Synthesis and in vitro antimicrobial evaluation of pentasubstituted pyridine derivatives bearing the quinoline nucleus

Article abstract of DOI:10.1007/s00044-011-9568-6

A new series of penta-substituted pyridine derivatives bearing the quinoline nucleus have been synthesized by base-catalyzed cyclocondensation reaction through multi-component reaction (MCR) approach. All the synthesized compounds were subjected to in vitro antimicrobial screening against three Gram positive bacteria (Bacillus subtilis, Clostridium tetani, Streptococcus pneumoniae), three Gram negative bacteria (Escherichia coli, Salmonella typhi, Vibrio cholerae), and two fungi (A. fumigatus, Candida albicans). Reviewing the data, majority of the compounds were found to be active against B. subtilis and C. tetani while the most effective compounds 4c and 4e demonstrated MIC 62.5 μg/ml against V. cholerae and E. coli respectively. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9568-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:616–623
DOI 10.1007/s00044-011-9568-6
ORIGINAL RESEARCH
Synthesis and in vitro antimicrobial evaluation of penta-
substituted pyridine derivatives bearing the quinoline nucleus
•
Jigar A. Makawana Manish P. Patel
•
Ranjan G. Patel
Received: 30 September 2010 / Accepted: 12 January 2011 / Published online: 29 January 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A new series of penta-substituted pyridine
derivatives bearing the quinoline nucleus have been syn-
thesized by base-catalyzed cyclocondensation reaction
through multi-component reaction (MCR) approach. All
the synthesized compounds were subjected to in vitro
antimicrobial screening against three Gram positive bac-
teria (Bacillus subtilis, Clostridium tetani, Streptococcus
pneumoniae), three Gram negative bacteria (Escherichia
coli, Salmonella typhi, Vibrio cholerae), and two fungi
(A. fumigatus, Candida albicans). Reviewing the data,
majority of the compounds were found to be active against
B. subtilis and C. tetani while the most effective com-
pounds 4c and 4e demonstrated MIC 62.5 lg/ml against
V. cholerae and E. coli respectively.
2007) and some of 3-cyano-2-pyridone derivatives having
anti-inflammatory activity (Amr and Abdulla, 2006).
Moreover, the polysubstituted pyridine represents molec-
ular framework that serve as a platform for development of
pharmaceutical agents. Of the pharmacologically active
pyridine derivatives, pyridine-3,5-dicarbonitriles have
attracted much interest in recent years because of their
significant synthetic as well as medicinal utility. Thus, the
synthesis of highly functionalized pyridine derivatives has
become an active area of research (Anabha et al., 2007;
Fletcher et al., 2006; Movassaghi and Hill, 2006; Shinde
et al., 2010; Sridhar et al., 2009).
On the other hand, quinoline derivatives are possessing
high activity profile due to their wide range of useful
biological properties including antibacterial (Kalluraya
et al., 2008), antifungal (Rana et al., 2008), antimycobac-
terial (Mital et al., 2006), antimalarial (Charris et al., 2005;
Dave et al., 2009), anti-inflammatory (Bava and Kumar
2009) and anticancer activity (Shi et al., 2008). Encouraged
by their potential clinical applications and in continuation
of our previous investigations on biopotent heterocycles
(Ladani et al., 2009a, b; Ladani et al., 2010; Mungra et al.,
2010; Nirmal et al., 2009; Shah et al., 2009; Thakor et al.,
2007; Thumar and Patel, 2009a, b), our efforts are focused
to design and synthesize more biologically potent hetero-
cyclic systems via combination of both therapeutically
active moieties quinoline and pyridine together in a single
scaffold.
