Synthesis of novel 3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one condensed s-triazinyl piperazines and piperidines as antimicrobial agents

Article abstract of DOI:10.1007/s00044-011-9842-7

Synthesis and antimicrobial activity of a new series of 3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-2H-chromen- 2-ones based on various substituted piperazines and piperidines incorporating a 1,3,5-triazine moiety are reported in this article. 3-{5-[(4,6-dichloro

Full text of DOI:10.1007/s00044-011-9842-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3119–3132
DOI 10.1007/s00044-011-9842-7
ORIGINAL RESEARCH
Synthesis of novel 3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-2H-chromen-
2-one condensed s-triazinyl piperazines and piperidines
as antimicrobial agents
•
•
•
Rahul V. Patel Amit B. Patel Premlata Kumari
Kishor H. Chikhalia
Received: 19 August 2011 / Accepted: 21 October 2011 / Published online: 11 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Synthesis and antimicrobial activity of a new
series of 3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-2H-chromen-
2-ones based on various substituted piperazines and
piperidines incorporating a 1,3,5-triazine moiety are
reported in this article. 3-{5-[(4,6-dichloro-1,3,5-triazin-
2-yl)sulfanyl]-1,3,4-oxadiazol-2-yl}-2H-chromen-2-one 3
was obtained by the reaction of 2,4,6-trichloro-1,3,5-tri-
azine 1 with 3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-2H-chro-
men-2-one 2 which was obtained by following the method
reported in the literature. Intermediate 3 was then con-
densed with 8-hydroxyquinoline 4 to form 3-(5-{[4-chloro-
6-(quinolin-4-yloxy)-1,3,5-triazin-2-yl]sulfanyl}-1,3,4-ox-
adiazol-2-yl)-2H-chromen-2-one 5. This was further trea-
ted with various substituted piperazines and piperidines to
obtain the title compounds 7a–u, which were then sub-
jected to determine their in vitro biological efficacy against
bacterial and fungal strains as two Gram-positive bacteria
(S. aureus, B. cereus), six Gram-negative bacteria (E. coli,
P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris,
and S. flexneria) and two fungal species (A. niger, and
C. albicans) with an intent to develop novel class of anti-
microbial agents. The results indicate that some of the
novel s-triazines have noteworthy activity in MIC (lg/ml)
and zone of inhibition (mm) indicating potential leads for
further drug discovery study. All the final compounds were
1
structurally elucidated on the basis of IR, H NMR, 13C
NMR, 19F NMR spectroscopy, and elemental analysis.
Keywords 3-(5-Sulfanyl-1,3,4-oxadiazol-2-yl)-2H-
chromen-2-one Á 2,4,6-Trichloro-1,3,5-triazine Á
Antimicrobial activity
Introduction
During the past few decades, the human population is
affected with significant increase in the frequency of life-
treating infectious diseases because of the increasing
number of multi-drug-resistant microbial pathogens. These
organisms possessed the ability to withstand attack by
antimicrobial drugs currently available, and the uncon-
trolled rise in resistant pathogens, which threatens lives
(Nathan, 2004). Significant impact of the affliction of
infectious disease in developing countries highlights the
need for more antimicrobial therapeutic alternatives with
increased potency to maintain a pool of new bioactive
candidates. Its success crucially relies on the search for
new chemical entities, which are distinct from those of the
well-known classes of antimicrobial agents.
R. V. Patel (&) Á A. B. Patel Á P. Kumari
Department of Applied Chemistry, S. V. National Institute
of Technology, Surat 395 007, Gujarat, India
e-mail: rahul.svnit11@gmail.com
1,3,5-Triazines, electron-rich nitrogen heterocycles,
occupies an extremely important role in the field of
medicinal chemistry since they display a fascinating array
of pharmacological properties such as antimicrobial
(Udaya et al., 2010; Zhou et al., 2008; Srinivas et al.,
2006), antimycobacterial (Jignesh et al., 2010), anticancer
(Bakharev et al., 2008; Rita et al., 2004), and antiviral
(Yuan-Zhen et al., 2008). Besides, 1,3,4-oxadiazoles
A. B. Patel
e-mail: amit.svnit10@gmail.com
P. Kumari
e-mail: premlatakumari1@gmail.com
K. H. Chikhalia
Department of Chemistry, School of Science, Gujarat
University, Ahmedabad 380025, Gujarat, India
e-mail: chikhalia_kh@yahoo.com
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Med Chem Res (2012) 21:3119–3132
nucleus has drawn great attention because of its pharma-
cological importance as antibacterial (Desai and Amit,
2011; Mohammed et al., 2010; Jha et al., 2010; Chawla
et al., 2010; Vivek et al., 2008; Cacic et al., 2006; Sahin
et al., 2002) and antifungal (Liu et al., 2008; Chen et al.,
2007). Due to appealing diverse biological properties
among all the hydroxyquinoline derivatives, the adorable
chemistry of 8-hydroxyquinoline has gained much impor-
tance such as antimicrobial (Ritu et al., 2010; Okide et al.,
2000) and antituberculosis (Crystal and Carl, 2010;
Urbanski et al., 1951). In addition, piperazine and piperi-
dine derivatives have proved to elicit wide range of
inhibitory activities (Kerns et al., 2003; Upadhayaya et al.,
2004). Encouraged by the afore-mentioned findings, it was
rationalized to synthesize novel biologically active s-tri-
azinyl compounds supported with a variety of pharmaco-
phoric groups which would impart potential bioactivities.
Recently, we reported the synthesis and antimicrobial
activity of some new s-triazine analogues (Patel et al.,
2011) bearing 4-hydroxycoumarin as well as 7-hydroxy-4-
methyl coumarin moieties, and the compounds showed
good in vitro antimicrobial activity. Locking at the above
findings and to extend the structure–activity relationships
(SARs) of such s-triazine-based analogues, we have deci-
ded to introduce coumarin moiety in the form of oxadiazole
nucleus to the s-triazine core. The purpose of this investi-
gation was to elucidate the influence of the presence of
various cyclic amines to the s-triazine core and the effect of
the oxadiazole nucleus based on coumarin moiety to the
biological profiles of the resultant molecules.
carbohydrazide 1c. The resulting carbohydrazide moiety
was cyclized using sodium hydroxide in the presence of
carbon disulfide to form the corresponding cyclized oxadi-
azole nucleus, 3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-2H-
chromen-2-one 2. The resulting oxadiazole intermediate was
further treated with 2,4,6-trichloro-1,3,5-triazine in the
presence of triethyl amine at 0–5°C to obtain compound 3
in good yield. The intermediate 3 was reacted with
8-hydroxyquinoline at 45–50°C to afford the final interme-
diate 5 which was then treated with various piperazine and
piperidine bases to obtain the aimed compounds 7a–u at
reflux temperature. The correct synthesis of 7a–u was con-
firmed on the basis of IR, 1H NMR, 13C NMR, and 19F NMR
spectral analyses (Dandia et al., 2004), and the purity was
ascertained by elemental analysis (Scheme 2).
Antimicrobial activity
The antibacterial investigation carried out for the title
compounds presented in Table 1 revealed that all the final
analogues succeeded to indicate excellent to moderate
activity against the examined representative microorgan-
isms. Compounds 7s, 7t, and 7u with strong electronega-
tive trifluoromethyl functional group and electron-donating
methoxy functionalization at the phenyl ring of piperazine
base condensed to the nucleus contributed considerable
activity (MIC, 12.5 lg/ml) against both the mentioned
Gram-positive bacteria. In addition, same methoxy group-
substituted analogues (7t and 7u) along with compounds
7h, 7n, and 7i bearing electron-donating acetyl linkage to
the N-atom of piperazine ring and two methyl functional
groups at the third and fifth positions of piperidine moiety
and in the form of isopropyl linkage, respectively, endowed
with excellent activity (MIC, 12.5 lg/ml) against Gram-
negative strains, P. aeruginosa, S. typhi, and S. flexneria.
Final analogues with electron-withdrawing halogen sub-
stituent(s) like chlorine (7c, 7d, and 7p) and fluorine (7q,
7r, and 7s) exhibited strong inhibitory action toward Gram-
negative strains E. coli and P. vulgaris at the MIC level of
25 lg/ml. Moreover, condensation of unsubstituted het-
erocyclic moieties in the form of piperidine 7e and mor-
pholine 7f as well as in the form of pyridine or pyrimidine
Results and discussion
Chemistry
Synthesis of intermediates and target compounds was
accomplished according to the steps illustrated in Scheme 1.
