Synthesis and in vitro antimicrobial evaluation of novel 2-amino-6-(phenylthio)-4-(2-(phenylthio)quinolin-3-yl)pyridine-3, 5-dicarbonitriles

Article abstract of DOI:10.1007/s00044-012-0292-7

A new series of 2-thiophenoxyquinoline-based penta-substituted pyridine derivatives, 6(a-r), has been synthesized by base-catalyzed cyclocondensation reaction through multi-component reaction (MCR) approach. In vitro antimicrobial activity of the synthesi

Full text of DOI:10.1007/s00044-012-0292-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:2912–2920
DOI 10.1007/s00044-012-0292-7
ORIGINAL RESEARCH
Synthesis and in vitro antimicrobial evaluation of novel
2-amino-6-(phenylthio)-4-(2-(phenylthio)quinolin-3-yl)pyridine-
3,5-dicarbonitriles
•
Mehul B. Kanani Manish P. Patel
Received: 29 May 2012 / Accepted: 20 October 2012 / Published online: 3 November 2012
Ó Springer Science+Business Media New York 2012
Abstract A new series of 2-thiophenoxyquinoline-based
penta-substituted pyridine derivatives, 6(a–r), has been
synthesized by base-catalyzed cyclocondensation reaction
through multi-component reaction (MCR) approach.
In vitro antimicrobial activity of the synthesized com-
pounds was investigated against a representative panel of
pathogenic strains, specifically three Gram-positive bacte-
ria (Streptococcus pneumoniae, Bacillus subtilis, Clos-
tridium tetani), three Gram-negative bacteria (Escherichia
coli, Salmonella typhi, Vibrio cholerae) and two fungi
(Aspergllus fumigatus, Candida albicans). Majority of the
compounds were found to be equipotent or more potent
than that of the standard drugs.
derivatives possess anti-inflammatory activity (Amr and
Abdulla, 2006). Moreover, the polysubstituted pyridines
represent molecular framework that serves as a platform
for the development of new antimicrobial 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 function-
alized 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).
On the premise that the quinoline moiety is found in a
large variety of naturally occurring compounds and also
chemically useful synthons bearing diverse bioactivities
like antimicrobial (Kategaonkar et al., 2010), antitubercu-
losis (Kumar et al., 2011), anti-inflammatory (Bava and
Kumar 2009), antitumor (Li et al., 2006), analgesic (Kidwai
and Negi, 1997), antimalarial (Dave et al., 2009, Charris
et al., 2005 and Kaur et al., 2010), anticancer activity
(Shi et al., 2008), and anti-HIV (Strekowski et al., 1991).
Over the past few years, we have been principally engrossed
in the synthesis of quinoline incorporating structures for
antimicrobial evaluations (Jardosh and Patel, 2012; Mungra
et al., 2011a, b; Shah et al., 2011; Makawana et al., 2011b,
c; Thumar and Patel, 2009a, b; Kathrotiya et al., 2012).
It has been established that the presence of a thiophen-
oxy group at the 2nd position of the quinoline nucleus
influences antimicrobial activity of quinoline derivatives
and thus plays a vital role in the development of new
antimicrobial drugs (Makawana et al., 2011d).
Keywords Penta-substituted pyridine ꢀ Quinoline ꢀ
One-pot reaction ꢀ Antimicrobial activity
Introduction
The pyridine ring system is considered to be one of the
most imperative heterocycle in nature as it has the dis-
tinction of being the parent nucleus in countless derivatives
of biologic relevance. Among them, 2-amino-3-cyanopyr-
idine derivatives are well known for their antimicrobial
activity (Makawana et al., 2011a; Mahmoud et al., 2007;
Mungra et al., 2009), isoniazid derivatives bearing the
pyridine nucleus possess anti-tubercular activity (Ashrafali
et al., 2010; Lourenco et al., 2007) and 3-cyano-2-pyridone
Various methods for the synthesis of penta-substituted
pyridines from aromatic and heterocyclic aldehydes using
different catalysts (Wang et al., 2009; Lakshmikantam
et al., 2010; Evdokimov et al., 2006; Heravi et al., 2010;
Mamgain et al., 2009; Sridhar et al., 2009; Singh and
M. B. Kanani ꢀ M. P. Patel (&)
Department of Chemistry, Sardar Patel University,
Vallabh Vidyanagar, Gujarat 388120, India
e-mail: patelmanish1069@yahoo.com
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Med Chem Res (2013) 22:2912–2920
2913
Singh, 2009; Banerjee and Sereda, 2009; Ranu et al., 2007)
are reported in the literature but not a single report has been
found where 2-thiophenoxy-3-formyl quinoline using
piperidine as the catalyst. Also, the most suitable protocol
for the synthesis of functionalized organic compounds
would be a one-pot reaction because the synthesis can be
performed without the isolation of intermediates and within
a short time (Boulard et al., 2004). Thus, in a view to
obtain biologically more potent heterocyclic system con-
taining two therapeutically active moieties, quinoline and
pyridine, the synthesis of some new penta-substituted
pyridine derivatives bearing quinoline nucleus by means of
the approach of multi-component reaction (MCR) is
reported in this article.