Keywords Pyridine ꢀ Quinoline ꢀ One-pot reaction ꢀ
Antimicrobial activity
Introduction
Many naturally occurring and synthetic compounds bearing
pyridine scaffold possess interesting biological properties
(Temple et al., 1992). Among them, 2-amino-3-cyanopyr-
idine derivatives are well known for their versatile bio-
logical activities like antimicrobial (Mahmoud et al., 2007;
Mungra et al., 2009), antifungal (Costa et al., 2008), iso-
niazid derivatives bearing the pyridine nucleus possess
anti-tubercular (Ashrafali et al., 2010; Lourenco et al.,
Various methods for the synthesis of penta-substituted
pyridines from aromatic and heterocyclic aldehydes
involving different catalysts (Evdokimov et al., 2006;
Heravi et al., 2010; Lakshmikantam et al., 2010; Singh and
Singh, 2009; Mamgain et al., 2009; Sridhar et al., 2009;
Banerjee and Sereda, 2009; Ranu et al., 2007) are available
but not a single report has been found where 2-chloro-3-
J. A. Makawana ꢀ M. P. Patel ꢀ R. G. Patel (&)
Department of Chemistry, Sardar Patel University,
Vallabh Vidyanagar 388120, Gujarat, India
e-mail: patelranjanben@yahoo.com
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Med Chem Res (2012) 21:616–623
617
formyl quinoline is used for the synthesis of penta-substi-
tuted pyridines using piperidine as basic catalyst. Also, the
most suitable protocol for the synthesis of functionalized
organic compounds would be a one-pot reaction due to the
fact that the synthesis can be performed without the iso-
lation of the intermediates, without discharging any func-
tional groups and within short reaction time (Boulard et al.,
2004). Thus, in a view to obtain more biologically potent
heterocyclic system, containing both therapeutically active
moieties quinoline and pyridine, we report herein the
synthesis of some new penta-substituted pyridine deriva-
tives bearing quinoline nucleus via MCR approach.
signals around d 106.74–167.19 ppm while C-3 and C-5
carbons of the pyridine ring, attached to the –C:N groups,
exhibited distinctive signals around d 94.04–94.87 ppm
and d 88.01–88.81 ppm, respectively, in 13C NMR
(DMSO-d6). The IR spectrum of compounds 4a–o exhib-
ited characteristic absorption bands at 3480–3395 and
3390–3300 cm-1 for –NH2 (asym. and sym. stretching) as
well as 2215–2200 cm-1 for –C:N stretching. Absorption
band around 750–755 cm-1 is mainly attributed to thioe-
ther linkage at sixth position of pyridine. The obtained
elemental analysis values are in good agreement with
theoretical data. Further, the molecular weight of selected
compounds, 4e and 4i were confirmed by its mass spectral
studies. Mass spectroscopy of above mentioned compounds
showed molecular ion peak (M ? 1) corresponding to the
exact mass. Mass spectra of compound 4e gave molecular
ion peak at m/z 462 (M ? 1) corresponding to molecular
formula C23H13N5SCl2 and 4i gave molecular ion peak at
m/z 458 (M ? 1) corresponding to molecular formula
C24H16N5OSCl. All spectroscopic data have been given in
experimental section.
The constitutions of all the products were confirmed
1
using H NMR, 13C NMR, FTIR, and elemental analysis.
All synthesized compounds were screened for in vitro
antimicrobial activity against eight human pathogens, of
which three are Gram positive bacteria (B. subtilis, C.
tetani, S. pneumoniae), three are Gram negative bacteria
(E. coli, S. typhi, V. cholerae) and two fungi (A. fumigatus,
C. albicans) using broth microdilution MIC (minimum
inhibitory concentration) method.
Results and discussion
Antimicrobial activity
Chemistry
All the glass apparatus used were sterilized before use.
Antimicrobial activity of all the synthesized compounds
was carried out by broth microdilution method (National
Committee for Clinical Laboratory Standards 2002).
Mueller–Hinton broth was used as nutrient medium to
grow and dilute the compound suspension for the test
bacteria and Sabouraud Dextrose broth used for fungal
nutrition. Inoculum size for test strain was adjusted to 108
CFU (colony forming unit) per milliliter by comparing the
turbidity. The strains used for the activity were procured
from (MTCC, microbial type culture collection) Institute of
Microbial Technology, Chandigarh. Each synthesized
compound was diluted obtaining 2000 lg/ml concentra-
tion, as a stock solution. The results are recorded in the
form of primary and secondary screening. The compounds
4a–o were screened for their antibacterial activity against
B. subtilis (MTCC 441), C. tetani (MTCC 449), S. pneu-
moniae (MTCC 1936), E. coli (MTCC 443), S. typhi
(MTCC 98) and V. cholerae (MTCC 3906) as well as for
antifungal activity against A. fumigatus (MTCC 3008) and
C. albicans (MTCC 227) at concentrations of 1000, 500,
and 250 lg/ml as primary screening. DMSO was used as
vehicle to get desired concentrations of compounds to test
upon microbial strains. The compounds found to be active
in the primary screening were further screened in a second
set of dilution at concentrations of 200, 100, 62.5, 50 lg/ml.
