In vitro antimicrobial assessment of coumarin-based s-triazinyl piperazines

Article abstract of DOI:10.1007/s00044-011-9676-3

A series of 1,3,5-triazine derivatives that contain aniline, coumarins (4-hydroxy coumarin and 7-hydroxy-4-methyl coumarin) and different piperazine moieties as substituent on the carbon atoms of the triazine ring have been synthesized by a simple and eff

Full text of DOI:10.1007/s00044-011-9676-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1611–1624
DOI 10.1007/s00044-011-9676-3
ORIGINAL RESEARCH
In vitro antimicrobial assessment of coumarin-based s-triazinyl
piperazines
•
•
•
Divyesh Patel Rahul Patel Premlata Kumari
Navin Patel
Received: 18 January 2011 / Accepted: 18 May 2011 / Published online: 1 June 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of 1,3,5-triazine derivatives that contain
aniline, coumarins (4-hydroxy coumarin and 7-hydroxy-4-
methyl coumarin) and different piperazine moieties as sub-
stituent on the carbon atoms of the triazine ring have been
synthesized by a simple and efficient synthetic protocol.
Comparative studies were performed on above series, which
were synthesized with conventional and microwave heating
methods. The microwave method was observed to be more
beneficial as it provides an increase in yield and 90–95%
reduction time. All the synthesized compounds were then
examined for their efficacy against two Gram -ve bacteria
(Escherichia coli and Pseudomonas aeruginosa), two Gram
?ve bacteria (Staphylococcus aureus and Bacillus subtilis)
and two fungal species (Candida albicans and Aspergillus
niger) with an intent to overcome multiple drug resistance to
the pathogenic strains. All the synthesized compounds were
wide gamut of biological activities, such as antimicrobial
(Zhou et al., 2008; Srinivas et al., 2006), antiprotozoal
(Alessandro et al., 2005), anticancer (Rita et al., 2004),
antimalarial (Sergio et al., 2008) and antiviral (Yuan-Zhen
et al., 2008) activity. Recently, a series of some new
s-triazine analogues incorporating p-cyano aniline and
8-hydroxyquinoline substitutions were designed and syn-
thesized by our group (Rahul et al., 2010). These com-
pounds showed good to excellent in vitro antimicrobial
activity against most of the tested pathogenic microbes,
representing a promising lead for further optimization. To
extend their structure–activity relationships (SARs), we
have designed and synthesized a novel series based on the
modification of some structural units as p-cyano aniline
was replaced by simple aniline and 4-hydroxyquinoline has
been replaced by 4-hydroxycoumarin as well as 7-hydroxy-
4-methyl coumarin. We have introduced the similar
piperazine bases to both of the systems in an order to
identify the difference between the biological profiles of
the resultant series, in which activity was found to be
increased against most of studied strains of bacteria and
fungi in terms of MIC. The coumarins are heterocyclic
organic compounds, also known as benzo-2-pyrone deriv-
atives and mainly found in plants of the family of Rutaceae
1
structurally elucidated by IR, H NMR, 13C NMR and ele-
mental analysis.
Keywords 1,3,5-Triazines Á Coumarins Á Piperazines Á
Microwave irradiation Á Antimicrobial
Introduction
´
and Umbelliferae (Dekic et al., 2007). Natural and syn-
During the past few decades, 1,3,5-triazines have been
grabbing the attention of the synthetic chemists for their
thetic coumarin derivatives represent an important group of
organic compounds that are used as antibiotics (Estevez-
Braun and Gonzalez 1997; Hussain et al., 2003), fungicides
(Satyanarayana et al., 2008; Khalid et al., 2004), anti-
inflammatory (Anne et al., 2001; Khalid et al., 2010),
anticoagulant (Manolov and Danchev 1995), antitumor
(Raev et al., 1990), anti-urease (Zaheer-ul-Haq et al.,
2008), antileucemic (kotali et al., 2008), antioxidant and
insecticidal agents (Khan et al., 2002) and also showing
cytotoxic property (Ronad et al., 2010; Muhammad et al.,
D. Patel Á R. Patel Á P. Kumari (&)
Applied Chemistry Department, S.V. National Institute
of Technology, Surat 395007, India
e-mail: premlatakumari@gmail.com
N. Patel
Department of Chemistry, V.N. South Gujarat University,
Surat 395007, India
123

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Med Chem Res (2012) 21:1611–1624
2006) and leishmanicidal activity (Khan et al., 2008).