3-carbaldehydes 3(a–f), malononitrile 4 and thiophenols 5(a–
c) in ethanol, containing a catalytic amount of piperidine at
reflux temperature to afforded the target compounds 6(a–r) in
good to excellent yield (71–90 %). The formation of com-
pounds 6(a–r) may proceed via the initial formation of an
intermediate 7 afforded by Knoevenagel condensation of an
aldehyde with malononitrile, which would undergo intermo-
lecular cyclization, driven through the nucleophilic attack of
thiophenols in basic reaction medium.
The structures of all the synthesized compounds were
confirmed by 1H NMR, 13C NMR, and FTIR spectrometry.
Elemental analysis and mass spectrometry were performed
1
for few selected compounds. In the H NMR (DMSO-d6)
spectrum of compound 6n, aromatic protons, as well as –NH2
protons, resonate as multiplets at d = 7.256–8.375 ppm and
protons from three methyl groups resonate as multiplets at
d = 2.35, 2.37 and 2.38 ppm. The 13C NMR spectrum of
compound 6n exhibited signals at d = 21.34, 21.42, and
21.48 ppm for three methyl groups in the molecule. All the
aromatic carbon atoms of compound 6n showed signals
d = 115–166 ppm in the 13C NMR spectrum. The C-3 and
C-5 carbon atoms of the pyridine ring, attached to the nitrile
group, exhibited signals at d = 88.59 and 94.58 ppm,
respectively. The IR spectrum of compound 6n exhibited two
characteristic absorption bands at 3470–3372 cm-1 for
symmetric and asymmetric N–H stretching and one band at
for 2210 –C:N stretching. Absorption band at 759 cm-1 is
mainly attributed to thioether linkage. The structures of the
selected compounds, 6c, 6l, and 6n, were confirmed by mass
spectrometry. The mass spectra detected the expected
Result and discussion
Chemistry
The reaction sequence employed for the syntheses of the title
compounds 3(a–f) and 6(a–r) is depicted in Schemes 1, 2. The
starting materials 2-chloro-3-formylquinolines 1(a–b) were
synthesized according to the Vilsmeier-Haack reaction (Meth-
Cohn and Bramha, 1978) and converted to 2-thiophenox-
yquinolin-3-carbaldehydes 3(a–f) by nucleophilic displace-
ment of a chloro group at C-2 of 1(a–b) with substituted
thiophenoxygroupsinthepresenceofdimethylformamideand
anhydrous potassium carbonate. Subsequently, the one-pot
three component cyclocondensation of 2-thiphenoxyquinolin-
Scheme 1 Synthetic pathway
for the synthesis of pyridine
derivatives of
2-thiophenoxyquinoline 6(a–r)
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Med Chem Res (2013) 22:2912–2920
Scheme 2 Plausibe
mechanistic pathway for the
synthesis of pyridine derivatives
6(a–r)
molecular ion signals corresponding to respective molecular
formula of synthesized compounds. Mass spectra of com-
pound 6n gave molecular ion peak at 529.7 (M ? 1) corre-
sponding to the molecular formula C31H23N5S2. The
spectroscopicdata for all thesynthesized compoundare given
in the experimental section.
sulfoxide (DMSO) was used as the vehicle to get the desired
concentrations of compounds. The compounds showing
activity against microbes in the primary screening were
further screened in a second set of dilution at concentrations
of 200, 100, 62.5, 50, and 25 lg/mL. The suspension of
10 lL was further inoculated in a 96-well plate and growth
was noted after 24 and 48 h. The lowest concentration,
which showed no visible growth (turbidity) after spot sub-
culture, was considered as the minimum inhibitory con-
centration (MIC) for each compound. In the present study,
ampicillin and norfloxacin were used as standard antibac-
terial drugs, whereas griseofulvin was used as standard
antifungal drug. The values of MIC are summarized in
Table 1.
Antimicrobial activity
All the glasswares were sterilized before use. Antimicro-
bial activity of all the synthesized compounds was carried
out by broth microdilution method [National Committee
for Clinical Laboratory Standards (NCCLS) (2002)].
Mueller–Hinton broth was used as the nutrient medium for
the test bacteria and Sabouraud dextrose broth was for the
test fungi. Inoculum size for the test strains was adjusted to
108 CFU [Colony Forming Unit] per milliliter by com-
paring the Mac Fernald standard turbidity. The strains used
for [MTCC—Microbial Type Culture Collection] antimi-
crobial activity were procured from the Institute of
Microbial Technology, Chandigarh, India. Each synthe-
sized compound was diluted with DMSO so as to have the
stock solution of 2000 lg/mL concentration as a stock solu-
tion. The results were recorded in the form of primary and
secondary screening. The compounds 3(a–f) and 6(a–r)
were screened for their antibacterial activity against
Streptococcus pneumoniae (MTCC 1936), Clostridium
tetani (MTCC 449), Bacillus subtilis (MTCC 441), Sal-
monella typhi (MTCC 98), Vibrio cholerae (MTCC 3906),
and Escherichia coli (MTCC 443) as well as for antifungal
activity against Aspergillus fumigatus (MTCC 3008)
and Candida albicans (MTCC 227) at concentrations of
1000, 500, and 250 lg/mL for primary screening. Dimethyl
The examination of the data summarized in Table 1
reveals that many compounds were found to be active
against Gram-positive bacteria, while some of the com-
pounds were found to be active against Gram-negative
bacterial and fungal species compared to that of standard
antimicrobial drugs.