10 ll suspensions from each well were further inoculated
and growth was noted after 24 and 48 h. The lowest
The required 2-chloro-3-formyl quinoline 1a–e was pre-
pared by Vilsmeier-Haack reaction according to literature
procedure (Meth-Cohn and Bramha, 1978).
In this study, a series of penta-substituted pyridine
derivatives 4a–o has been synthesized by one-pot three-
component cyclocondensation reaction of 2-chloro-3-for-
myl quinoline 1a–e, malononitrile 2 and thiophenol 3a–c, in
presence of piperidine as catalyst. The above mixture in
refluxing ethanol gives moderate to good yield, i.e.,
57–86% (Scheme 1). In accordance with the mechanism
suggested in literature (Evdokimov et al., 2006), the first
step of this process may involve the Knoevenagel conden-
sation of an aldehyde with malononitrile to form the cor-
responding heterylidenenitrile derivative (A). The second
molecule of malononitrile then undergoes Michael addition
to (A) followed by simultaneous thiolate addition to –C:N
of the adduct and cyclization to dihydropyridine (B) which
on aromatization and oxidation under the reaction condi-
tions leads to pyridine derivatives 4a–o (Scheme 2).
The structures of all the new synthesized compounds
were established by H NMR, 13C NMR, FTIR, elemental
1
analysis, and molecular weight of some selected com-
pounds confirmed by mass spectrometry. In 1H NMR
(DMSO-d6) spectra, aromatic protons as well as –NH2
proton of pyridine derivatives 4a–o resonate as multiplets
at around d 7.21–8.95 ppm. Aromatic carbons exhibited
123

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Med Chem Res (2012) 21:616–623
Scheme 1 General synthetic
route for the title compounds
4a–0
Scheme 2 Plausible
mechanistic pathway for the
synthesis of title compounds
4a–0
concentration, which showed no visible growth (turbidity)
after spot subculture was considered as MIC for each
compound. In this study, ampicillin and norfloxacin were
used as standard antibacterial drugs, whereas griseofulvin
was used as standard antifungal drugs. The protocols were
summarized in Table 1.
showed excellent activity (MIC 100 lg/ml) upon compar-
ison with ampicillin (MIC 250 lg/ml). Compounds 4e
(R1=CH3, R2=H, R3=Cl), 4l (R1=H, R2=CH3, R3=CH3) and
4o (R1=Cl, R2=H, R3=CH3) against B. subtilis as well as
compounds 4g (R1=OCH3, R2=H, R3=H), 4h (R1=OCH3,
R2=H, R3=Cl), 4l (R1=Cl, R2=H, R3=CH3), 4m (R1=H,
R2=CH3, R3=H) and 4o (R1=H, R2=CH3, R3=CH3) against
C. tetani were found to have better activity (MIC 200 lg/ml)
than ampicillin (MIC 250 lg/ml).
Moreover, against fungal pathogen C. albicans, com-
pound 4k (R1=Cl, R2=H, R3=Cl) showed excellent activity
(MIC 200 lg/ml) while compounds 4f (R1=CH3, R2=H,
R3=CH3), 4j (R1=Cl, R2=H, R3=H), and 4l (R1=Cl, R2=H,
R3=CH3) were found to possess better activity (MIC
250 lg/ml) as compared to griseofulvin (MIC 500 lg/ml).
Compounds 4a (R1=H, R2=H, R3=H), 4b (R1=H, R2=H,
R3=Cl), 4c (R1=H, R2=H, R3=CH3), 4g (R1=OCH3, R2=H,
The examination of the data (Table 1) revealed that
majority of the compounds showed good antibacterial and
antifungal activity when compared with ampicillin, nor-
floxacin, and griseofulvin.
