substitution at the C-7 position to inhibit the growth of
microorganisms. Compound 7h (2-aminothiazole substitution at the C-7 position)
exhibited the most potent antimicrobial activity among all the synthesized
compounds in this series. It showed the highest antimicrobial activity on P.
aeruginosa. Compound 7h also showed moderate activity against Bacillus cereus,
Bacillus pumilus, S. pyrogenes, Enterococcus faecalis, and Pseudomonas oleovo-
rans, indicating wide-spectrum antimicrobial activity. It possessed the least
antimicrobial activity against Klebsiella pneumoniae. Substitution with 4-nitro-
phenylamino (7b), phenylamino (7c), ureido (7f), and thioureido (7g) at the C-7
position showed promising results against a wide range of microbial organisms.
Compounds with 4-amino-1,2,4-triazole substitution (7k) and 4-aminopyridine
substitution (7l) at C-7 showed the least effect on the growth of microorganisms,
indicating less effectiveness of these compounds. The MICs of compounds 7h and
7c were carried out on P. aeruginosa and S. pyrogenes by the agar-dilution
method. Compound 7h showed MICs of 3 and 5 lg, respectively, whereas 7c
showed MICs of 9 and 4 lg, respectively.
These findings indicate that substitution at the C-7 position is essential to
enhance the antimicrobial activity of a given series of quinoline-4-carboxylic acid
derivatives.
Conclusion
In summary, we have demonstrated a practical application for the microwave-
enhanced synthesis of 2-phenyl-7-substitutedaryl/alkylaminoquinoline-4-carboxylic
acids. Spectacular results have been obtained, clearly indicating the potentialities
and advantages of this new technique compared with conventional methods. All the
synthesized compounds showed good antimicrobial activity against various
organisms, indicating a wide spectrum of antimicrobial activity. The structure–
activity relationship (SAR) study demonstrated the comparative activity of
compounds 2-aminothiazole substitution (7h) and aniline substitution (7c) against
all microorganisms. The SAR study also showed that substitution on C-7 is essential
to obtain the desired antimicrobial activity. The MIC of both 7h and 7c is less than
10 lg, which showed the effectiveness of these compounds. The synthesized series

Med Chem Res (2010) 19:392–402
397
of quinoline-4-carboxylic acids can be developed further to show their best use in
various infectious disease conditions.
Experimental approach
General
Melting points were taken in the open capillary on an electrically heated metal block
and are uncorrected. The FT-IR spectra were recorded on a Jasco FT-IR 6100
spectrometer. The 1H NMR spectra were recorded in a BRUKER DPX-200
spectrometer operation at 200 MHz in dimethyl sulphoxide (DMSO d6) with
tetramethylsilane (TMS) as an internal standard. The mass spectra were recorded on
a Waters Micromass Q-Tof Micro. An elemental analysis was performed on a
Perkin Elmer 2400 series II. The reactions were carried out in a domestic
microwave oven (KenStar OM 20 DGQ, KenStar Kitchen Appliances India Ltd.,
Aurangabad, India). The compounds of the current invention were synthesized using
the methods described in the following sections.
Conventional method (Scheme 1)
Synthesis of 7-chloro-2-phenyl-quinoline-4-carboxylic acid (5)
An equi-mole quantity of the starting materials was taken and reacted. Benzalde-
hyde 1 (0.01 mole, 1.06 g) and pyruvic acid 2 (0.01 mole, 0.88 g, 0.70 mL) were
dissolved in 20 mL of absolute ethanol 3 and refluxed over a steam bath with a
calcium chloride guard tube. As the solution started boiling, m-chloroaniline 4 (0.01
mole, 1.27 g) dissolved in 20 mL of absolute ethanol was added drop-wise and
continued refluxing for 5–6 h. The refluxing was stopped, and the solution was kept
overnight at room temperature. Solids precipitated from the solution were filtered,
washed with small quantity of ether, and dried. The intermediate 7-chloro-2-phenyl-
quinoline-4-carboxylic acid 5 was recrystallized with absolute ethanol, and the
melting point was reported.
Synthesis of 2-phenyl-7-substitutedaryl/alkylamino-quinoline-4-carboxylic acids
(7a–7l)
The compound 5 (0.01 mole, 2.83 g) was dissolved in 20 mL of N,N-dimethyl
formamide. Anhydrous potassium carbonate (0.02 mole, 2.7 g), copper acetate (0.01
mole, 1.82 g), and substituted amine 6 (0.01 mole) were added. The mixture was
refluxed on the heating metal for 4–5 h. After completion of refluxing, the solution
was added to crushed ice and stirred well. The solids were separated out, filtered,
and dried. The solid 2- phenyl-7-substitutedaryl/alkylamino-quinoline-4-carboxylic
acids (7a–7l) were purified with acetic acid–sodium hydroxide solution. The
melting points were reported.