Review of the antimicrobial activities of 2-thiophenoxy-
quinolines and their pyridine derivatives (Table 1) indicated
that compounds 3c (R1 = H, R2 = Cl) and 3f (R1 = CH3,
R2 = Cl) showed MIC = 200 lg mL-1 and 100 lg mL-1
,
respectively against E. coli; but, upon cyclocondensation of
these compounds with malononitrile and 4-chlorothiophenol
theresult compounds6h (R1 = H, R2 = Cl, R3 = Cl)and6p
(R1 = CH3, R2 = Cl, R3 = Cl) have been found to possess
increased potency since MIC for both the compounds was
62.5 lg mL-1 against E. coli. Similarly, compounds 3d
(R1 = CH3, R2 = H) and 3f (R1 = CH3, R2 = Cl) showed
MIC = 200 lg mL-1 and MIC = 100 lg mL-1, respec-
tively, against gram negative bacteria E. coli, but their
cyclocondensed derivatives, 6l (R1 = CH3, R2 = H, R3 = Cl)
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Med Chem Res (2013) 22:2912–2920
2915
Table 1 In vitro antimicrobial activity of 2-thiophenoxyquinolines 3a–f and their pyridine derivatives 6a–r
Compound
Minimum inhibitory concentration (MIC, lg/ml)
Gram-positive bacteria Gram-negative bacteria
Fungi
S.P.
MTCC
1936
C.T.
MTCC
449
B.S.
MTCC
441
S.T.
MTCC
98
V.C.
MTCC
3906
E.C.
MTCC
443
A.F.
MTCC
3008
C.A.
MTCC
227
3a(R1 = H, R2 = H)
200
250
100
500
250
500
500
250
500
250
200
250
200
200
100
250
250
500
250
200
250
250
100
500
100
10
250
250
200
250
250
500
500
250
200
200
250
100
200
250
500
250
200
200
500
250
100
250
250
500
250
50
200
250
250
500
250
500
500
200
250
250
250
200
100
100
250
250
500
500
250
100
250
250
100
500
250
100
50
250
250
250
200
200
125
200
125
250
125
250
200
200
100
200
200
100
100
200
125
100
200
200
100
100
10
200
250
200
250
125
100
200
250
250
200
200
200
100
200
200
250
500
200
250
250
200
100
250
200
100
10
200
200
250
200
250
100
250
100
250
200
250
200
100
62.5
200
200
250
50
1000
200
250
1000
1000
[1000
500
3b(R1 = H, R2 = CH3)
3c(R1 = H, R2 = Cl)
[1000
[1000
250
3d(R1 = CH3, R2 = H)
3e(R1 = CH3, R2 = CH3)
3f(R1 = CH3, R2 = Cl)
1000
500
200
6a(R1 = H, R2 = H, R3 = H)
6b(R1 = H, R2 = H, R3 = CH3)
6c(R1 = H, R2 = H, R3 = Cl)
6d(R1 = H, R2 = CH3, R3 = H)
6e(R1 = H, R2 = CH3, R3 = CH3)
6f(R1 = H, R2 = CH3, R3 = Cl)
6g(R1 = H, R2 = Cl, R3 = H)
6h(R1 = H, R2 = Cl, R3 = CH3)
6i(R1 = H, R2 = Cl, R3 = Cl)
6j(R1 = CH3, R2 = H, R3 = H)
6k(R1 = CH3, R2 = H, R3 = CH3)
6l(R1 = CH3, R2 = H, R3 = Cl)
6m(R1 = CH3, R2 = CH3, R3 = H)
6n(R1 = CH3, R2 = CH3, R3 = CH3)
6o(R1 = CH3, R2 = CH3, R3 = Cl)
6p(R1 = CH3, R2 = Cl, R3 = H)
6q(R1 = CH3, R2 = Cl, R3 = CH3)
6r(R1 = CH3, R2 = Cl, R3 = Cl)
Ampicillin
250
250
1000
1000
500
1000
[1000
1000
[1000
1000
[1000
1000
250
1000
[1000
200
250
500
1000
1000
[1000
[1000
250
500
250
100
200
100
62.5
200
50
500
1000
[1000
[1000
250
1000
1000
[1000
500
500
100
10
–
–
Norfloxacin
–
–
Ciprofloxacin
50
100
–
25
25
25
–
–
Griseofulvin
–
–
–
–
–
100
500
Nystatin
–
–
–
–
–
–
100
100
S.P., Streptococcus pneumoniae; C.T., Clostridium tetani; B.S., Bacillus subtilis; S.T., Salmonella typhi; V.C., Vibrio cholerae; E.C., Esche-
richia coli; A.F., Aspergillus fumigatus; C.A., Candida albicans
‘–’ represents ‘not tested’
Bold numbers indicate more or equally potent compounds compared to standard drugs
and 6r (R1 = CH3, R2 = Cl, R3 = Cl) displayed excellent
activity (MIC = 50 lg mL-1) against E. coli.
more effective against C. albicans than griseofulvin
(MIC = 500 lg mL-1).