Regarding their high-fluorescence ability, they are widely
used as optical-whitening agents (Karasovskii and Bolotin
1984), brighteners (Zabradnik, 1992) and laser dyes (Ma-
eda, 1994) and also as fluorescent probes in biology and
medicine (Haugland, 2002). More recently, coumarin
derivatives have been evaluated in the treatment of human
immunodeficiency virus, because of their ability to inhibit
human immunodeficiency virus enzyme integrase (Serge
et al., 2002). Among the various coumarin derivatives,
4-substituted coumarins are important group of coumarin
derivatives showing various biological activities and also
other applications (Sanjeev et al., 2006). On account of
medicinal as well as other applications, hydroxy deriva-
tives of 4-methyl coumarins are considered as important
group of coumarin derivatives (Tyagi et al., 2008). For
example, 7-hydroxy-4-methyl coumarin (-methylumbellif-
erone) is used as spasmolytic drug in several European
countries (Kultti et al., 2009), fluorescent brightener, effi-
cient laser dye, standard for fluorometric determination of
enzymatic activity, as a starting material for the preparation
of insecticide (Murray et al., 1982), as precursor for furano
coumarins and many other derivatives of substituted cou-
marins and analytical reagents (Palaniappan and Chandra
shekhar 2004). It is also used therapeutically as a chola-
gogue that is well known to be conjugated with glucuronic
acid and sulfate and has been often used as a model
compound in conjugation studies (Miyauchi et al., 1987).
Piperazines have been shown to possess a remarkably
broad spectrum of biological activity, including antimi-
crobial (Singh et al., 2001; Kerns et al., 2003), antimalarial
(Adina et al., 2003), antimicobacterial (Upadhayaya et al.,
2010), dual calcium antagonist and antioxidant (Makoto
et al., 2002), a novel class of mixed D2/D4 receptor
antagonists (He et al., 2002) and tetrazole nucleus con-
taining piperazine derivatives are recently reported as anti-
fungal agents (Ram Shankar et al., 2004).
and fungal strains. Among the attractive ways of solving
multidrug resistance is the synthesis of novel molecules that
should preferably consist chemical characteristics that clearly
differ from those of existing agents and are biologically active
by the virtue of the presence of critical structural features.
Results and discussion
Chemistry
We have synthesized a series of coumarins, such as
4-hydroxy coumarin and 7-hydroxy-4-methyl coumarin-
based s-triazinyl piperazines 5a–k and 6a–k as illustrated in
Scheme 1. Two basic approaches, conventional heating and
microwave irradiation, were applied for the final nucleo-
philic substitution reactions, resulted in significant decrease
in reaction time by the adoption of microwave irradiation
technique. The disubstituted s-triazine intermediate 3a and
3b were obtained by the reaction between (4,6-Dichloro-
[1,3,5]triazin-2-yl)-phenyl-amine 1 and 4-hydroxy couma-
rin 2a and 7-hydroxy-4-methyl coumarin 2b in the presence
of 60% NaH at 45–50°C. Condensation of 3a, 3b with
appropriate piperazine substituents in 1,4-dioxane at
70–80°C provided the target compounds 5a–k and 6a–k.
Compound 1 was prepared by the reaction between 2,4,6–
trichloro-[1,3,5]triazine and aniline in THF with the cata-
lytic amount of triethyl amine and stirred for 4 h at 0–5°C.
Formation of the product was confirmed by a sharp band at
3,296.45 cm-1 for –NH stretching in IR spectrum and
signal between 6.97 and 7.70 d ppm for aromatic protons
and singlet at 10.17 d ppm for –NH in 1H NMR confirmed
its formation. Compound 1 was converted to 4-(4-chloro-6-
phenylamino-[1,3,5]triazin-2-yloxy)-chromen-2-one 3a and
7-(4-chloro-6-phenylamino-[1,3,5]triazin-2-yloxy)-4-methyl-
chromen-2-one 3b by its reaction with 4-hydroxy couma-
rin 2a and 7-hydroxy-4-methyl coumarin 2b. Linkage of
hydroxy group of coumarins with (4,6-dichloro-[1,3,5,]tria-
zin-2-yl)-phenyl-amine was confirmed by appearance of
C–O–C stretching band at 1,254.21 cm-1 and a strong band
at 1,697.21 cm-1 for C=O of coumarin. Further confirmed by
13C NMR spectrum, which showed C=O signals of coumarins
around 158.61–162.06 d ppm. Further desired compounds
5a–k and 6a–k were incurred by substituting different
piperazine derivatives 4a–k on 3a and 3b by conventional
heating as well as under microwave irradiation.