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Microwave-irradiated method
Synthesis of 7-chloro-2-phenyl-quinoline-4-carboxylic acid (5)
Benzaldehyde 1 (0.01 mole, 1.06 g) and pyruvic acid 2 (0.01 mole, 0.88 g, 0.70 ml)
were taken in a closed vessel and irradiated for 30 s at 160 W of output power.
Next, m-chloroaniline 4 (0.01 mole, 1.27 g) was added, and they again were put into
an oven for 30 s at 160 W of output power. The yellow colored residue was
dissolved in absolute ethanol, filtered, washed with a small quantity of ether, and
dried. The intermediate 7-chloro-2-phenyl-quinoline-4- carboxylic acid 5 was
recrystallized with absolute ethanol, and the melting point was reported.
Synthesis of 2-phenyl-7-substitutedaryl/alkylamino-quinoline-4-carboxylic acids
(7a–7l)
To the compound 5 (0.01 mole, 2.83 g), anhydrous potassium carbonate (0.02 mole,
2.7 g), copper acetate (0.01 mole, 1.82 g), and substituted amine 6 (0.01 mole) were
added. The mixture was irradiated for 30 to 200 s at 160 to 480 W of output power.
After completion of irradiation, the resulting mixture was added to crushed ice and
stirred well. The solids were separated out, filtered, and dried. The solid 2-phenyl-7-
substituted aryl/alkylamino-quinoline-4-carboxylic acids 7a–7l were purified with
acetic acid–sodium hydroxide solution. The melting points were reported.
7-Chloro-2-phenyl-quinoline-4-carboxylic acid (5) M.p. 182–184°C. IR (KBr): m:
1
3280 (OH), 1720 (C=O), 1610 (C=N), 1585 cm-1 (C=C). H NMR (DMSO-d6): d
7.1–7.8 (8 H, m, Ar–H), 8.5 (1 H, s, 3-H), 10.63 (1H, s, –COOH). MS (ESI): m/z
284.1 (M? ? 2). Anal. Calcd for C16H10O2NCl: C, 67.74; H, 3.55; N, 4.94. Found:
C, 67.70; H, 3.60; N, 4.92.
2-Phenyl-7-(p-tolylamino)quinoline-4-carboxylic acid (7a) M.p. 165–167°C. IR
1
(KBr): m: 3350 (NH), 3310 (OH), 1705(C=O), 1610 (C=N), 1580 cm-1 (C=C). H
NMR (DMSO-d6) d: 2.5 (3 H, s, –CH3), 7.1–7.7 (12 H, m, Ar–H), 8.2 (1 H, s, 3-H),
9.1 (1 H, s, –NH–), 10.55 (1 H, s, –COOH). MS (ESI): m/z 353.3 (M?). Anal. Calcd
for C23H18O2N2: C, 77.95; H, 5.12; N, 7.90. Found: C, 77.90; H, 5.15; N, 7.94.
7-(4-Nitrophenylamino)-2-phenylquinoline-4-carboxylic acid (7b) M.p. 170–
172°C. IR (KBr): m: 3350 (NH), 3240 (OH), 1720 (C=O), 1620 (C=N), 1605
(C=C), 1535 cm-1 (NO2). 1H NMR (DMSO-d6) d: 7.2–7.9 (12 H, m, Ar–H), 8.9 (1
H, s, 3–H), 9.3 (1 H, s, –NH–), 11.42 (1 H, s, –COOH). MS (ESI): m/z 384.1 (M?).
Anal. Calcd for C22H15O4N3: C, 68.57; H, 3.92; N, 10.90. Found: C, 68.60; H, 3.95;
N, 10.94.
2-Phenyl-7-(phenylamino)quinoline-4-carboxylic acid (7c) M.p. 155–157°C. IR
(KBr): m: 3300 (NH), 3250 (OH), 1725 (C=O), 1625 (C=N), 1595 cm-1 (C=C). 1H

Med Chem Res (2010) 19:392–402
399
NMR (DMSO-d6) d: 7.1–7.9 (13 H, m, Ar–H), 8.2 (1 H, s, 3-H), 9.20 (1 H, s, –NH–),
10.40 (1 H, s, –COOH). MS (ESI): m/z 341.2 (M??1). Anal. Calcd for C22H16O2N2:
C, 77.63; H, 4.74; N, 8.23. Found: C, 77.66; H, 4.76; N, 8.20.