Compounds 6f and 6o (MIC = 100 lg mL-1) showed
excellent activity toward C. tetani compared to ampicillin
(MIC = 250 lg mL-1). Against Gram-positive bacteria B.
Against B. subtilis, compounds 6c, 6d, 6e, 6i, 6j, 6m, 6o,
and 6p (MIC = 250 lg mL-1) were found to be equipo-
tent with ampicillin (MIC = 250 lg mL-1). In case of S.
typhi, compounds 6h, 6k, 6l, 6o, and 6r (MIC = 100 lg
mL-1) displayed inhibition similar to ampicillin (MIC =
100 lg mL-1). Compounds 6i and 6q (MIC = 100 lg
mL-1) showed results equivalent to that of ampicillin
(MIC = 100 lg mL-1) toward S. pneumonia. Against
C.tetani, compounds 6b, 6e, 6h, 6j, 6n, 6p, and 6q
Subtilis, compound 6g, 6h, 6n, and 6q (MIC = 100 lgmL-1
)
showed activity higher than that of ampicillin (MIC = 250
lg mL-1) and equivalent to norfloxacin (MIC = 100 lg
mL-1). Compounds 6c, 6d, 6g, and 6k (MIC = 200 lg
mL-1) displayed activity better than ampicillin toward C.
tetani. Compound6g (MIC = 200 lg mL-1)wasfoundtobe
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Med Chem Res (2013) 22:2912–2920
(MIC = 250 lg mL-1) were found to be equipotent with
ampicillin (MIC = 250 lg mL-1).
2400 series-II elemental analyzer and all compounds are
within the range of 0.4 %. The IR spectra were recorded
by KBr pellet method on a Perkin-Elmer Spectrum GX
FT-IR spectrophotometer. The characteristic peaks are
reported in cm-1. The 1H NMR and 13C NMR spectra were
recorded in DMSO-d6 on a Bruker Avance NMR spec-
trometer using TMS as an internal standard, at 400 MHz
and 100 MHz, respectively. Chemical shifts are reported in
parts per million (ppm). Mass spectra were scanned on a
Shimadzu LCMS 2010 spectrometer (Shimadzu, Tokyo,
Japan).
Moreover, against C. albicans, compounds 6a, 6h, and 6n
(MIC = 250 lg mL-1) revealed better inhibitory action as
compared to the standard drug griseofulvin (MIC = 500 lg
mL-1), whereas compounds 6d, 6i, and 6r (MIC = 500 lg
mL-1
)
showed activity comparable to griseofulvin
(MIC = 500 lg mL-1). Majority of the compounds were
active toward E. coli, B. subtilis, and C. tetani. Unfortunately,
none of the synthesized compounds were found sufficiently
potent to inhibit fungal pathogen A. fumigatus.
The compounds 6(a–r) exerted significant inhibitory
activities against the growth of tested bacterial and fungal
strains (Table 1). The data also revealed that derivatization
at positions R1, R2, and R3 of the parent molecule pro-
duced marked improvement in the potency of the synthe-
sized analogs as antimicrobial agents and demonstrated the
following assumptions regarding the structural activity
relationship (SAR).
General procedure for the synthesis of compounds
6(a–r)
A mixture of 2-thiophenoxy-quinoline 3(a–f) (5 mmol),
malononitrile 4 (10 mmol), thiophenol 5(a–c) (5 mmol),
and piperidine (5 mol%) in ethanol (10 ml) was charged in
a 100-ml round bottom flask equipped using a condenser.
The reaction mixture was stirred at reflux temperature for
3.5 h. After completion of a reaction, monitored by TLC,
the separated solid was filtered, washed with methanol, and
recrystallized from chloroform to obtain the pure solid
compounds 6(a–r). The physicochemical and spectro-
scopic characterization data of the synthesized compounds
6(a–r) are given below.