Microwave technology has become a powerful tool in
organic synthesis, because by employing this technique, it
is generally possible to prepare organic compounds very
fast, with high purity and better yields compared with other
more conventional methods (Kappe and Stadler 2005). In
particular, we carried out the reaction of 4-(4-Chloro-6-
phenylamino-[1,3,5]triazin-2-yloxy)-chromen-2-one (3a)
and 7-(4-Chloro-6-phenylamino-[1,3,5]triazin-2-yloxy)-4-
methyl-chromen-2-one (3b) with different amines under
microwave irradiation. This method proved to be superior
to the traditional heating.
Antimicrobial efficacy of 1,3,5-triazine motivated us to
synthesize coumarin-based 1,3,5-triazinyl piperazines and
to examine the antimicrobial action of the resultant sys-
tems. The newly synthesized scaffolds are of two types on
the basis of the presence of type of coumarin entity
attached to s-triazine core.
Significant impact of the burden of infectious disease in
developing countries because of multidrug resistant posed by
bacteria has driven us to synthesize potent new scaffold and to
examine them against the representative panel of bacterial
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Med Chem Res (2012) 21:1611–1624
1613
Cl
N
Scheme 1
NH 2
N
N
+
Cl
Cl
Phenylamine
2,4,6-Trichloro-[1,3,5]triazine
THF
N
NaH
Cl
N
N
Cl
NH
(4,6-Dichloro-[1,3,5]triazin-2-yl)-phenyl-amine 1
+
CH3
OH
HO
O
O
O
O
4-Hydroxy-chromen-2-one 2a
7-Hydroxy-4-methyl-chromen-2-one 2b
THF NaH
Cl
THF NaH
N
Cl
O
N
O
O
O
O
N
N
N
N
HN
HN
O
CH 3
4-(4-Chloro-6-phenylamino-[1,3,5]triazin-2-yloxy)-
7-(4-Chloro-6-phenylamino-[1,3,5]triazin-2-yloxy)-4-methyl-chromen-2-
chromen-2-one
one
3a
3b
+
+
4a-k
4a-k (R)
(R)
MW
1,4-Dioxne
MW
1,4-Dioxne
K2CO 3
K2CO 3
R
N
N
N
R
O
N
O
O
O
O
N
N
HN
O
HN
CH 3
6a-k
5a-k
The antimicrobial screening results are represented in
Tables 1 and 2 for 4-hydroxy coumarin-based scaffolds
(5a–k) and 7-hydroxy-4-methyl coumarin-based scaffolds
(6a–k), respectively.
one chlorine atoms on the phenyl ring of the piperazine
moiety attached to 4-hydroxy coumarin bearing s-triazine
scaffolds and 7-hydroxy-4-methyl coumarin bearing s-tri-
azine scaffold, respectively displayed strong inhibition
against Gram -ve bacteria and both the fungal strains.
Compound 5h found to possess excellent activity against
Gram -ve E. coli, whereas compound 5c indicated half of
the MIC as compared with 5h. Furthermore, the said
compound 5c inhibited growth of Gram -ve P. aeruginosa
with higher zone of inhibition and higher MIC than the
The bioassay results revealed that the compounds 5a,
5b, and 6a, 6b bearing methyl and ethyl piperazine linkage,
respectively proved to have moderate inhibitory action
against all the bacterial and fungal strains. 5a and 5b are
more or less equal active. Similarly, 6a and 6b are also
roughly equally active. Compounds 5c and 6c containing
123

1614
Med Chem Res (2012) 21:1611–1624
Amines 4a-k (R-H) coupled to compound 3a and 3b
N-isopropyl piperazine, respectively, showed poor-to-
moderate activity against the examined representative
microorganisms. The final scaffold bearing N-acetyl piper-
azine 5h and 6h showed to have potent inhibitory action
against Gram -ve E. coli. Actually, the compound 5h
strongly inhibited Gram ?ve S. aureus with slightly
increased MIC compared with most potent analogues of its
family. The highest potency has been observed in case of the
newly synthesized analogues bearing heterocycle entity,
such as pyridine or pyrimidine attached to piperazine moi-
ety, which is incorporated to basic s-triazine core. Com-
pounds 5j, 5k, 6j and 6k displayed excellent Gram ?ve
strain inhibitory efficiency. In addition, compounds 5j, 5k,
6j and 6k are proved to have good activity against examined
Gram -ve strains and fungal strains too (Tables 3, 4).