2-Phenyl-7-(piperazin-1-yl)quinoline-4-carboxylic acid (7d) M.p. 168–170°C. IR
(KBr): m: 3320 (NH), 3230 (OH), 1715 (C=O), 1625 (C=N), 1575 cm-1 (C=C). 1H
NMR (DMSO-d6) d: 3.25–3.4 (8 H, m, piperazine-H), 3.8 (1 H, m, piperazine-NH),
7.2–7.9 (8 H, m, Ar–H), 8.3 (1 H, s, 3-H), 11.25 (1 H, s, –COOH). MS (ESI): m/z
332.2 (M?). Anal. Calcd for C20H19O2N3: C, 72.05; H, 5.74; N, 12.60. Found: C,
72.02; H, 5.77; N, 12.55.
2-Phenyl-7-(4-sulfamoylphenylamino)quinoline-4-carboxylic acid (7e) M.p. 172–
174°C. IR (KBr): m: 3310 (NH), 3250 (OH), 1720 (C=O), 1615 (C=N), 1595 (C=C),
3350, 3340, 1355 cm-1 (SO2NH2). 1H NMR (DMSO-d6) d: 2.5 (2 H, s, –SO2NH2),
7.1–7.8 (12 H, m, Ar–H), 8.7 (1 H, s, 3-H), 9.4 (1 H, s, –NH–), 11.90 (1 H, s,
–COOH). MS (ESI): m/z 419.3 (M?). Anal. Calcd for C22H17O4N3S: C, 63.00; H,
4.09; N, 10.02. Found: C, 63.03; H, 4.10; N, 10.03.
2-Phenyl-7-ureidoquinoline-4-carboxylic acid (7f) M.p. 170–172°C. IR (KBr): m:
1
3330 (NH), 3170 (OH), 1705 (C=O), 1570 (C=N), 1555 cm-1 (C=C). H NMR
(DMSO-d6) d: 7.1–7.9 (8 H, m, Ar–H), 8.3 (1 H, s, 3-H), 8.7 (2 H, s, –NH2), 9.1 (1
H, s, –NH–), 10.90 (1 H, s, –COOH). MS (ESI): m/z 307.3 (M?). Anal. Calcd for
C17H13O3N3: C, 67.44; H, 4.26; N, 13.67. Found: C, 67.50; H, 4.30; N, 13.61.
2-Phenyl-7-thioureidoquinoline-4-carboxylic acid (7g) M.p. 160–162°C. IR
(KBr): m: 3230 (NH), 3200 (OH), 1715 (C=O), 1620 (C=N), 1590 (C=C),
1
1180 cm-1 (C=S). H NMR (DMSO-d6) d: 7.1–7.7 (8 H, m, Ar–H), 7.9 (2 H, s,
–NH2), 8.7 (1 H, s, 3-H), 10.2 (1 H, s, –NH–), 11.90 (1 H, s, –COOH). MS (ESI):
m/z 325.3 (M? ? 2). Anal. Calcd for C17H13O2N3S: C, 63.14; H, 4.05; N, 12.99.
Found: C, 63.11; H, 4.02; N, 12.98.
2-Phenyl-7-(thiazol-2-ylamino)quinoline-4-carboxylic acid (7h) M.p. 158–160°C.
IR (KBr): m: 3250 (NH), 3200 (OH), 1713 (C=O), 1605 (C=N), 1595 cm-1 (C=C).
1H NMR (DMSO-d6) d: 6.59 (1 H, d, 5H of thiazole), 7.1 (1 H, d, 4H of thiazole),
7.4–7.8 (8 H, m, Ar–H), 8.4 (1 H, s, 3-H), 10.2 (1 H, s, –NH), 10.32 (1 H, s,
–COOH). MS (ESI): m/z 350 (M? ? 3). Anal. Calcd for C19H13O2N3S: C, 65.69;
H, 3.77; N, 12.10. Found: C, 65.67; H, 3.79; N, 12.13.
7-(4-Methoxyphenylamino)-2-phenylquinoline-4-carboxylic acid (7i) M.p. 146–
148°C. IR (KBr): m: 3300 (NH), 3160 (OH), 1715 (C=O), 1610 (C=N), 1590 cm-1
(C=C). 1H NMR (DMSO-d6) d: 3.4 (3 H, s, –OCH3), 7.1–7.7 (12 H, m, Ar–H), 8.3
(1 H, s, 3-H), 9.4 (1 H, s, –NH), 10.81 (1 H, s, –COOH). MS (ESI): m/z 373 (M?
?3). Anal. Calcd for C23H18O3N2: C, 74.58; H, 4.90; N, 7.56. Found: C, 74.60; H,
4.94; N, 7.54.

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7-(Carboxymethylamino)-2-phenylquinoline-4-carboxylic acid (7j) M.p. 153–
155°C. IR (KBr): m: 3320 (NH), 3280 (OH), 1715 (C=O), 1620 (C=N),
1590 cm-1 (C=C). 1H NMR (DMSO-d6) d: 3.4 (2 H, d, –CH2), 6.6 (1 H, s,
–NH), 7.1–7.7 (8 H, m, Ar–H), 8.2 (1 H, s, 3-H), 11.86 (1 H, s, –COOH). MS (ESI):
m/z 325.2 (M??2). Anal. Calcd for C18H13O4N2: C, 67.07; H, 4.38; N, 8.69. Found:
C, 67.09; H, 4.40; N, 8.70.