Compound 6h (R1 = H, R2 = Cl, R3 = Cl) revealed
outstanding inhibitory action against most of the tested
bacteria and fungi but replacement of H by CH3 at R1
decreased the potency of the resulting compound 6q
(R1 = CH3, R2 = Cl, R3 = Cl) against E. coli and S. ty-
phi. Moreover, Compounds having electron-withdrawing
Cl group at position R2 improves the antimicrobial activity
of the compounds 6h, 6i, 6q, and 6r against S. typhi and
E. coli. Furthermore, the replacement of –H with –CH3 at
the 6-position of the quinoline nucleus makes a marked
difference in the antimicrobial effectiveness of the tested
compounds. Compound 6h (R1 = H, R2 = Cl, R3 = CH3)
revealed outstanding inhibitory action against E. coli
(MIC = 62.5 lg mL-1), S. typhi (MIC = 100 lg mL-1),
and C. albicans (MIC = 250 lg mL-1); but, upon
replacing (R1 = H) by (R1 = CH3) increase the potency
of the resulting compound 6q (R1 = CH3, R2 = Cl,
R3 = CH3) against E. coli (MIC = 62.5 lg mL-1),
S. typhi (MIC = 100 lg mL-1) and C. albicans (MIC =
250 lg mL-1) was observed.
2-Amino-6-(phenylthio)-4-(20-(phenylthio)quinolin-30-
yl)pyridine-3,5-dicarbonitrile (6a)
Yield 76 %, m.p. 229 °C, Anal. Calcd. for C28H17N5S2
(487.09 gm/mol): C 68.97, H 3.51, N 14.36 % Found: C
68.74, H 3.29, N 14.16 %. IR (KBr, cm-1): 3400 and 3370
1
(N–H str), 2215 (C:N str), 756 (C–S–C thioether str). H
NMR (400 MHz, DMSO-d6): d 7.41–8.93 (m, 17H,
Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d: 88.70
(C–C:N), 94.73 (C–C:N), 128.23, 128.91, 129.60,
129.88, 129.94, 130.08, 130.42, 132.32, 134.51, 135.51,
138.08, 114.93, 115.25, 125.74, 127.12, 127.71, 127.75,
148.01(Ar–C), 155.51, 155.69, 159.82, 166.68 (Ar–C–S).
Experimental
2-Amino-4-(20-(phenylthio)quinolin-30-yl)-6-
(p-tolylthio)pyridine-3,5-dicarbonitrile (6b)
All the reagents were obtained commercially and after
further purification. Solvents used were of analytical grade.
All the melting points were taken in open capillaries and
are uncorrected. Thin-layer chromatography (TLC, on
aluminum plates precoated with silica gel 60 F254, 0.25-
mm thickness, Merck Darmstadt, Germany) was used for
monitoring the progress of all reactions. Hexane:Ethyl-
acetate (1:1) was used as an eluent and UV radiation and/or
iodine were used as the visualizing agents. Elemental
analysis (% C, H, N) was carried out using Perkin-Elmer
Yield 71 %, m.p.211 °C, Anal. Calcd. for C29H19N5S2
(501.11 gm/mol) C 69.44, H 3.82, N 13.96 % Found: C
6924, H 3.70, N 13.71 %. IR (KBr, cm-1): 3412 and 3315
1
(N–H str), 2203 (C:N str), 761 (C–S–C thioether str). H
NMR (400 MHz, DMSO-d6), d: 2.31 (s, 3H, CH3),
7.41–8.93 (m, 16H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 21.36 (CH3), 88.61 (C–C:N), 94.49 (C–
C:N), 128.70, 129.40., 129.69, 129.84, 130.19, 130.32,
130.52, 134.68, 135.61, 138.50, 115.07, 115.15, 125.20,
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Med Chem Res (2013) 22:2912–2920
2917
125.89, 127.57, 127.61, 128.43, 148.10 (Ar–C), 155.31,
155.51, 159.91, 167.03 (Ar–C–S).
64.61, H 3.10, N 12.77 %. IR (KBr, cm-1): 3425 and 3365
1
(N–H str), 2217 (C:N str), 739 (C–S–C thioether str). H
NMR (400 MHz, DMSO-d6), d: 2.35 (s, 3H, CH3),
7.41–8.93 (m, 15H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 21.35 (CH3), 88.51 (C–C:N), 94.68 (C–
C:N), 129.61, 129.81, 129.97, 130.09, 130.24, 132.49,
134.61, 135.61, 138.10, 114.91, 115.24, 125.77, 127.17,
127.81, 127.91, 128.29, 128.49, 148.19 (Ar–C), 155.49,
155.71, 159.72, 166.19 (Ar–C–S).
2-Amino-6-(400-chlorophenylthio)-4-(20-
(phenylthio)quinolin-30-yl)pyridine-3,5-dicarbonitrile (6c)
Yield 86 %, m.p. 219 °C, Anal. Calcd. for C28H16ClN5S2
(521.05 gm/mol) C 64.42, H 3.09, N 13.42 % Found: C
64.25, H 2.7, N 13.29 %. IR (KBr, cm-1): 3480 and 3320
1
(N–H str), 2212 (C:N str), 772 (C–S–C thioether str). H
NMR (400 MHz, DMSO-d6), d: 7.41–8.93 (m, 16H,
Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d: 88.73
(C–C:N), 94.51 (C–C:N), 128.71, 129.71, 129.81,
130.01, 130.38, 130.82, 132.42, 134.61, 135.81, 138.02,
114.87, 115.17, 125.47, 127.21, 127.69, 127.57, 128.31,
148.30(Ar–C), 155.31, 155.61, 159.92, 165.90 (Ar–C–S).