Salicylaldehyde and diethylmalonate were reacted in the
presence of piperidine in ethanol to form ethyl-2-oxo-2H-
chromene-3-carboxylate 1b which on treatment with
99% hydrazine hydrate yielded 2-oxo-2H-chromonene-3-
Scheme 1 Synthetic pathway
for oxadiazole intermediate 2
O
C
O
C
COOCH2CH3
O
Piperidine
Ethanol
CHO
O
O
CH2
H2C
CH2
O
CH3
OH
H3C
1b
1a
N
N
CONHNH2
O
CS2/KOH
Ethanol
NHNH2.H2O
Ethanol
SH
O
O
O
O
1c
2
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Med Chem Res (2012) 21:3119–3132
3121
Scheme 2 Synthetic pathway
for final analogues 7a–u where,
[6a–u (R)] bases coupled to
compound 5
N N
Cl
N
N
Cl
N
Cl
N
Acetone
S
O
SH
O
N
N
N
10% NaHCO3
O
O
N
O
O
Cl
Cl
3
2
1
Cl
N
N
N
N
N
Acetone
S
O
N
O
3
10% NaHCO3
O
O
N
OH
5
R
N
4
N
N
N
N
N
1,4-dioxane
O
S
O
6 (a-u)
5
10% NaHCO3
O
O
7a-u
Where, [6a-u (R)] bases coupled to compound 5
O
6h
HN
N
CH3
HN
N
C
HN
N
CH
6o
6p
6a
CH3
CH3
CH3
HN
N
CH
F
6i
6b HN
N
CH2 CH3
HN
N
HC
N
Cl
Cl
6j
6q
N
HN
HN
HN
HN
N
6c HN
N
Cl
Cl
N
N
6k
6r
6s
N
F
HN
N
N
6d HN
N
CF3
6e
6l
HN
HN
CH2
HN
HN
N
OCH3
OCH3
H3CO
CH2
6f
6m
O
CH2
6t HN
N
CH3
6g
N
6n
6u
N
OCH3
HN
HN
HN
CH3
123

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Med Chem Res (2012) 21:3119–3132
Table 1 In-vitro antimicrobial activity
R
X
N
N
N
N
N
N
O
O
S
O
N
O
Entry
R
X
Zone of inhibition [mm (MIC in lg/ml)]
S.a B.c E.c P.a
K.p
12 (100)
S.t
16 (100)
P.v
11 (100)
S.f
18 (100)
7a
7b
7c
7d
CH3
N
N
N
N
13 (100) \10 (100)
12 (100)
19 (100)
18 (100)
14 (100)
20 (50)
C2H5
15 (100)
17 (100)
21 (50)
13 (100)
17 (100)
22 (25)
16 (100)
25 (25)
24 (25)
14 (100)
15 (100)
21 (25)
16 (100)
17 (100)
19 (100)
12 (100)
19 (100)
17 (100)
20 (100)
19 (100)
21 (100)
Cl
Cl
Cl
7e
7f
–CH2
O
11 (100) \10 (100) \10 (100)
15 (100)
16 (100)
13 (100)
20 (50)
22 (25)
14 (100) \10 (100) \10 (100)
14 (100)
15 (100) \10 (100)
12 (100) \10 (100)
16 (100) \10 (100)
11 (100)
7g
N
\10 (100)
11 (100) \10 (100)
15 (100) \10 (100)
7h
7i
COCH3
N
20 (50)
19 (100)
21 (50)
21 (50)
13 (100)
16 (100)
22 (25)
18 (100)
22 (25)
16 (100)
21 (50)
22 (25)
17 (100)
13 (100)
21 (50)
14 (100)
15 (100)
16 (100)
15 (100)
19 (100)
16 (100)
23 (12.5)
21 (25)
13 (100)
14 (100)
22 (25)
22 (25)
22 (12.5)
20 (50)
18 (100)
15 (100)
14 (100)
16 (100)
23 (25)
24 (25)
22 (50)
22 (50)
13 (100)
11 (100)
24 (25)
14 (100)
CH3
HC
N
CH3
7j
N
18 (100)
18 (100)
14 (100)
18 (100)
N
N
7k
7l
N
N
N
19 (100) \10 (100) \10 (100) \10 (100)
H2C
7m
7n
7o
–CH2
–CH2
N
12 (100) \10 (100) \10 (100)
14 (100) \10 (100)
H2C
3,5-CH3
CH
20 (50)
22 (12.5)
16 (100)
14 (100)
23 (12.5)
19 (100)
13 (100) \10 (100)
12 (100) \10 (100)
123

Med Chem Res (2012) 21:3119–3132
3123
Table 1 continued
Entry
R
X
N
Zone of inhibition [mm (MIC in lg/ml)]
S.a
B.c
E.c
P.a
K.p
S.t
P.v
S.f
16 (100)
7p
20 (50)
21 (50)
25 (25)
16 (100)
19 (100)
19 (100)
20 (100)
CH
Cl
F
7q
N
19 (100)
20 (50)
23 (25)
19 (100)
20 (50)
20 (50)
22 (25)
19 (100)
7r
7s
F
N
N
22 (25)
21 (50)
23 (25)
22 (50)
21 (50)
21 (25)
16 (100)
21 (25)
19 (100)
21 (50)
21 (50)
23 (25)
17 (100)
21 (100)
CF3
24 (12.5)
24 (12.5)
H3CO
H2C
OCH3
OCH3
7t
N
N
23 (12.5)
22 (25)
23 (12.5)
23 (12.5)
19 (100)
17 (100)
22 (12.5)
23 (12.5)
18 (100)
19 (100)
24 (12.5)
24 (12.5)
20 (100)
18 (100)
23 (25)
22 (50)
7u
OCH3
Cip.
30 (1.56)
–
31 (0.39)
–
32 (1.56)
–
33 (0.78)
–
33 (0.78)
–
30 (0.39)
–
31 (0.39)
–
32 (1.56)
–
DMSO
Cip.—ciprofloxacin, S.a—Staphylococcus aureus, B.c—Bacillus cereus, E.c—Escherichia coli, P.a—Pseudomonas aeruginosa, K.p—Klebsiella
pneumoniae, S.t—Salmonella typhi, P.v—Proteus vulgaris– S.f—Shigella flexneria
moieties attached to the piperazine coupling agent were
found essential to contribute to potential efficacy (MIC,
25 lg/ml) to inhibit the growth of Gram-negative strain
K. pneumoniae. The bioassay results obtained for the
efficacy of the newly synthesized analogues against fungal
strains is summarized in Table 2 revealed that the final
analogues with fluorine, chlorine, and methoxy substitution
at the phenyl ring of piperazine base (7c, 7d, 7n, 7p, 7r, 7s,
7t, and 7u) contributed the best antifungal activity against
both the mentioned fungal strains at the MIC level ranging
from 25 to 50 lg/ml.
activity when compared to their antifungal activity. Among
these compounds a clear trend of improved activity has
been shown to be because of the chloro or fluoro, methyl
linker in the form of acetyl group, isopropyl linker, and two
methyl group-substituted piperidine moieties as well as in
the form of methoxy functional group substitution to the
phenyl ring of piperazine bases. The oxadiazole nucleus
played an important role to contribute to the enhanced
activity. Therefore, it was concluded that there exists ample
scope for further study in this class of compounds with
appropriate structural modification. In order to gain more
bioactivity profile, the compounds are subjected to deter-
mine anticancer and anti-HIV activities, and the results will
be published in due course.
Conclusion
From the bioassay it is clear that the introduction of
appropriate substituent on the s-triazine ring would lead to
the more active antimicrobial derivatives. It can be stated
that the variation of antimicrobial activity may be associ-
ated with the nature of the tested microorganisms and is
due to the chemical structure of the tested compounds. In
general, the compounds showed improved antibacterial
Experimental section
Melting points were determined in open capillaries on a
Veego electronic apparatus VMP-D (Veego Instrument
Corporation, Mumbai, India) and used as uncorrected. IR
spectra (4,000–400 cm-1) of synthesized compounds were
123

3124
Med Chem Res (2012) 21:3119–3132
recorded on a Shimadzu 8400-S FT-IR spectrophotometer
(Shimadzu India PVT. LTD., Mumbai, India) using KBr
pellets at S. V. National Institute of Technology, Surat,
India. Thin layer chromatography was performed on object
glass slides (2 9 7.5 cm) coated with silica gel-G and
refluxed for 10 h. The content was concentrated to half of
the volume and allowed to cool. The solid mass thus
obtained (reaction was monitored by thin layer chroma-
tography in toluene–acetone solvent system) on cooling
was retained by filtering and washed with small amount of
ice-cooled ethanol to afford 1c as white solid, Yield: 88%,
mp: 137–140°C, IR (KBr) cm-1: 3385, 3290 (NHs), 1721
1
spots were visualized under UV irradiation. H NMR and
13C NMR spectra were recorded on a Varian 400 MHz
model spectrometer (Varian India PVT. LTD., Mumbai,
India) using DMSO as a solvent and TMS as internal
1
(CO, coumarin), 1687 (C=O, amide); H NMR (400 MHz,
DMSO-d6) d 8.24 (1H, s, H-4, coumarin), 8.12 (m, 1H,
CONHNH2), 7.62–7.39 (4H, m, Ar–H), 4.78 (s, 2H, NH2,
D2O exchangeable).