Against Gram negative bacteria E. coli, compound 4e
(R1=CH3, R2=H, R3=Cl) and against V. cholerae, com-
pound 4c (R1=H, R2=H, R3=CH3) have shown excellent
activity (MIC 62.5 lg/ml) as compared to ampicillin (MIC
100 lg/ml) as well as against Gram positive bacteria
B. subtilis, compounds 4f (R1=CH3, R2=H, R3=CH3), 4j
(R1=Cl, R2=H, R3=H) and 4 m (R1=H, R2=CH3, R3=H)
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Med Chem Res (2012) 21:616–623
619
Table 1 Antibacterial and antifungal activity of compounds 4a–o
Minimum inhibitory concentration (MIC) expressed in lg/ml
Compound
Gram-positive bacteria
Gram-negative bacteria
Fungal species
Bs. MTCC
441
Ct. MTCC
449
Sp. MTCC
1936
Ec. MTCC
443
St. MTCC
98
Vc. MTCC
3906
Af. MTCC
3008
Ca. MTCC
227
4a
250
250
250
500
200
100
250
250
500
100
250
200
100
250
200
250
100
–
500
250
250
500
250
500
200
200
500
250
500
200
200
250
200
250
50
250
250
200
250
200
100
250
250
500
200
500
250
100
250
200
100
10
200
100
100
200
62.5
250
500
200
500
200
250
200
100
500
200
100
10
200
150
100
200
100
200
500
200
500
250
250
200
200
500
250
100
10
200
250
62.5
250
200
500
500
200
500
200
500
200
250
500
200
100
10
500
500
4b
1000
[1000
[1000
500
1000
[1000
[1000
500
4c
4d
4e
4f
500
250
4g
1000
[1000
[1000
250
1000
1000
[1000
250
4h
4i
4j
4k
500
200
4l
500
250
4m
1000
[1000
[1000
–
1000
[1000
[1000
–
4n
4o
Ampicillin
Norfloxacin
Griseofulvin
–
–
–
–
–
–
–
100
500
Bs., Bacillus subtilis, Ct., Clostridium tetani, Sp., Streptococcus pneumoniae, Ec., Escherichia coli; St., Salmonella typhi; Vc., Vibrio cholerae;
Af., Aspergillus fumigatus; Ca., Candida albicans
R3=H), 4h (R1=OCH3, R2=H, R3=Cl), 4k (R1=Cl, R2=H,
R3=Cl), and 4n (R1=H, R2=CH3, R3=Cl) as compared to
ampicillin (MIC 250 lg/ml) as well as compounds 4f
(R1=CH3, R2=H, R3=CH3), 4j (R1=Cl, R2=H, R3=H), and
4m (R1=H, R2=CH3, R3=H) as compared to norfloxacin
(MIC 100 lg/ml) have shown equipotent activity towards
B. subtilis. Compounds 4b (R1=H, R2=H, R3=Cl), 4c
(R1=H, R2=H, R3=CH3), 4e (R1=CH3, R2=H, R3=Cl), 4j
(R1=Cl, R2=H, R3=H) and 4n (R1=H, R2=CH3, R3=Cl)
were found equipotent against C. tetani as compared to
ampicillin (MIC 250 lg/ml), while compounds 4f
(R1=CH3, R2=H, R3=CH3) and 4m (R1=H, R2=CH3, R3=H)
showed comparable activity to ampicillin (MIC 100 lg/ml)
against S. pneumoniae.
Experimental
All the reagents were obtained commercially and used with
further purification. Solvents used were of analytical grade.
All melting points were taken in open capillaries and are
uncorrected. Thin-layer chromatography (TLC, on alumi-
num plates coated with silica gel 60 F254, 0.25 mm thick-
ness, Merck) was used for monitoring the progress of all
reactions, purity and homogeneity of the synthesized
compounds. Elemental analysis (% C, H, N) was carried
out by Perkin-Elmer 2400 series-II elemental analyzer at
Sophisticated Instrumentation Centre for Applied Research
& Training (SICART), Vallabh Vidhyanagar and all
compounds are within 0.4% of theory specified. The
FTIR spectra were recorded using potassium bromide disc
on a Shimadzu FTIR 8401 spectrophotometer and only the
Further, compounds 4b (R1=H, R2=H, R3=Cl), 4c (R1=H,
R2=H, R3=CH3) and 4m (R1=H, R2=CH3, R3=H) against
Escherichia coli as well as compounds 4c (R1=H, R2=H,
R3=CH3) and 4e (R1=CH3, R2=H, R3=Cl) against S. typhi
have been found to possess equipotent activity of ampicillin
(MIC 100 lg/ml). Whereas, compounds 4a (R1=H, R2==H,
R3=H) and 4e (R1=CH3, R2=H, R3=Cl) were found to be
equipotent with griseofulvin (MIC 500 lg/ml) against
C. albicans. Unfortunately, none of the tested compounds
were found to be active against A. fumigatus.