7-(4H-1,2,4-triazol-4-ylamino)-2-phenylquinoline-4-carboxylic acid (7k) M.p.
140–143°C. IR (KBr): m: 3300 (NH), 3210 (OH), 1705 (C=O), 1610 (C=N),
1
1575 cm-1 (C=C). H NMR (DMSO-d6) d: 7.1–7.4 (8 H, m, Ar–H), 8.1 (1 H, s,
3-H), 8.35 (2 H, s, 3 and 5-H of triazole), 9.1 (1 H, s, –NH–), 12.50 (1 H, s,
–COOH). MS (ESI): m/z 331.2 (M?). Anal. Calcd for C18H13O2N5: C, 69.25; H,
3.95; N, 21.14. Found: C, 69.29; H, 3.90; N, 21.10.
2-Phenyl-7-(pyridin-4-ylamino)quinoline-4-carboxylic acid (7l) M.p. 163–165°C.
IR (KBr): m: 3350 (NH), 3260 (OH), 1725 (C=O), 1610 (C=N), 1570 cm-1 (C=C).
1H NMR (DMSO-d6) d: 7.0–7.5 (10 H, m, Ar–H; 3 and 5-H of pyridine), 8.1 (1 H,
s, 3-H), 8.4 (2 H, s, 2 and 6-H of pyridine), 9.3 (1 H, s, –NH–), 11.91 (1 H, s,
–COOH). MS (ESI): m/z 342.2 (M?). Anal. Calcd for C21H15O2N3: C, 73.89; H,
4.43; N, 12.31. Found: C, 73.92; H, 4.40; N, 12.30.
Biologic activity
In vitro antimicrobial studies
All the synthesized compounds were screened by the agar well-diffusion method for
their antimicrobial activity, and MIC study was carried out by the agar-dilution
method. The bacterial strains were procured from the Microbial Type Culture
Collection & Gene Bank (Chandigarh, India). The antimicrobial activity of the
synthesized compounds was screened against the following bacterial strains: six
gram-positive microbial organisms (Staphylococcus aureus [MTCC 737], Bacillus
subtilis [MTCC 2397], B. cereus [MTCC 430], B. pumilus [MTCC 1640], S.
pyrogenes [MTCC 442], K. pneumoniae [MTCC 109]) and four gram-negative
microbial organisms (Eschericnia coli [MTCC 1652], E. faecalis [MTCC 439], P.
aeruginosa [MTCC 741], P. oleovorans [MTCC 617]). For all the synthesized
compounds, a 10-lg/well concentration in DMSO was evaluated for antimicrobial
activity. Nutrient agar and broth media were used for the preparation of the stock
cultures and subcultures of all the microorganisms. Nutrient agar medium (M00-
500G) and nutrient broth medium (M002-500G) were purchased from HI MEDIA
Lab Ltd. (Mumbai, India). Freshly prepared nutrient agar medium was used during
each experimental procedure.
The melted nutrient agar medium was poured into sterilized petri dishes to a
uniform depth and allowed to solidify under aseptic conditions. The bacterial
suspension, prepared from a subculture of bacterial strains, then was streaked over

Med Chem Res (2010) 19:392–402
401
the medium surface using a sterile cotton swab to ensure confluent growth of
organism. The wells, each 6 mm in diameter, were made by a sterile cork borer in
the petri dish. The sample solutions of test compounds and the standard drugs were
loaded separately into each well with the help of a micropipette. Inoculated plates
were incubated in a biochemical oxygen demand (BOD) incubator at 37 1°C for
24 h. The zone of inhibition diameter produced by each compound was measured in
millimeters using the Antibiotic Zone Reader (Kshitij Innovations, Ambala Cant,
India). The results for the synthesized compounds were screened against the
standard drugs ofloxacin and gentamycin, with DMSO as a vehicle.
The agar-dilution method was used to determine the MIC of the synthesized
compounds. The test compounds were dissolved in DMSO and further diluted with
nutrient broth medium to make the final concentration of 10–100 lg/mL. Then,
1 mL of the solution so obtained was added to 10 mL of melted agar medium at a
temperature of 40–50°C. The melted agar medium was added to the sterile petri dish
and allowed to solidify. All the petri dishes loaded with the test compounds were
inoculated with a loopful of a bacterial suspension on the surface of the solidified
agar. The petri dishes were incubated at 37 1°C for 24 h, after which the MICs
were recorded by visual observation. The MIC was taken as the highest dilution
(least concentration) of the test compound showing no detectable growth.
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