1
standard with H resonant frequency of 400 MHz and 13C
resonant frequency of 100 MHz. 19F NMR spectra were
obtained on the same spectrometer using CDCl3 as a sol-
vent and CFCl3 as an external standard, positive for
downfield shift with 19F resonant frequency of 400 MHz.
Synthesis of 3-(5-mercapto-1,3,4-oxadiazol-2-yl)-2H-
chromen-2-one 2
1
The H NMR, 13C NMR and 19F NMR chemical shifts
were reported as parts per million (ppm) downfield from
TMS (Me4Si) and CFCl3 and were performed at Centre for
Excellence, Vapi, India. The splitting patterns are desig-
nated as follows: s, singlet; d, doublet; m, multiplet.
Elemental analyses were performed on a Heraeus Carlo
Erba 1180 CHN analyzer. All the spectral data were con-
sistent with the proposed structure and micro-analysis
within 0.2% of theoretical values which are summarized
in Table 3 along with physical data.
To a solution of the 2-oxo-2H-chromene-3-carbohydrazide,
1c (2.5 g, 0.01 mol) in ethanol (50 ml) at 0°C, carbon
disulfide (0.01 mol), and potassium hydroxide (0.01 mol)
were added, and the reaction mixture was refluxed until the
evolution of H2S gas ceased. Excess solvents were evap-
orated under reduced pressure, and the residue was dis-
solved in water and then acidified with dilute hydrochloric
acid (10%) to pH 6. The precipitate was filtered off, dried,
and crystallized from ethanol to give 2 (Bhat et al., 2008).
The completion of reaction was monitored by thin layer
chromatography in n-hexane: ethyl acetate (8:2) solvent
system. Yield 72%, mp: 166–168°C, IR (KBr) cm-1: 2591
(SH), 1726 (CO, coumarin), 1629, 1531 (2C=N, oxadiaz-
ole), 1043 (C–O–C, oxadiazole); 1H NMR (400 MHz,
DMSO-d6) d 14.51 (br s, 1H, SH), 8.21 (1H, s, H-4, cou-
marin), 7.58–7.37 (m, 4H, Ar–H).
Synthetic part
Synthesis of ethyl 2-oxo-2H-chromene-3-carboxylate 1b
Salicylaldehyde 1a (10 g, 0.045 mol) and diethylmalonate
(7.34 g, 0.045 mol) were dissolved in ethanol (150 ml) to
give clear solution. Piperidine (18 ml) was added, and the
mixture was refluxed for 5 h. After the completion of the
reaction (monitored by thin layer chromatography in tolu-
ene–ethyl acetate solvent system), the content was con-
centrated to small volume. Then, the reaction mixture was
poured onto crushed ice, and the resulting solid was fil-
tered, dried, and recrystallized from ethanol to afford 1b as
3-{5-[(4,6-Dichloro-1,3,5-triazin-2-yl)sulfanyl]-1,3,4-
oxadiazol-2-yl}-2H-chromen-2-one 3
To a stirred solution of 2,4,6-trichloro-1,3,5-triazine
(18.4 g, 0.1 mol) in acetone (80 ml), the solution of 3-(5-
sulfanyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one (24.6 g,
0.1 mol) in acetone (100 ml) was added at 0–5°C, and the
pH was maintained neutral by the addition of potassium
bicarbonate solution. Stirring was continued at 0–5°C for
4 h. After the completion of the reaction, the stirring was
stopped, and the solution was treated with crushed ice. The
solid product obtained was filtered and dried. The progress
of the reaction was monitored by TLC using ethyl acetate–
hexane (6:4) as an eluent. The crude product was purified
by crystallization from absolute alcohol to get the title
compound 3 (Patel et al., 2010); Yield 85%, mp: 178–
180°C; IR (KBr) cm-1: 1729 (C=O, coumarin), 1624,
1527 (2C=N, oxadiazole), 1040 (C–O–C, oxadiazole), 696
(C–S–C), 833 (s-triazine C3N3 str.), 752 (–Cl str.).
a white solid. Yield: 86%, mp: 124–125°C, IR (KBr) cm-1
:
1745 (C=O, ester), 1725 (CO, coumarin), 1677 (C=O),
1
1231 (C–O); H NMR (400 MHz, DMSO-d6) d 8.27 (1H,
s, H-4, coumarin), 7.52–7.29 (4H, m, Ar–H), 3.56 (q,
J = 5.9 Hz, 2H, –COOCH2–), 1.29 (t, J = 6.6 Hz, 3H,
–COOCH2CH3).
Synthesis of 2-oxo-2H-chromene-3-carbohydrazide 1c
2-Oxo-2H-chromene-3-carboxylate, 1b (5.0 g, 0.023 mol)
and hydrazine hydrate 99% (1.15 g, 0.023 mol) were dis-
solved in ethanol (100 ml) to give clear solution and
123

Med Chem Res (2012) 21:3119–3132
3125
Table 2 In-vitro antifungal activity
Table 2 continued
R
X
Entry
R
X
N
Zone of inhibition
[mm (MIC in lg/ml)]
A.n
C.a
N
N
F
7q
21 (100)
19 (100)
N
N
N
N
O
O
S
O
7r
7s
F
N
N
21 (100)
24 (25)
22 (50)
21 (50)
N
O
CF3
Entry
R
X
Zone of inhibition
[mm (MIC in lg/ml)]
H3CO
H2C
OCH3
OCH3
A.n
C.a
7t
N
N
24 (25)
22 (50)
7a
7b
CH3
N
N
\10 (100)
\10 (100)
11 (100)
C2H5
13 (100)
20 (50)
7u
24 (25)
30 (1.56)
–
22 (50)
33 (1.56)
–
OCH3
Cl
7c
N
N
20 (100)
Kit.
DMSO
Cl
Cl
7d
7e
7f
23 (25)
\10 (100)
12 (100)
21 (50)
\10 (100)
\10 (100)
\10 (100)
13 (100)
Kit.—ketoconazole, A.n—Aspergillus niger, A.f—Aspergillus fumi-
gates, A.c—Aspergillus clavatus, C.a—Candida albicans
–CH2
O
3-{5-[4-Chloro-6-(quinolin-8-yloxy)-1,3,5-triazin-2-
ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-2H-chromen-2-one 5
7g
7h
N
\10 (100)
16 (100)
To a stirred solution of 3-{5-[(4,6-dichloro-1,3,5-triazin-2-yl)
sulfanyl]-1,3,4-oxadiazol-2-yl}-2H-chromen-2-one(19.70 g,
0.05 mol) which was dissolved in acetone and potassium
bicarbonate solution was added to maintain the pH. Then, the
solution of 8-hydroxyquinoline (7.26 g, 0.05 mol) in acetone
was added dropwise, and the reaction was monitored by TLC
by using toluene–acetone (9:1) as an eluent. After the
completition of the reaction, it was poured into crushed ice,
filtered, and dried to get 5. Yield: 82%, mp: 242–245°C. IR
(KBr) cm-1: 1741 (C=O, coumarin), 1619, 1540 (2C=N of
oxadiazole), 1256 (C–O–C), 1041 (C–O–C, oxadiazole), 829
(s-triazine C3N3 str.), 749 (–Cl str.), 701 (C–S–C).
COCH3
N
CH3
HC
7i
N
N
N
N
12 (100)
14 (100)
11 (100)
17 (100)
CH3
7j
7k
7l
N
N
16 (100)
17 (100)
N
\10 (100)
\10 (100)
H2C
7m
7n
–CH2
–CH2
\10 (100)
13 (100)
16 (100)
H2C
General procedure for preparation of compounds
(7a–u)
3,5-CH3
23 (25)
To a solution of 5 (0.005 mol) in 1,4-dioxane (30 ml), the
respective substituted piperazine and piperidines deriva-
tives (0.005 mol) were added and potassium bicarbonate
solution was added to maintain the pH. The reaction
mixture was refluxed for 8–10 h. Progress of the reaction
was monitored by TLC using toluene–acetone (8:2) as
eluent. The mixture was then treated with crushed ice and
neutralized by dilute HCl. The precipitate thus obtained
was filtered off, dried, and recrystallized from THF to
afford the desired compounds 7a–u.