characteristic peaks are reported in cm-1. 1H NMR and 13
C
NMR spectra were recorded in DMSO-d6 on a Bruker
Avance 400F (MHz) spectrometer using solvent peak as
internal standard at 400 and 100 MHz, respectively.
Chemical shifts are reported in parts per million (ppm).
Mass spectra were scanned on a Shimadzu LCMS 2010
spectrometer. Mass spectra were scanned on a Shimadzu
LCMS 2010 spectrometer.
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1
General procedure for the synthesis of 2-amino-4-(2-
chloro-6 or 7-(un)-substituted-quinolin-3-yl)-6-[(4-
(un)-substituted phenyl)sulfanyl]pyridine-3,5-
dicarbonitrile (4a–o)
(–C:N stretching), 750 (C–S–C thioether stretching). H
NMR (400 MHz, DMSO-d6): d 2.35 (s, 3H, CH3), 7.33-
8.41 (m, 11H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 21.47 (CH3), 88.71 (C–CN), 94.61 (C–CN),
113.46, 114.07, 125.17, 126.46, 127.73, 129.21, 131.17,
135.13, 137.54, 137.92, 140.28, 144.31, 146.59, 151.31,
155.17, 153.09, 159.46, 166.31 (Ar–C).
A mixture of appropriate 2-chloro-3-formyl quinoline
1a–e (5 mmol), malononitrile 2 (10 mmol), thiophenol
3a–c (5 mmol) and 0.03 ml of piperidine in ethanol (10 ml)
were charged in 100 ml round bottom flask equipped with
condenser. The reaction mixture was stirred at reflux for 3 h.
On completion of reaction, monitored by TLC, the solid
separated was filtered, washed with methanol and recrys-
tallized from chloroform to obtain the pure solid sample
4a–o. The physicochemical and spectroscopic character-
ization data of the synthesized compounds 4a–o are given
below.
2-Amino-4-(2-chloro-6-methylquinolin-3-yl)-6-
(phenylsulfanyl)pyridine-3,5-dicarbonitrile (4d)
Yield 78%, m.p. 268–270°C, Anal. Calcd. for
C23H14N5SCl (427.91 g/mol): C 64.56, H 3.30, N 16.37%
Found: C 64.73, H 3.03, N 16.56%. IR (KBr, cm-1): 3400
and 3370 (asym. and sym. stretching of -NH2), 2207
1
(–C:N stretching), 755 (C–S–C thioether stretching). H
NMR (400 MHz, DMSO-d6): d 2.37 (s, 3H, CH3),
7.33–8.95 (m, 11H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 21.53 (CH3), 88.33 (C–CN), 94.76 (C–CN),
118.14, 120.22, 127.04, 127.84, 128.27, 128.78, 129.17,
129.54, 130.22, 130.19, 131.23, 134.67, 140.80, 142.12,
146.74, 149.15, 151.26, 165.61 (Ar–C).
2-Amino-4-(2-chloroquinolin-3-yl)-6-
(phenylsulfanyl)pyridine-3,5-dicarbonitrile (4a)
Yield 75%, m.p. 277–278°C, Anal. Calcd. for
C22H12N5SCl (413.88 g/mol): C 63.84, H 2.92, N 16.92%
Found: C 63.57, H 2.63, N 17.13%. IR (KBr, cm-1): 3410
and 3315 (asym. and sym. stretching of –NH2), 2212
2-Amino-4-(2-chloro-6-methylquinolin-3-yl)-6-[(4-
1
(–C:N stretching), 753 (C–S–C thioether stretching). H
chlorophenyl)sulfanyl]pyridine-3,5- dicarbonitrile (4e)
NMR (400 MHz, DMSO-d6): d 7.41-8.93 (m, 12H,
Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d: 88.18
(C–CN), 94.82 (C–CN), 118.21, 120.53, 127.19, 127.62,
128.06, 128.28, 128.57, 129.00, 130.42, 130.16, 131.38,
134.61, 140.93, 142.91, 146.08, 149.94, 151.67, 166.17
(Ar–C).