MS (m/z): 522 (M?), 523 (M ? 2).
2-Amino-4-(20-(400-chlorophenylthio)quinolin-30-yl)-6-
(phenylthio)pyridine-3,5-dicarbonitrile (6g)
Yield 74 %, m.p. 227 °C, Anal. Calcd. for C28H16ClN5S2
(521.05 gm/mol) C 64.42, H 3.09, N 13.42 % Found: C
64.33, H 2.88, N 13.07 %. IR (KBr, cm-1): 3438 and 3350
1
(N–H str), 2207 (C:N str), 745 (C–S–C thioether str). H
NMR (400 MHz, DMSO-d6), d: 7.41–8.93 (m, 16H,
Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d: 88.74
(C–C:N), 94.75 (C–C:N), 128.99, 129.61, 129.87,
129.89, 130.09, 130.59, 132.69, 134.51, 135.91, 138.09,
114.97, 115.29, 125.79, 127.17, 127.59, 127.79, 128.31,
148.11 (Ar–C), 155.52, 155.01, 159.01, 166.03 (Ar–C–S).
2-Amino-6-(phenylthio)-4-(20-(p-tolylthio)quinolin-30-
yl)pyridine-3,5-dicarbonitrile (6d)
Yield 82 %, m.p. 232 °C, Anal. Calcd. for C29H19N5S2
(501.11 gm/mol) C 69.44, H 3.82, N 13.96 % Found: C
69.35, H 3.67, N 13.69 %. IR (KBr, cm-1): 3460 and 3340
1
(N–H str), 2210 (C:N str), 749 (C–S–C thioether str). H
2-Amino-4-(20-(400-chlorophenylthio)quinolin-30-yl)-6-
(p-tolylthio)pyridine-3,5-dicarbonitrile (6h)
NMR (400 MHz, DMSO-d6), d: 2.34 (s, 3H, CH3),
7.41–8.93 (m, 16H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 21.41 (CH3), 88.69 (C–C:N), 94.69 (C–
C:N), 128.90, 129.69, 130.01, 130.20, 130.69, 130.97,
132.41, 134.91, 135.61, 138.07, 115.08, 115.25, 125.69,
127.32, 127.79, 127.89, 128.32, 148.50 (Ar–C), 155.71,
155.73, 159.92, 166.94 (Ar–C–S).
Yield 90 %, m.p. 237 °C, Anal. Calcd. for C29H18ClN5S2
(535.07 gm/mol): C 64.97, H 3.38, N 13.06 % Found: C
64.73, H 3.21, N 12.97 %. IR (KBr, cm-1): IR, m/cm-1
:
3450 and 3310 (N–H str), 2213 (C:N str), 759 (C–S–C
1
thioether str). H NMR (400 MHz, DMSO-d6), d: 2.34 (s,
3H, CH3), 7.41–8.93 (m, 15H, Ar–H ? NH2). 13C NMR
(100 MHz, DMSO-d6) d: 21.45 (CH3), 88.8 (C–C:N),
94.51 (C–C:N), 128.06, 130.72, 133.39, 134.28, 134.71,
135.64, 137.29, 139.39, 140.31, 115.07, 115.39, 123.67,
125.7, 126.78, 126.86, 127.53, 128.89, 146.71 (Ar–C),
154.91, 155.61, 159.71, 166.59 (Ar–C–S).
2-Amino-6-(p-tolylthio)-4-(20-(p-tolylthio)quinolin-30-
yl)pyridine-3,5-dicarbonitrile (6e)
Yield 80 %, m.p. 232 °C, Anal. Calcd. for C30H21N5S2
(515.12gm/mol) C 69.88, H 4.10, N 13.58 % Found: C
69.53, H 3.80, N 13.29 %. IR (KBr, cm-1): 3400 and 3370
1
(N–H str), 2209 (C:N str), 730 (C–S-C thioether str). H
2-Amino-6-(400-chlorophenylthio)-4-(20-(4000-
chlorophenylthio)quinolin-30-yl)pyridine-3,5-dicarbonitrile
(6i)
NMR (400 MHz, DMSO-d6), d: 2.30 (s, 3H, CH3), 2.00 (s,
3H, CH3), 7.41–8.93 (m, 15H, Ar–H ? NH2). 13C NMR
(100 MHz, DMSO-d6) d: 21.32 (CH3), 21.39 (CH3), 88.68
(C–C:N), 94.59 (C–C:N), 129.50, 129.50, 129.50,
130.29, 130.42, 132.63, 134.89, 135.71, 138.52, 115.19,
115.19, 125.98, 127.30, 127.69, 127.76, 128.39, 128.79,
148.20 (Ar–C), 155.21, 155.61, 159.10, 166.61 (Ar–C–S).