7o
CH
N
11 (100)
22 (50)
\10 (100)
CH
7p
N
22 (50)
Cl
123

3126
Med Chem Res (2012) 21:3119–3132
Table 3 Physical and analytic data of the synthesized compounds
R
X
N
N
N
N
N
N
O
O
S
O
N
O
Entry
R
X
Yield
(%)
M.P
(°C)
Molecular
formula
Elemental analysis
Found (%)
Calc. (%)
C
C
H
N
H
N
7a
7b
7c
7d
7e
7f
CH3
N
78
74
69
80
66
62
70
79
73
65
77
71
69
61
240–243
234–235
245–247
252–254
189–192
177–179
278–279
240–241
222–224
255–256
270–271
219–222
265–266
261–262
C28H22N8O4S
C29H24N8O4S
59.35
3.91
19.78
59.26
59.87
59.78
56.73
60.82
58.48
63.09
58.41
60.51
61.07
59.00
63.39
65.52
61.99
3.83
19.82
C2H5
N
59.99
59.77
56.82
60.97
58.58
63.05
58.58
60.59
61.04
59.04
63.54
65.51
62.16
4.17
3.50
3.18
3.84
3.46
3.85
3.73
4.41
3.68
3.52
4.08
4.24
4.35
19.30
16.90
16.06
17.78
17.71
17.82
18.85
18.84
20.02
22.21
17.44
15.28
16.92
4.09
3.46
3.25
3.81
3.32
3.76
3.66
4.40
3.61
3.43
3.98
4.15
4.21
19.14
16.94
15.94
17.73
17.63
17.80
18.80
18.78
19.92
22.26
17.59
15.31
16.81
Cl
N
C33H23ClN8O4S
C33H22Cl2N8O4S
C28H21N7O4S
C27H19N7O5S
C33H24N8O4S
C29H22N8O5S
C30H26N8O4S
C32H23N9O4S
C31H22N10O4S
C34H26N8O4S
C35H27N7O4S
C30H25N7O4S
Cl
Cl
N
–CH2
O
7g
7h
7i
N
COCH3
N
CH3
HC
N
CH3
7j
N
N
N
7k
7l
N
N
H2C
N
7m
7n
–CH2
–CH2
H2C
3,5-CH3
CH
7o
N
59
289–290
C40H30N8O4S
66.84
4.21
15.59
66.86
4.17
15.62
123

Med Chem Res (2012) 21:3119–3132
3127
Table 3 continued
Entry
R
X
N
Yield
(%)
M.P
(°C)
Molecular
formula
Elemental analysis
Found (%)
Calc. (%)
C
C
H
N
H
N
7p
61
280–282
C40H29ClN8O4S
63.78
3.88
14.88
63.68
3.74
14.77
CH
Cl
F
7q
7r
7s
N
N
N
73
71
65
255–257
251–253
282–283
C33H23FN8O4S
C33H23FN8O4S
C34H23F3N8O4S
61.29
61.29
58.62
3.59
3.59
3.33
17.33
17.33
16.08
61.15
61.18
58.51
3.56
3.53
3.39
17.37
17.28
16.12
F
CF3
H3CO
H2C
OCH3
OCH3
7t
N
N
62
83
292–293
219–220
C37H32N8O7S
C34H26N8O5S
60.65
62.00
4.40
3.98
15.29
17.01
60.59
62.04
4.31
3.91
15.30
16.98
7u
OCH3
3-{5-[4-(4-Methyl-piperazin-1-yl)-6-(quinolin-8-yloxy)-
1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chromen-2-
one 7a. IR (KBr) cm-1: 1734 (C=O, coumarin), 1623, 1536
(2C=N of oxadiazole), 1258 (C–O–C), 1140 (N–N, oxa-
diazole), 1050 (C–O–C–, oxadiazole), 830 (s-triazine C3N3
str.), 699 (C–S–C); 1H NMR (400 MHz, DMSO-d6) d 8.92
(dd, J = 7.5, 1.6 Hz, 1H, C2 proton of quinoline), 8.61 (dt,
J = 7.5, 1.6 Hz, 1H, C4 proton of quinoline), 8.02 (s, 1H,
C4 proton of coumarin), 7.74 (dd, J = 7.2, 1.8 Hz, 1H, C5
proton of coumarin), 7.61 (dt, J = 7.1, 1.3 Hz, 1H, C5
proton of quinoline), 7.52–7.28 (m, Ar–H), 3.45 (br s, 4H,
piperazine), 3.85 (br s, 4H, piperazine), 1.92 (s, 1H,
N–CH3); 13C NMR (100 MHz, DMSO-d6): d = 177.82
(1C, C-2, C–S–C, s-triazine to oxadiazole ring), 172.54
(1C, C-4, C–O–C, s-triazine to quinoline ring), 169.69,
168.23 (2C, C=O, coumarin and s-triazine to piperazine
C–N), 163.27 (C-2, oxadiazole), 159.20 (C-5, oxadiazole),
149.45-117.93 (17C, Ar–C), 49.94, 46.37 (4C, piperazine),
23 (1C, N–CH3).
8.66 (dt, J = 7.8, 1.7 Hz, 1H, C4 proton of quinoline), 7.99
(s, 1H, C4 proton of coumarin), 7.79 (dd, J = 7.7, 1.6 Hz,
1H, C5 proton of coumarin), 7.64 (dt, J = 7.3, 1.4 Hz, 1H,
C5 proton of quinoline), 7.49–7.31 (m, Ar–H), 3.42 (br s,
4H, piperazine), 3.84 (br s, 4H, piperazine), 2.46 (q,
J = 8.2 Hz, 2H, N–CH2), 1.76 (t, J = 6.6 Hz 3H, N–CH2–
CH3) ppm; 13C NMR (100 MHz, DMSO-d6): d = 176.95
(1C, C-2, C–S–C, s-triazine to oxadiazole ring), 171.84
(1C, C-4, C–O–C, s-triazine to quinoline ring), 169.93,
168.04 (2C, s-triazine to piperazine C–N and C=O, cou-
marin), 163.55 (C-2, oxadiazole), 159.8 (C-5, oxadiazole),
151.63–119.07 (17C, Ar–C), 49.13, 45.61, 44.95 (7c,
piperazine ring carbon atoms and N–CH2), 23.98 (1C,
–CH3).
3-{5-[4-[4-(3-Chloro-phenyl)-piperazin-1-yl]-6-(quinolin-
8-yloxy)-1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-
chromen-2-one 7c. IR (KBr) cm-1: 1733 (C=O, coumarin),
1624, 1530 (2C=N of oxadiazole), 1256 (C–O–C), 1162
(N–N, oxadiazole), 1028 (C–O–C–, oxadiazole), 827
1
3-{5-[4-(4-Ethyl-piperazin-1-yl)-6-(quinolin-8-yloxy)-1,3,
5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chromen-2-
one 7b. IR (KBr) cm-1: 1739 (C=O, coumarin), 1630,
1542 (2C=N of oxadiazole), 1254 (C–O–C), 1148 (N–N,
oxadiazole), 1045 (C–O–C–, oxadiazole), 832 (s-triazine
(s-triazine C3N3 str.), 700 (C–S–C); H NMR (400 MHz,
DMSO-d6) d 8.96 (dd, J = 7.8, 1.4 Hz, 1H, C2 proton of
quinoline), 8.65 (dt, J = 7.7, 1.3 Hz, 1H, C4 proton of
quinoline), 8.05 (s, 1H, C4 proton of coumarin), 7.78 (dd,
J = 7.6, 1.7 Hz, 1H, C5 proton of coumarin), 7.66 (dt,
J = 7.8, 1.5 Hz, 1H, C5 proton of quinoline), 7.55–7.34
(m, Ar–H), 7.02 (t, J = 7.2 Hz, 1H), 6.89 (dt, J = 6.8,
1
C3N3 str.), 697 (C–S–C); H NMR (400 MHz, DMSO-d6)
d 8.87 (dd, J = 7.2, 1.3 Hz, 1H, C2 proton of quinoline),
123

3128
Med Chem Res (2012) 21:3119–3132
1.1 Hz, 1H), 3.47 (br s, 4H, piperazine), 3.81 (br s, 4H,
piperazine); 13C NMR (100 MHz, DMSO-d6): d = 177.46
(1C, C-2, C–S–C, s-triazine to oxadiazole ring), 172.91
(1C, C-4, C–O–C, s-triazine to quinoline ring), 169.83,
168.12 (2C, s-triazine to piperazine C–N and C=O, cou-
marin), 164.24 (C-2, oxadiazole), 159.99 (C-5, oxadiaz-
ole), 150.93–118.28 (23C, Ar–C), 48.31, 46.85 (4C,
piperazine).