Yield 86%, m.p. 283–284°C, Anal. Calcd. for
C23H13N5SCl2 (462.35 g/mol): C 59.75, H 2.83, N 15.15%
Found: C 59.56, H 3.12, N 14.87%. IR (KBr, cm-1): 3480
and 3320 (asym. and sym. stretching of –NH2), 2200
1
(–C:N stretching), 750 (C–S–C thioether stretching). H
NMR (400 MHz, DMSO-d6): d 2.54 (s, 3H, CH3),
7.57–8.68 (m, 10H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 21.57 (CH3), 88.59 (C–CN), 94.31 (C–CN),
114.70, 114.99, 126.01, 126.55, 127.40, 127.65, 128.12,
130.04, 135.22, 135.54, 137.32, 138.94, 140.19, 145.56,
146.44, 155.28, 159.76, 166.30 (Ar–C), MS: 462 (M ? 1)
(exact mass = 461.03 g/mol).
2-Amino-4-(2-chloroquinolin-3-yl)-6-[(4-
chlorophenyl)sulfanyl]pyridine-3,5-dicarbonitrile (4b)
Yield 68%, m.p. 230–232°C, Anal. Calcd. for C22H11N5SCl2
(448.33 g/mol): C 58.94, H 2.47, N 15.62% Found: C 58.72,
H 2.71, N 15.51%. IR (KBr, cm-1): 3415 and 3365 (asym.
and sym. stretching of –NH2), 2206 (–C:N stretching), 751
(C–S–C thioether stretching). 1H NMR (400 MHz, DMSO-
d6): d 7.51–8.68 (m, 11H, Ar–H ? NH2). 13C NMR
(100 MHz, DMSO-d6) d: 88.21 (C–CN), 94.67 (C–CN),
114.66, 115.95, 126.13, 126.51, 127.74, 128.14, 130.37,
134.49, 137.13, 138.30, 139.45, 140.16, 143.44, 147.23,
152.71, 155.39, 159.16, 165.59 (Ar–C).
2-Amino-4-(2-chloro-6-methylquinolin-3-yl)-6-[(4-
methylphenyl)sulfanyl]pyridine-3,5-dicarbonitrile (4f)
Yield 69%, m.p. 262–263°C, Anal. Calcd. for C24H16N5SCl
(441.94 g/mol): C 65.23, H 3.65, N 15.85% Found: C 65.47,
H 3.91, N 16.03%. IR (KBr, cm-1): 3400 and 3323 (asym.
and sym. stretching of –NH2), 2215 (–C:N stretching), 752
(C–S–C thioether stretching). 1H NMR (400 MHz, DMSO-
d6): d 2.41 (s, 3H, CH3), 2.49 (s, 3H, CH3), 7.39–8.54 (m,
10H, Ar–H ? NH2); 13C NMR (100 MHz, DMSO-d6) d:
21.18 (CH3), 21.42 (CH3), 88.62 (C–CN), 94.51 (C–CN),
114.13, 125.23, 126.75, 127.33, 128.04, 128.94, 131.29,
134.20, 137.83, 138.22, 139.73, 145.17, 146.88, 150.61,
153.20, 155.77, 159.15, 166.43 (Ar–C).
2-Amino-4-(2-chloroquinolin-3-yl)-6-[(4-
methylphenyl)sulfanyl]pyridine-3,5-dicarbonitrile (4c)
Yield 73%, m.p. 258–260°C, Anal. Calcd. for
C23H14N5SCl (427.91 g/mol): C 64.56, H 3.30, N 16.37%
Found: C 64.43, H 2.97, N 16.08%. IR (KBr, cm-1): 3395
and 3355 (asym. and sym. stretching of -NH2), 2210
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Med Chem Res (2012) 21:616–623
621
cm-1): 3420 and 3380 (asym. and sym. stretching of
2-Amino-4-(2-chloro-6-methoxyquinolin-3-yl)-6-
(phenylsulfanyl)pyridine-3,5-dicarbonitrile (4g)
-NH2), 2210 (–C:N stretching), 755 (C–S–C thioether
stretching). H NMR (400 MHz, DMSO-d6): d 7.24-8.67
1
(m, 11H, Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6)
d: 88.01 (C–CN), 94.63 (C–CN), 115.21, 115.97, 125.46,
126.75, 127.11, 128.30, 130.82, 133.14, 137.23, 137.67,
139.24, 145.12, 146.22, 149.98, 155.64, 153.72, 160.81,
165.56 (Ar–C).