Yield 79 %, m.p. 231 °C, Anal. Calcd. for C28H15N5S2Cl
(555.01 gm/mol): C 60.43, H 2.72, N 12.58 % Found: C
60.23, H 2.41, N 12.35 %. IR (KBr, cm-1): 3468 and 3323
1
(N–H str), 2201 (C:N str), 765 (C–S–C thioether str). H
NMR (400 MHz, DMSO-d6), d: 7.41–8.93 (m, 15H,
Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d: 88.53
(C–C:N), 94.70 (C–C:N), 128.01, 130.74, 132.78,
133.40, 134.48, 134.81, 135.61, 137.30, 139.41, 140.21114.91,
115.29, 123.69, 125.79, 126.89, 127.51, 127.90, 146.73
(Ar–C), 154.92, 155.63, 159.70, 166.69 (Ar–C–S).
2-Amino-6-(400-chlorophenylthio)-4-(20-(p-
tolylthio)quinolin-30-yl)pyridine-3,5-dicarbonitrile (6f)
Yield 77 %, m.p.218 °C, Anal. Calcd. for C29H18ClN5S2
(535.07gm/mol) C 64.97, H 3.38, N 13.06 % Found: C
123

2918
Med Chem Res (2013) 22:2912–2920
1
2-Amino-4-(60-methyl-20-(phenylthio)quinolin-30-yl)-6-
(phenylythio)pyridine-3,5-dicarbonitrile (6j)
(N–H str), 2243 (C:N str), 741 (C–S–C thioether str). H
NMR (400 MHz, DMSO-d6), d: 2.39 (s, 3H, CH3), 2.46 (s,
3H, CH3), 7.42–8.93 (m, 15H, Ar–H ? NH2). 13C NMR
(100 MHz, DMSO-d6) d: 21.39 (CH3), 21.43 (CH3), 88.64
(C–C:N), 94.59 (C–C:N), 129.61, 129.88, 129.93,
130.09, 130.41, 132.41, 134.59, 135.47, 138.07, 114.99,
115.49, 125.39, 127.31, 127.79, 128.07, 128.41, 128.99,
148.09(Ar–C), 155.71, 155.71, 159.91, 166.81(Ar–C–S).
Yield 73 %, m.p. 209 °C, Anal. Calcd. for C29H19N5S2
(501.11 gm/mol): C 69.44, H 3.82, N 13.96 % Found: C
69.23, H 3.69, N 13.66 %. IR (KBr, cm-1): 3415 and 3340
1
(N–H str), 2209 (C:N str), 747 (C–S–C thioether str). H
NMR (400 MHz, DMSO-d6), d: 2.38 (s, 3H, CH3),
7.41–8.93 (m, 16H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 21.46 (CH3), 88.48 (C–C:N), 94.69 (C–
C:N), 128.08, 130.72, 130.79, 133.31, 134.21, 134.62,
135.45, 137.29, 139.34, 140.31, 115.04, 115.39, 129.69,
125.70, 126.89, 127.86, 127.60, 127.81, 146.81 (Ar–C),
154.89, 155.61, 159.85, 166.91(Ar–C–S).
2-Amino-4-(60-methyl-20-(p-tolylthio)quinolin-30-yl)-6-
(p-tolylthio)pyridine-3,5-dicarbonitrile (6n)
Yield 87 %, m.p. 235 °C, Anal. Calcd. for C31H23N5S2
(529.14 gm/mol): C 70.29, H 4.38, N 13.22 % Found: C
70.01, H 4.19, N 13.07 %. IR (KBr, cm-1): 3470 and 3372
2-Amino-4-(6-methyl-20-(phenylthio)quinolin-30-yl)-6-
(p-tolythio)pyridine-3,5-dicarbonitrile (6k)
1
(N–H str), 2210 (C:N str), 759 (C–S–C thioether str). H
NMR (400 MHz, DMSO-d6), d: 2.37 (s, 3H, CH3), 2.43 (s,
3H, CH3), 2.56 (s, 3H, CH3), 7.41–8.93 (m, 14H,
Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d: 21.34
(CH3), 21.42 (CH3), 21.48 (CH3), 88.59 (C–C:N), 94.58
(C–C:N), 128.05, 130.52, 130.72, 133.28, 134.18,
134.61, 135.46, 137.26, 115.02, 115.29, 123.66, 125.74,
126.68, 127.50, 127.80, 139.25, 140.21, 146.70(Ar–C),
154.96, 155.67, 159.90, 166.98(Ar–C–S). MS (m/z): 529.7
(M?).
Yield 77 %, m.p. 215 °C, Anal. Calcd. for C30H21N5S2
(515.12 gm/mol): C 69.88, H 4.10, N 13.58 % Found: C
69.57, H 3.90, N 13.29 %. IR (KBr, cm-1): 3455 and 3380
(N–H str), 2214 (C:N str), 751 (C–S–C thioether str).1H
NMR (400 MHz, DMSO-d6), d: 2.36 (s, 3H, CH3), 2.38 (s,
3H, CH3), 7.41–8.93 (m, 15H, Ar–H ? NH2). 13C NMR
(100 MHz, DMSO-d6) d: 21.41 (CH3), 21.49 (CH3), 88.49
(C–C:N), 94.52 (C–C:N), 130.53, 130.61, 133.29,
134.16, 134.46, 135.49, 137.16, 139.34, 140.31 115.06,
115.31, 123.70, 125.89, 126.69, 127.54, 127.89, 129.09,
146.81(Ar–C), 154.91, 155.69, 155.89, 166.82 (Ar–C–S).