DMSO- d6) d 8.98 (dd, J = 7.9, 1.7 Hz, 1H, C2 proton of
quinoline), 8.56 (dt, J = 6.9, 1.8 Hz, 1H, C4 proton of
quinoline), 8.06 (s, 1H, C4 proton of coumarin), 7.81 (dd,
J = 7.6, 1.9 Hz, 1H, C5 proton of coumarin), 7.66 (dt,
J = 7.8, 1.6 Hz, 1H, C5 proton of quinoline), 7.54–7.37 (m,
Ar–H), 3.94 (t, J = 4.7 Hz, 4H, morpholine), 3.66 (t,
J = 5.6 Hz, 4H, morpholine). 13C NMR (100 MHz, DMSO-
d6): d = 177.92 (1C, C-2, C–S–C, s-triazine to oxadiazole
ring), 173.64 (1C, C-4, C–O–C, s-triazine to quinoline ring),
169.44, 168.22 (2C, s-triazine to morpholine C–N and C=O,
coumarin), 163.68 (C-2, oxadiazole), 159.77 (C-5, oxadi-
azole), 150.54-119.62 (19C, Ar–C), 66.47 (morpholine C-3
and C-5), 53.67 (morpholine C-2 and C-6).
3-{5-[4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-6-(quin-
olin-8-yloxy)-1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-
yl}-chromen-2-one 7d. IR (KBr) cm-1: 1729 (C=O, cou-
marin), 1625, 1533 (2C=N of oxadiazole), 1255 (C–O–C),
1167 (N–N, oxadiazole), 1052 (C–O–C–, oxadiazole), 835
1
(s-triazine C3N3 str.), 699 (C–S–C); H NMR (400 MHz,
3-{5-[4-(4-Phenyl-piperazin-1-yl)-6-(quinolin-8-yloxy)-
1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chromen-
2-one 7g. IR (KBr) cm-1: 1733 (C=O, coumarin), 1626,
1532 (2C=N of oxadiazole), 1256 (C–O–C), 1170 (N–N,
oxadiazole), 1041 (C–O–C–, oxadiazole), 829 (s-triazine
DMSO-d6) d 8.88 (dd, J = 7.2, 1.1 Hz, 1H, C2 proton of
quinoline), 8.67 (dt, J = 7.6, 1.6 Hz, 1H, C4 proton of
quinoline), 8.01 (s, 1H, C4 proton of coumarin), 7.80 (dd,
J = 7.5, 1.9 Hz, 1H, C5 proton of coumarin), 7.59 (dt,
J = 7.2, 1.3 Hz, 1H, C5 proton of quinoline), 7.50–7.28
(m, Ar–H), 7.18 (dd, J = 6.6, 1.2 Hz, 1H), 6.92 (dd,
J = 7.1, 1.4 Hz, 1H), 6.79 (t, J = 8.1 Hz, 1H), 3.49 (br s,
4H, piperazine), 3.85 (br s, 4H, piperazine); 13C NMR
(100 MHz, DMSO-d6): d = 178.15 (1C, C-2, C–S–C,
s-triazine to oxadiazole ring), 172.69 (1C, C-4, C–O–C,
s-triazine to quinoline ring), 170.38, 168.62 (2C, s-triazine
to piperazine C–N and C=O, coumarin), 163.17 (C-2,
oxadiazole), 160.23 (C-5, oxadiazole), 151.44-123.85
(23C, Ar–C), 49.02, 48.28 (4C, piperazine).
1
C3N3 str.), 701 (C–S–C); H NMR (400 MHz, DMSO-d6)
d 8.93 (dd, J = 7.6, 1.1 Hz, 1H, C2 proton of quinoline),
8.59 (dt, J = 7.0, 1.4 Hz, 1H, C4 proton of quinoline), 8.03
(s, 1H, C4 proton of coumarin), 7.77 (dd, J = 7.8, 1.6 Hz,
1H, C5 proton of coumarin), 7.61 (dt, J = 7.7, 1.5 Hz, 1H,
C5 proton of quinoline), 7.50–7.29 (m, Ar–H), 3.49 (br s,
4H, piperazine), 3.86 (br s, 4H, piperazine); 13C NMR
(100 MHz, DMSO-d6): d = 177.01 (1C, C-2, C–S–C,
s-triazine to oxadiazole ring), 171.92 (1C, C-4, C–O–C,
s-triazine to quinoline ring), 169.77, 167.07 (2C, s-triazine
to piperazine C–N and C=O, coumarin), 164.05 (C-2,
oxadiazole), 158.82 (C-5, oxadiazole), 151.65–117.36
(23C, Ar–C), 49.42, 46.64 (4C, piperazine).
3-{5-[4-Piperidin-1-yl-6-(quinolin-8-yloxy)-1,3,5-triazin-
2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chromen-2-one 7e. IR
(KBr) cm-1: 1724 (C=O, coumarin), 1631, 1551 (2C=N of
oxadiazole), 1254 (C–O–C), 1146 (N–N, oxadiazole), 1051
(C–O–C–, oxadiazole), 829 (s-triazine C3N3 str.), 701 (C–S–
3-{5-[4-(4-Acetyl-piperazin-1-yl)-6-(quinolin-8-yloxy)-
1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chromen-
2-one 7h. IR (KBr) cm-1: 1732 (C=O, coumarin), 1622,
1540 (2C=N of oxadiazole), 1256 (C–O–C), 1149 (N–N,
oxadiazole), 1054 (C–O–C–, oxadiazole), 831 (s-triazine
1
C); H NMR (400 MHz, DMSO-d6) d 8.90 (dd, J = 7.2,
1.6 Hz, 1H, C2 proton of quinoline), 8.62 (dt, J = 7.3,
1.5 Hz, 1H, C4 proton of quinoline), 7.98 (s, 1H, C4 proton
of coumarin), 7.73 (dd, J = 7.2, 1.4 Hz, 1H, C5 proton of
coumarin), 7.63 (dt, J = 7.7, 1.2 Hz, 1H, C5 proton of
quinoline), 7.48–7.35 (m, Ar–H), 3.87 (t, J = 5.5 Hz, 4H,
piperidine), 3.71 (t, J = 5.3 Hz, 4H, piperidine), 1.72–1.68
(m, 2H, piperidine). 13C NMR (100 MHz, DMSO-d6):
d = 177.49 (1C, C-2, C–S–C, s-triazine to oxadiazole ring),
171.58 (1C, C-4, C–O–C, s-triazine to quinoline ring),
170.31, 168.72 (2C, s-triazine to piperidine C–N and C=O,
coumarin), 163.74 (C-2, oxadiazole), 159.06 (C-5, oxadi-
azole), 152.07–118.28 (17C, Ar–C), 46.68, 29.11, 22.90 (7c,
piperidine).
1
C3N3 str.), 700 (C–S–C); H NMR (400 MHz, DMSO-d6)
d 8.90 (dd, J = 7.7, 1.2 Hz, 1H, C2 proton of quinoline),
8.65 (dt, J = 7.3, 1.6 Hz, 1H, C4 proton of quinoline), 8.05
(s, 1H, C4 proton of coumarin), 7.79 (dd, J = 7.6, 1.4 Hz,
1H, C5 proton of coumarin), 7.66 (dt, J = 7.8, 1.6 Hz, 1H,
C5 proton of quinoline), 7.52–7.36 (m, Ar–H), 3.46 (br s,
4H, piperazine), 3.85 (br s, 4H, piperazine), 2.21 (s, 3H,
–CH3); 13C NMR (100 MHz, DMSO-d6): d = 178.10 (1C,
C-2, C–S–C, s-triazine to oxadiazole ring), 172.18 (1C,
C-4, C–O–C, s-triazine to quinoline ring), 170.09, 169.91,
167.63 (3C, s-triazine to piperazine C–N, C=O, coumarin
and C=O of acetyl linkage), 163.94 (C-2, oxadiazole),
159.86 (C-5, oxadiazole), 152.18–120.42 (17C, Ar–C),
49.35, 46.90 (4C, piperazine), 23.37 (1C, –CH3).