Yield 61%, m.p. 278-279°C, Anal. Calcd. for
C23H14N5OSCl (443.91 g/mol): C 62.23, H 3.18, N
15.78% Found: C 62.34, H 2.94, N 15.49%. IR (KBr,
cm-1): 3415 and 3380 (asym. and sym. stretching of
-NH2), 2200 (–C:N stretching), 751 (C–S–C thioether
stretching). 1H NMR (400 MHz, DMSO-d6): d 3.48 (s, 3H,
OCH3), 7.42-8.78 (m, 11H, Ar–H ? NH2). 13C NMR
(100 MHz, DMSO-d6) d: 57.01 (OCH3), 88.32 (C–CN),
94.04 (C–CN), 108.12, 113.93, 114.96, 123.51, 124.86,
127.54, 127.87, 129.26, 130.63, 135.84, 138.54, 139.02,
142.80, 143.87, 147.39, 153.03, 158.63, 166.25 (Ar–C).
2-Amino-4-(2,6-dichloroquinolin-3-yl)-6-[(4-
chlorophenyl)sulfanyl]pyridine-3,5-dicarbonitrile (4k)
Yield 64%, m.p. 254–256°C, Anal. Calcd. for
C22H10N5SCl3 (482.77 g/mol): C 54.73, H 2.09, N 14.51%
Found: C 54.88, H 2.31, N 14.41%. IR (KBr, cm-1): 3455
and 3390 (asym. and sym. stretching of -NH2), 2200
2-Amino-4-(2-chloro-6-methoxyquinolin-3-yl)-6-[(4-
1
chlorophenyl)sulfanyl]pyridine-3,5-dicarbonitrile (4h)
(–C:N stretching), 750 (C–S–C thioether stretching). H
NMR (400 MHz, DMSO-d6): d 7.21–8.15 (m, 10H,
Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d: 88.18
(C–CN), 94.87 (C–CN), 113.63, 115.63, 126.29, 127.10,
128.07, 128.22, 131.31, 134.73, 137.18, 137.93, 139.80,
141.20, 143.22, 149.19, 152.10, 155.33, 158.16, 166.83
(Ar–C).
Yield 57%, m.p. 284–285°C, Anal. Calcd. for
C23H13N5OSCl2 (478.35 g/mol): C 57.75, H 2.74, N
14.64% Found: C 57.51, H 2.41, N 14.88%. IR (KBr,
cm-1): 3430 and 3300 (asym. and sym. stretching of
-NH2), 2213 (–C:N stretching), 753 (C–S–C thioether
stretching). 1H NMR (400 MHz, DMSO-d6): d 3.63 (s, 3H,
OCH3), 7.33–8.53 (m, 10H, Ar–H ? NH2). 13C NMR
(100 MHz, DMSO-d6) d: 56.24 (OCH3), 88.15 (C–CN),
94.25 (C–CN), 107.21, 114.03, 114.96, 121.23, 122.15,
124.20, 125.01, 126.34, 127.22, 129.76, 133.44, 136.45,
139.98, 142.08, 151.78, 156.21, 159.09, 166.73 (Ar–C).