2-Amino-6-(400-chlorophenylthio)-4-(60-methyl-20-
(p-tolylthio)quinolin-30-yl)pyridine-3,5-dicarbonitrile (6o)
Yield 75 %, m.p. 230 °C, Anal. Calcd. for C30H20ClN5S2
(549.08 gm/mol): C 65.50, H 3.66, N 12.73 % Found: C
65.21, H 3.42, N 12.57 %. IR (KBr, cm-1): 3465 and 3370
2-Amino-6-(400-chlorophenylthio)-4-(60-methyl-
20-(phenylthio)quinolin-30-yl)pyridine-3,5-
dicarbonitrile (6l)
1
(N–H str), 2206 (C:N str), 768 (C–S–C thioether str). H
NMR (400 MHz, DMSO-d6), d: 2.35 (s, 3H, CH3), 2.44 (s,
3H, CH3), 7.41–8.93 (m, 14H, Ar–H ? NH2). 13C NMR
(100 MHz, DMSO-d6) d: 21.33 (CH3), 21.41 (CH3), 88.62
(C–C:N), 94.69 (C–C:N), 130.77, 133.29, 134.28,
134.67, 135.47, 132916, 139.14, 140.27, 115.07, 115.32,
123.63, 125.77, 126.68, 127.51, 127.80, 129.07, 130.57,
146.77(Ar–C), 154.90, 155.77, 155.98, 167.03(Ar–C–S).
Yield 82 %, m.p. 225 °C, Anal. Calcd. for C29H18ClN5S2
(535.07 gm/mol): C 64.97, H 3.38, N 13.06 % Found: C
64.57, H 3.21, N 12.89 %. IR (KBr, cm-1): 3430 and 3380
1
(N–H str), 2217 (C:N str), 741 (C–S–C thioether str). H
NMR (400 MHz, DMSO-d6), d: 2.34 (s, 3H, CH3),
7.41–8.93 (m, 15H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 21.49 (CH3), 88.61 (C–C:N), 94.63 (C–
C:N), 130.53, 130.70, 133.29, 134.29, 134.71, 135.61,
137.29, 139.51, 140.31, 115.07, 115.37, 123.69, 125.84,
126.81, 127.54, 127.84, 128.09, 146.71(Ar–C), 154.91,
155.71, 159.93, 166.99(Ar–C–S). MS (m/z): 535.8 (M?),
536.8(M ? 2).
2-Amino-4-(20-(400-chlorophenylthio)-60-methylquinolin-30-
yl)-6-(phenylthio)pyridine-3,5-dicarbonitrile (6p)
Yield 73 %, m.p.223 °C, Anal. Calcd. for C29H18ClN5S2
(535.07 gm/mol): C 64.97, H 3.38, N 13.06 % Found: C
64.73, H 3.17, N 12.81 %. IR (KBr, cm-1): 3455 and 3350
2-Amino-4-(60-methyl-20-(p-tolylthio)quinolin-30-yl)-6-
(phenylthio)pyridine-3,5-dicarbonitrile (6m)
1
(N–H str), 2211 (C:N str), 721 (C–S–C thioether str). H
NMR (400 MHz, DMSO-d6), d: 2.41 (s, 3H, CH3),
7.41–8.93 (m, 15H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 21.47 (CH3), 88.53 (C–C:N), 94.64 (C–
C:N), 130.73, 133.29, 134.19, 134.71, 135.47, 137.29,
Yield 83 %, m.p. 217 °C, Anal. Calcd. for C30H21N5S2
(515.12 gm/mol): C 69.88, H 4.10, N 13.58 % Found: C
69.60, H 3.85, N 13.25 %. IR (KBr, cm-1): 3430 and 3380
123

Med Chem Res (2013) 22:2912–2920
2919
Instrumentation Centre for Applied Research and Training (SICART),
Vallabh Vidyanagar, for their help in performing elemental analysis.
Oxygen Healthcare Research Pvt. Ltd., Ahmedabad for providing
mass spectrometry facilities and Dhanji P. Rajani, Microcare Labo-
ratory, 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 Meritorious Students.
139.25, 140.29, 115.30, 115.21, 123.61, 125.70, 126.71,
127.59, 127.89, 129.19, 130.62, 146.74(Ar–C), 154.98,
155.97, 155.96, 166.91(Ar–C–S).
2-Amino-4-(20-(400-chlorophenylthio)-60-methylquinolin-30-
yl)-6-(p-tolylthio)pyridine-3,5-dicarbonitrile (6q)
Yield 75 %, m.p. 230 °C, Anal. Calcd. for C30H20ClN5S2
(549.08 gm/mol): C 65.50, H 3.66, N 12.73 % Found: C
65.29, H 3.38, N 12.50 %. IR (KBr, cm-1): 3485 and 3315
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