3-{5-[4-Morpholin-4-yl-6-(quinolin-8-yloxy)-1,3,5-triazin-
2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chromen-2-one 7f. IR
(KBr) cm-1: 1730 (C=O, coumarin), 1619, 1547 (2C=N of
oxadiazole), 1375 (Morpholine C–O–C str.), 1256 (C–O–C),
1139 (N–N, oxadiazole), 1043 (C–O–C–, oxadiazole), 834
3-{5-[4-(4-Isopropyl-piperazin-1-yl)-6-(quinolin-8-yloxy)-
1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chromen-2-
one 7i. IR (KBr) cm-1: 1733 (C=O, coumarin), 1640, 1551
1
(s-triazine C3N3 str.), 698 (C–S–C); H NMR (400 MHz,
123

Med Chem Res (2012) 21:3119–3132
3129
(2C=N of oxadiazole), 1255 (C–O–C), 1154 (N–N, oxa-
diazole), 1062 (C–O–C–, oxadiazole), 837 (s-triazine C3N3
str.), 697 (C–S–C); 1H NMR (400 MHz, DMSO-d6) d 8.98
(dd, J = 7.6, 1.8 Hz, 1H, C2 proton of quinoline), 8.55 (dt,
J = 7.6, 1.4 Hz, 1H, C4 proton of quinoline), 8.00 (s, 1H,
C4 proton of coumarin), 7.80 (dd, J = 7.3, 1.3 Hz, 1H, C5
proton of coumarin), 7.64 (dt, J = 7.3, 1.9 Hz, 1H, C5
proton of quinoline), 7.55–7.31 (m, Ar–H), 3.45 (br s,
4H, piperazine), 3.80 (br s, 4H, piperazine), 2.21 (d,
J = 6.2 Hz, 6H, –2CH3), 1.90 (m, 1H, –CH); 13C NMR
(100 MHz, DMSO-d6): d = 177.40 (1C, C-2, C–S–C,
s-triazine to oxadiazole ring), 172.68 (1C, C-4, C–O–C,
s-triazine to quinoline ring), 170.34, 168.25 (2C, s-triazine
to piperazine C–N and C=O, coumarin), 162.82 (C-2,
oxadiazole), 157.70 (C-5, oxadiazole), 150.74–121.48
(17C, Ar–C), 53.80, 50.34, 48.13 (7c, piperazine ring and
N–CH at isopropyl linkage), 30.48 (2C, 2CH3).
C=O, coumarin), 164.70 (C-2, oxadiazole), 159.38 (C-5,
oxadiazole), 148.16–119.03 (21C, Ar–C), 49.58, 47.34
(4C, piperazine).
3-{5-[4-(4-Benzyl-piperazin-1-yl)-6-(quinolin-4-yloxy)-
1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chromen-
2-one 7l. IR (KBr) cm-1: 1741 (C=O, coumarin), 1622,
1531 (2C=N of oxadiazole), 1256 (C–O–C), 1160 (N–N,
oxadiazole), 1041 (C–O–C–, oxadiazole), 833 (s-triazine
1
C3N3 str.), 699 (C–S–C); H NMR (400 MHz, DMSO-d6)
d 8.91 (dd, J = 7.7, 1.5 Hz, 1H, C2 proton of quinoline),
8.66 (dt, J = 7.8, 1.1 Hz, 1H, C4 proton of quinoline), 8.03
(s, 1H, C4 proton of coumarin), 7.76 (dd, J = 7.1, 1.1 Hz,
1H, C5 proton of coumarin), 7.59 (dt, J = 7.0, 1.5 Hz, 1H,
C5 proton of quinoline), 7.47–7.27 (m, Ar–H), 3.50 (br s,
4H, piperazine), 3.81 (br s, 4H, piperazine), 2.19 (s, 2H, N–
CH2); 13C NMR (100 MHz, DMSO-d6): d = 177.67 (1C,
C-2, C–S–C, s-triazine to oxadiazole ring), 172.55 (1C,
C-4, C–O–C, s-triazine to quinoline ring), 169.85, 168.35
(2C, s-triazine to piperazine C–N and C=O, coumarin),
164.32 (C-2, oxadiazole), 160.67 (C-5, oxadiazole),
152.43–116.76 (23C, Ar–C), 66.90 (N–CH2, piperazine
nitrogen atom to phenyl ring), 51.28, 46.34 (4C,
piperazine).
3-{5-[4-(4-Pyridin-2-yl-piperazin-1-yl)-6-(quinolin-8-yloxy)-
1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chromen-
2-one 7j. IR (KBr) cm-1: 1740 (C=O, coumarin), 1620,
1533 (2C=N of oxadiazole), 1254 (C–O–C), 1165 (N–N,
oxadiazole), 1061 (C–O–C–, oxadiazole), 833 (s-triazine
1
C3N3 str.), 696 (C–S–C); H NMR (400 MHz, DMSO-d6)
d 8.89 (dd, J = 7.6, 1.8 Hz, 1H, C2 proton of quinoline),
8.60 (dt, J = 7.2, 1.7 Hz, 1H, C4 proton of quinoline), 8.06
(s, 1H, C4 proton of coumarin), 7.81 (dd, J = 7.6, 1.5 Hz,
1H, C5 proton of coumarin), 7.59 (dt, J = 6.8, 1.2 Hz, 1H,
C5 proton of quinoline), 7.49–7.25 (m, Ar–H), 7.09 (dd,
J = 8.0, 1.2 Hz, 1H, pyridyl), 6.78–6.81 (m, 2H), 3.52 (br
s, 4H, piperazine), 3.88 (br s, 4H, piperazine), 13C NMR
(100 MHz, DMSO-d6): d = 176.36 (1C, C-2, C–S–C,
s-triazine to oxadiazole ring), 172.90 (1C, C-4, C–O–C,
s-triazine to quinoline ring), 169.21, 168.04 (2C, s-triazine
to piperazine C–N and C=O, coumarin), 163.32 (C-2,
oxadiazole), 159.30 (C-5, oxadiazole), 151.57-118.15
(21C, Ar–C), 48.52, 44.98 (4C, piperazine).
3-{5-[4-(4-Benzyl-piperidin-1-yl)-6-(quinolin-4-yloxy)-
1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chromen-
2-one 7m. IR (KBr) cm-1: 1733 (C=O, coumarin), 1627,
1548 (2C=N of oxadiazole), 1256 (C–O–C), 1157 (N–N,
oxadiazole), 1050 (C–O–C–, oxadiazole), 835 (s-triazine
1
C3N3 str.), 696 (C–S–C); H NMR (400 MHz, DMSO-d6)
d 8.88 (dd, J = 7.3, 1.6 Hz, 1H, C2 proton of quinoline),
8.62 (dt, J = 7.5, 1.2 Hz, 1H, C4 proton of quinoline), 8.08
(s, 1H, C4 proton of coumarin), 7.73 (dd, J = 7.1, 1.5 Hz,
1H, C5 proton of coumarin), 7.64 (dt, J = 7.3, 1.2 Hz, 1H,
C5 proton of quinoline), 7.51–7.30 (m, Ar–H), 3.77 (4H, t,
J = 7.8 Hz, piperidine), 3.59 (4H, t, J = 8.3 Hz, piperi-
dine), 2.48 (2H, s, N–CH2), 1.94 (1H, t, J = 6.8 Hz, -CH,
piperidine); 13C NMR (100 MHz, DMSO-d6): d = 177.90
(1C, C-2, C–S–C, s-triazine to oxadiazole ring), 173.24
(1C, C-4, C–O–C, s-triazine to quinoline ring), 169.57,
168.65 (2C, s-triazine to piperidine C–N and C=O, cou-
marin), 162.91 (C-2, oxadiazole), 160.05 (C-5, oxadiaz-
ole), 148.95–122.51 (23C, Ar–C), 48.07, 43.61, 36.46,
30.77 (6C, piperazine ring carbon atoms and N–CH2).
3-{5-[4-(3,5-Dimethyl-piperidin-1-yl)-6-(quinolin-4-yloxy)-
1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chromen-
2-one 7n. IR (KBr) cm-1: 1740 (C=O, coumarin), 1625,
1540 (2C=N of oxadiazole), 1258 (C–O–C), 1159 (N–N,
oxadiazole), 1048 (C–O–C–, oxadiazole), 836 (s-triazine
3-{5-[4-(4-Pyrimidin-2-yl-piperazin-1-yl)-6-(quinolin-8-
yloxy)-1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chro-
men-2-one 7k. IR (KBr) cm-1: 1729 (C=O, coumarin),
1636, 1546 (2C=N of oxadiazole), 1255 (C–O–C), 1164
(N–N, oxadiazole), 1055 (C–O–C–, oxadiazole), 829
1
(s-triazine C3N3 str.), 700 (C–S–C); H NMR (400 MHz,
DMSO-d6) d 8.87 (dd, J = 6.8, 2.2 Hz, 1H, C2 proton of
quinoline), 8.64 (dt, J = 7.8, 1.9 Hz, 1H, C4 proton of
quinoline), 8.47–8.49 (m, 2H, pyrimidyl), 8.07 (s, 1H, C4
proton of coumarin), 7.72 (dd, J = 7.1, 1.0 Hz, 1H,
C5 proton of coumarin), 7.60 (dt, J = 7.5, 1.4 Hz, 1H, C5
proton of quinoline), 7.55–7.31 (m, Ar–H), 6.71 (t, J =
6.6 Hz, 1H, pyrimidyl), 3.39 (br s, 4H, piperazine), 3.89 (br
s, 4H, piperazine), 13C NMR (100 MHz, DMSO-d6):
d = 176.94 (1C, C-2, C–S–C, s-triazine to oxadiazole
ring), 172.34 (1C, C-4, C–O–C, s-triazine to quinoline
ring), 169.57, 167.22 (2C, s-triazine to piperazine C–N and
1
C3N3 str.), 699 (C–S–C); H NMR (400 MHz, DMSO-d6)
d 8.95 (dd, J = 7.7, 1.8 Hz, 1H, C2 proton of quinoline),
8.57 (dt, J = 7.1, 1.0 Hz, 1H, C4 proton of quinoline), 8.01
(s, 1H, C4 proton of coumarin), 7.76 (dd, J = 7.4, 1.4 Hz,
1H, C5 proton of coumarin), 7.67 (dt, J = 7.6, 1.5 Hz, 1H,
123

3130
Med Chem Res (2012) 21:3119–3132
C5 proton of quinoline), 7.54–7.26 (m, Ar–H), 3.73 (dd,
J = 12.5, 7.2 Hz, 2H, piperidine), 2.91 (dd, J = 12.9,
7.3 Hz, 2H, piperidine), 1.79–1.73 (m, 3H, piperidne), 1.63
(d, J = 6.7 Hz, 6H, 2CH3). 13C NMR (100 MHz, DMSO-
d6): d = 177.23 (1C, C-2, C–S–C, s-triazine to oxadiazole
ring), 172.07 (1C, C-4, C–O–C, s-triazine to quinoline
ring), 170.24, 167.44 (2C, s-triazine to piperidine C–N and
C=O, coumarin), 163.44 (C-2, oxadiazole), 159.15 (C-5,
oxadiazole), 149.08–118.20 (17C, Ar–C), 48.17, 46.71,
29.16 (7c, piperidine), 19.18 (2C, 2CH3).