2-Amino-4-(2,6-dichloroquinolin-3-yl)-6-[(4-
methylphenyl)sulfanyl]pyridine-3,5-dicarbonitrile (4l)
Yield 69%, m.p. 286-288°C, Anal. Calcd. for
C23H13N5SCl2 (462.35 g/mol): C 59.75, H 2.83, N 15.15%
Found: C 59.58, H 2.52, N 14.90%. IR (KBr, cm-1): 3435
and 3350 (asym. and sym. stretching of –NH2), 2215
2-Amino-4-(2-chloro-6-methoxyquinolin-3-yl)-6-[(4-
1
methylphenyl)sulfanyl]pyridine-3,5-dicarbonitrile (4i)
(–C:N stretching), 755 (C–S–C thioether stretching). H
NMR (400 MHz, DMSO-d6): d 2.53 (s, 3H, CH3),
7.40–8.53 (m, 10H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 21.47 (CH3), 88.39 (C–CN), 94.20 (C–CN),
113.86, 114.13, 124.14, 126.54, 126.70, 128.93, 132.21,
135.75, 136.03, 137.13, 141.11, 144.15, 144.98, 150.51,
153.76, 155.44, 158.33, 165.87 (Ar–C).
Yield 82%, m.p. 291–292°C, Anal. Calcd. for
C24H16N5OSCl (457.93 g/mol): C 62.95, H 3.52, N
15.29% Found: C 62.69, H 3.79, N 15.58%. IR (KBr,
cm-1): 3420 and 3310 (asym. and sym. stretching of
-NH2), 2205 (–C:N stretching), 754 (C–S–C thioether
stretching). 1H NMR (400 MHz, DMSO-d6): d 2.38 (s, 3H,
CH3), 3.95 (s, 3H, OCH3), 7.34–8.63 (m, 10H, Ar–
H ? NH2). 13C NMR (100 MHz, DMSO-d6) d: 21.41
(CH3), 56.32 (OCH3), 88.28 (C–CN), 94.18 (C–CN),
106.74, 114.75, 115.06, 123.47, 125.46, 127.72, 127.95,
129.90, 130.72, 135.54, 139.34, 140.31, 143.78, 143.83,
155.28, 159.03, 159.79, 167.19 (Ar–C), MS: 458 (M ? 1)
(Exact mass = 457.08 g/mole).
2-Amino-4-(2-chloro-7-methylquinolin-3-yl)-6-
(phenylsulfanyl)pyridine-3,5-dicarbonitrile (4m)
Yield 72%, mp 275–276°C, Anal. Calcd. for C23H14N5SCl
(427.91 g/mol): C 64.56, H 3.30, N 16.37% Found: C
64.71, H 3.11, N 16.48%. IR (KBr, cm-1): 3410 and 3365
(asym. and sym. stretching of –NH2), 2213 (-C:N
stretching), 753 (C–S–C thioether stretching). 1H NMR
(400 MHz, DMSO-d6): d 2.52 (s, 3H, CH3), 7.30–8.95 (m,
11H, Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d:
21.53 (CH3), 88.31 (C–CN), 94.53 (C–CN), 118.31,
120.29, 126.85, 127.22, 128.32, 128.61, 129.08, 129.73,
130.24, 131.03, 131.35, 134.57, 139.88, 141.11, 146.79,
149.62, 151.30, 165.83 (Ar–C).
2-Amino-4-(2,6-dichloroquinolin-3-yl)-6-
(phenylsulfanyl)pyridine-3,5-dicarbonitrile (4j)
Yield 77%, m.p. 234–236°C, Anal. Calcd. for
C22H11N5SCl2 (448.33 g/mol): C 658.94, H 2.47, N
15.62% Found: C 58.71, H 2.69, N 15.51%. IR (KBr,
123

622
Med Chem Res (2012) 21:616–623
analysis. As well as Oxygen Healthcare Research Pvt. Ltd.,
Ahmadabad for providing mass spectrometry facilities and Dhanji P.
Rajani, Microcare Laboratory, Surat for antimicrobial screening of
the compounds reported herein. One of the authors is grateful to
UGC, New Delhi for a Research Fellowship in Sciences for Merito-
rious Students.
2-Amino-4-(2-chloro-7-methylquinolin-3-yl)-6-[(4-
chlorophenyl)sulfanyl]pyridine-3,5-dicarbonitrile (4n)
Yield 79%, m.p. 250–252°C, Anal. Calcd. For
C23H13N5SCl2 (462.35 g/mol): C 59.75, H 2.83, N 15.15%
found: C 59.61, H 3.11, N 14.98%. IR (KBr, cm-1): 3400
and 3385 (asym. and sym. stretching of -NH2), 2209
1
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