DMSO-d6) d 8.88 (dd, J = 7.6, 1.3 Hz, 1H, C2 proton of
quinoline), 8.66 (dt, J = 7.7, 1.2 Hz, 1H, C4 proton of
quinoline), 8.04 (s, 1H, C4 proton of coumarin), 7.80 (dd,
J = 7.5, 1.8 Hz, 1H, C5 proton of coumarin), 7.69 (dt,
J = 7.8, 1.5 Hz, 1H, C5 proton of quinoline), 7.56–7.35
(m, Ar–H), 6.82 (dd, J = 12.6, 6.5 Hz, 2H), 6.70–6.74 (m,
1H), 6.57 (dd, J = 12.8, 6.3 Hz, 1H), 3.47 (br s, 4H,
piperazine), 3.83 (br s, 4H, piperazine); 13C NMR
(100 MHz, DMSO-d6): d = 176.84 (1C, C-2, C–S–C,
s-triazine to oxadiazole ring), 172.82 (1C, C-4, C–O–C,
s-triazine to quinoline ring), 169.61, 168.37 (2C, s-triazine
to piperazine C–N and C=O, coumarin), 164.78 (C-2,
oxadiazole), 158.71 (C-5, oxadiazole), 152.26 (1C, C–F),
151.31-118.17 (22C, Ar–C), 51.62, 48.33 (4C, piperazine);
19F NMR (400 MHz, CDCl3): d -119.93 (1F, s, C–F).
3-{5-[4-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-6-(quinolin-
4-yloxy)-1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-
chromen-2-one 7r. IR (KBr) cm-1: 1741 (C=O, coumarin),
1622, 1533 (2C=N of oxadiazole), 1256 (C–O–C), 1150
(N–N, oxadiazole), 1043 (C–O–C–, oxadiazole), 834
3-{5-[4-(4-Benzhydryl-piperazin-1-yl)-6-(quinolin-4-yloxy)-
1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-chromen-
2-one 7o. IR (KBr) cm-1: 1744 (C=O, coumarin), 1630,
1550 (2C=N of oxadiazole), 1251 (C–O–C), 1144 (N–N,
oxadiazole), 1047 (C–O–C–, oxadiazole), 830 (s-triazine
1
C3N3 str.), 701 (C–S–C); H NMR (400 MHz, DMSO-d6)
d 8.90 (dd, J = 7.5, 1.6 Hz, 1H, C2 proton of quinoline),
8.65 (dt, J = 7.7, 1.6 Hz, 1H, C4 proton of quinoline), 8.04
(s, 1H, C4 proton of coumarin), 7.72 (dd, J = 7.0, 1.6 Hz,
1H, C5 proton of coumarin), 7.60 (dt, J = 7.2, 1.3 Hz, 1H,
C5 proton of quinoline), 7.51–7.25 (m, Ar–H), 4.09 (s, 1H,
N–CH), 3.51 (br s, 4H, piperazine), 3.89 (br s, 4H, piper-
azine); 13C NMR (100 MHz, DMSO-d6): d = 178.35 (1C,
C-2, C–S–C, s-triazine to oxadiazole ring), 172.54 (1C, C-
4, C–O–C, s-triazine to quinoline ring), 169.14, 167.17
(2C, s-triazine to piperazine C–N and C=O, coumarin),
162.70 (C-2, oxadiazole), 158.44 (C-5, oxadiazole),
150.54–117.14 (30C, Ar–C), 49.77, 47.79 (4C, piperazine).
3-{5-[4-{4-[(4-Chloro-phenyl)-phenyl-methyl]-piperazin-
1-yl}-6-(quinolin-4-yloxy)-1,3,5-triazin-2-ylsulfanyl]-[1,3,4]ox-
adiazol-2-yl}-chromen-2-one 7p. IR (KBr) cm-1: 1732
(C=O, coumarin), 1616, 1521 (2C=N of oxadiazole), 1255
(C–O–C), 1153 (N–N, oxadiazole), 1042 (C–O–C–, oxa-
diazole), 829 (s-triazine C3N3 str.), 696 (C–S–C); 1H NMR
(400 MHz, DMSO-d6) d 8.86 (dd, J = 7.1, 1.2 Hz, 1H, C2
proton of quinoline), 8.57 (dt, J = 7.3, 1.1 Hz, 1H, C4
proton of quinoline), 7.99 (s, 1H, C4 proton of coumarin),
7.79 (dd, J = 7.3, 1.4 Hz, 1H, C5 proton of coumarin),
7.61 (dt, J = 7.5, 1.0 Hz, 1H, C5 proton of quinoline),
7.49–7.27 (m, Ar–H), 3.99 (s, 1H, N–CH), 3.42 (br s, 4H,
piperazine), 3.79 (br s, 4H, piperazine); 13C NMR
(100 MHz, DMSO-d6): d = 177.94 (1C, C-2, C–S–C,
s-triazine to oxadiazole ring), 172.11 (1C, C-4, C–O–C,
s-triazine to quinoline ring), 168.97, 167.75 (2C, s-triazine
to piperazine C–N and C=O, coumarin), 163.96 (C-2,
oxadiazole), 161.34 (C-5, oxadiazole), 151.40–116.84
(30C, Ar–C), 47.4, 46.0 (4C, piperazine).
1
(s-triazine C3N3 str.), 700 (C–S–C); H NMR (400 MHz,
DMSO-d6) d 8.97 (dd, J = 8.1, 1.6 Hz, 1H, C2 proton of
quinoline), 8.60 (dt, J = 7.1, 1.6 Hz, 1H, C4 proton of
quinoline), 8.00 (s, 1H, C4 proton of coumarin), 7.74 (dd,
J = 7.4, 1.7 Hz, 1H, C5 proton of coumarin), 7.66 (dt,
J = 7.6, 1.4 Hz, 1H, C5 proton of quinoline), 7.52–7.31
(m, Ar–H), 7.11 (dd, J = 13.5, 7.4 Hz, 2H), 6.66–6.63 (m,
1H), 6.49 (dd, J = 12.8, 6.8 Hz, 1H), 3.45 (br s, 4H,
piperazine), 3.85 (br s, 4H, piperazine); 13C NMR
(100 MHz, DMSO-d6): d = 177.04 (1C, C-2, C–S–C,
s-triazine to oxadiazole ring), 173.07 (1C, C-4, C–O–C,
s-triazine to quinoline ring), 170.25, 168.01 (2C, s-triazine
to piperazine C–N and C=O, coumarin), 163.51 (C-2,
oxadiazole), 158.54 (C-5, oxadiazole), 152.88 (1C, C–F),
152.08–118.59 (22C, Ar–C), 50.90, 46.93 (4C, piperazine);
19F NMR (400 MHz, CDCl3): d -116.38 (1F, s, C–F).
3-(5-{4-(Quinolin-4-yloxy)-6-[4-(3-trifluoromethyl-phe-
nyl)-piperazin-1-yl]-1,3,5-triazin-2-ylsulfanyl}-[1,3,4]oxa-
diazol-2-yl)-chromen-2-one 7s. IR (KBr) cm-1: 1730
(C=O, coumarin), 1638, 1531 (2C=N of oxadiazole), 1256
(C–O–C), 1166 (N–N, oxadiazole), 1046 (C–O–C–, oxa-
diazole), 838 (s-triazine C3N3 str.), 698 (C–S–C); 1H NMR
(400 MHz, DMSO-d6) d 8.92 (dd, J = 7.7, 1.5 Hz, 1H, C2
proton of quinoline), 8.64 (dt, J = 7.3, 1.4 Hz, 1H, C4
proton of quinoline), 8.07 (s, 1H, C4 proton of coumarin),
7.75 (dd, J = 7.8, 1.6 Hz, 1H, C5 proton of coumarin),
7.61 (dt, J = 7.4, 1.7 Hz, 1H, C5 proton of quinoline),
7.53–7.28 (m, Ar–H), 7.05 (dt, J = 7.5, 1.6 Hz, 1H), 3.48
(br s, 4H, piperazine), 3.84 (br s, 4H, piperazine); 13C
NMR (100 MHz, DMSO-d6): d = 176.96 (1C, C-2, C–S–
C, s-triazine to oxadiazole ring), 172.16 (1C, C-4, C–O–C,
s-triazine to quinoline ring), 170.46, 167.35 (2C, s-triazine
to piperazine C–N and C=O, coumarin), 162.98 (C-2,
3-{5-[4-[4-(2-Fluoro-phenyl)-piperazin-1-yl]-6-(quinolin-
4-yloxy)-1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-2-yl}-
chromen-2-one 7q. IR (KBr) cm-1: 1738 (C=O, coumarin),
1630, 1531 (2C=N of oxadiazole), 1256 (C–O–C), 1166
(N–N, oxadiazole), 1041 (C–O–C–, oxadiazole), 829
1
(s-triazine C3N3 str.), 700 (C–S–C); H NMR (400 MHz,
123

Med Chem Res (2012) 21:3119–3132
3131
oxadiazole), 158.66 (C-5, oxadiazole), 149.38-119.92
(24C, Ar–C including C–CF3 at 130.12 and CF3 at 125.02),
51.55, 49.57 (4C, piperazine); 19F NMR (400 MHz,
CDCl3): d -64.6 (6F, s, 2-CF3).
typhi MTCC 733, and Proteus vulgaris MTCC 1771) and
fungi (Aspergillus niger MTCC 282, Aspergillus fumigatus
MTCC 343, Aspergillus clavatus MTCC 1323, and Candida
albicans MTCC 183) species using the agar diffusion test
(Gillespie, 1994). The Mueller–Hinton agar media were
sterilized (autoclaved at 120°C for 30 min), poured at uni-
form depth of 5 mm and allowed to solidify. The microbial
suspension (105 CFU/ml) (0.5 McFarland Nephelometery
Standards) was streaked over the surface of media using a
sterile cotton swab to ensure even growth of the organisms.
The tested compounds were dissolved in dimethyl sulfoxide
to give solutions of 3.12–100 lg/ml. Sterile filter paper disks
measuring 6.25 mm in diameter (Whatman no. 1 filter
paper), previously soaked in a known concentration of the
respective test compound in dimethyl sulfoxide, were placed
on the solidified nutrient agar medium that had been inoc-
ulated with the respective microorganism, and the plates
were incubated for 24 h at (37 1) °C. A control disk
impregnated with an equivalent amount of dimethyl sulf-
oxide without any sample was also used and did not pro-
duce any inhibition. Ciprofloxacin and ketoconazole
(100 lg/disk) were used as control drugs for antibacterial
and antifungal activities, respectively, and assayed for MICs
at the concentration levels 1.56, 0.39, 1.56, 1.56, 0.78 and
0.39 lg/ml in the present study.
3-(5-{4-(Quinolin-4-yloxy)-6-[4-(2,3,4-trimethoxy-benzyl)-
piperazin-1-yl]-1,3,5-triazin-2-ylsulfanyl}-[1,3,4]oxadiazol-
2-yl)-chromen-2-one 7t. IR (KBr) cm-1: 1736 (C=O,
coumarin), 1631, 1540 (2C=N of oxadiazole), 1252 (C–O–
C), 1150 (N–N, oxadiazole), 1039 (C–O–C–, oxadiazole),
833 (s-triazine C3N3 str.), 701 (C–S–C); 1H NMR
(400 MHz, DMSO-d6) d 8.86 (dd, J = 7.2, 1.2 Hz, 1H, C2
proton of quinoline), 8.55 (dt, J = 7.0, 1.3 Hz, 1H, C4
proton of quinoline), 8.05 (s, 1H, C4 proton of coumarin),
7.80 (dd, J = 7.7, 1.3 Hz, 1H, C5 proton of coumarin),
7.67 (dt, J = 7.8, 1.7 Hz, 1H, C5 proton of quinoline),
7.55–7.24 (m, Ar–H), 7.06 (d, J = 7.4 Hz, 1H), 6.79 (d,
J = 7.8 Hz, 1H), 3.89 (br s, 4H, piperazine), 3.78 (s, 1H,
N-CH2), 3.68 (s, 9H, 3OCH3), 3.49 (br s, 4H, piperazine);
13C NMR (100 MHz, DMSO-d6): d = 178.17 (1C, C-2, C–
S–C, s-triazine to oxadiazole ring), 172.90 (1C, C-4, C–O–
C, s-triazine to quinoline ring), 169.07, 168.15 (2C, s-tri-
azine to piperazine C–N and C=O, coumarin), 164.05 (C-2,
oxadiazole), 160.61 (C-5, oxadiazole), 153.71–121.62
(23C, Ar–C), 60.78, 60.34 (3C, 3OCH3), 48.31, 44.83 (4C,
piperazine), 39.22 (1C, –CH2).
3-{5-[4-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-6-(quin-
olin-4-yloxy)-1,3,5-triazin-2-ylsulfanyl]-[1,3,4]oxadiazol-
2-yl}-chromen-2-one 7u. IR (KBr) cm-1: 1740 (C=O,
coumarin), 1620, 1543 (2C=N of oxadiazole), 1257 (C–O–
C), 1158 (N–N, oxadiazole), 1041 (C–O–C–, oxadiazole),
834 (s-triazine C3N3 str.), 697 (C–S–C); 1H NMR
(400 MHz, DMSO-d6) d 8.98 (dd, J = 7.9, 1.7 Hz, 1H, C2
proton of quinoline), 8.58 (dt, J = 7.2, 1.2 Hz, 1H, C4
proton of quinoline), 8.01 (s, 1H, C4 proton of coumarin),
7.81 (dd, J = 7.7, 1.5 Hz, 1H, C5 proton of coumarin),
7.63 (dt, J = 7.4, 1.7 Hz, 1H, C5 proton of quinoline),
7.52–7.34 (m, Ar–H), 7.13 (d, J = 8.4 Hz, 1H), 6.81 (d,
J = 7.8 Hz, 1H), 4.07 (s, 3H, OCH3), 3.82 (br s, 4H,
piperazine), 3.50 (br s, 4H, piperazine). 13C NMR
(100 MHz, DMSO-d6): d = 177.77 (1C, C-2, C–S–C,
s-triazine to oxadiazole ring), 172.44 (1C, C-4, C–O–C,
s-triazine to quinoline ring), 169.55, 168.44 (2C, s-triazine
to piperazine C–N and C=O, coumarin), 163.04 (C-2, oxa-
diazole), 160.32 (C-5, oxadiazole), 151.97–118.38 (23C,
Ar–C), 56.07 (1C, –OCH3), 50.0, 48.1 (4C, piperazine).
To determine the minimum inhibitory concentration
(Hawkey and Lewis, 1994), a stock solution of the synthe-
sized compound (100 lg/ml) in dimethyl sulfoxide was
prepared, and graded quantities of the test compounds were
incorporated in a specified quantity of molten sterile agar,
i.e., nutrient agar for evaluation of antibacterial activity and
sabouraud dextrose agar for antifungal activity. The medium
containing the test compound was poured into a Petri dish at
a depth of 4–5 mm and allowed to solidify under aseptic
conditions. A suspension of the respective microorganism of
*105 CFU/ml was prepared and applied to plates with
serially diluted compounds with concentrations in the range
of 3.12–100 lg/ml in dimethyl sulfoxide and incubated at
(37 1) °C for 24 h (bacteria) or 48 h (fungi). The lowest
concentration of the substance that prevents the develop-
ment of visible growth is considered to be the MIC value.
Acknowledgments The authors are thankful to the faculty of the
Department of Applied Chemistry, S. V. National Institute of Tech-
nology, Surat for providing the scholarship, encouragement, and
facilities.
Antimicrobial activity
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