HN
N
4g
4a
HN
N
CH 3
O
HN
N
C2H5
4b
4h
HN
N
C
CH3
CH 3
Cl
4c
HN
N
4i
HN
N
CH
CH 3
Cl
Cl
N
HN
N
4d
HN
N
4j
Conclusions
4e
HN
In this study, the potential of a range of coumarin-based 1,3,5-
triazine analogues as antimicrobial agents against selected
Gram ?ve, Gram -ve bacterial and fungal strains has been
demonstrated. Microwave irradiation prevailed for the final
nucleophiphilic substitution of coumarino 1,3,5-triazines
with various substituted piperazines. Microwave irradiation
affords the compounds in good yields and high purities.
7-Hydroxy-4-methyl coumarin-based s-triazinyl piperazines
possess better activity as compared with the scaffolds consists
of 4-hydroxy coumarin-based s-triazinyl piperazines except
the analogues bearing N-acetyl piperazine as coupling agent.
Coumarin-based 1,3,5-triazine analogues acquitting methyl/
ethyl piperazine as coupling agent are more or less equally
active. Incorporation of two chlorine atoms to the phenyl ring
of piperazine enhances the activity. Although, activity assay
presented in this study indicated that several compounds
showed improved antimicrobial activity as compared with
our previous study with 8-hydroxyquinoline. The dependence
of the antimicrobial activity of new compounds observed for
the analogues bearing heterocycle entity such as pyridine or
pyrimidine, halogen functionality as well as morpholine or
piperidine moieties incorporated to the nucleus. However, the
final analogue with two chlorine atom substitution to the
piperazinyl phenyl ring indicated greater activity profile than
the same analogue with one chlorine atom. Therefore, it may
be concluded that the presence of the chlorine atom(s) sig-
nificantly enhances the biological efficacy of the resultant
compound(s).
N
N
4k
HN
N
O
NH
4f
Scheme 1 continued
other analogues of the same series. The increased activity
found in case of 6c as compared with compound 5c in case
of inhibiting Gram -ve P. aeruginosa and both the fungal
strains. The observed activity strongly suggests that the
incorporation of two chlorine atoms at the phenyl ring of
piperazine moiety was much more beneficial to contribute
promising antibacterial as well as antifungal values.
4-Hydroxy coumarin derivative 5d successfully inhibited
Gram ?ve B. subtilis and Gram -ve P. aeruginosa,
whereas 7-hydroxy-4-methyl coumarin derivative 6d
showed potent activity with excellent minimum inhibitory
concentration as well as zone of inhibition against all the
examined bacterial and fungal strains. The observation
indicated incorporation of two chlorine atom to the phenyl
ring of piperazine was more beneficial than one chlorine
atom. The newly synthesized analogues containing piper-
idine and morpholine linkages are proved to have good-
to-moderate activity. Particularly, compounds 5e and 5f
bearing 4-hydroxy coumarin linked s-triazine condensed
with piperidine and morpholine, respectively, exhibited
higher zone of inhibition towards Gram -ve E. coli and
A. niger fungi. Incorporation of piperidine and morpholine
to the analogues consist of 7-hydroxy-4-methyl coumarin
evidenced greater inhibitory efficiency as compared with
the analogues consist of only 4-hydroxy coumarin. Com-
pound 5g, 6g and 5i, 6i bearing N-phenyl piperazine and
Experimental section
Microwave-assisted reactions were carried out by using
rotative solid phase microwave reactor (ROTO SYNTH,
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Med Chem Res (2012) 21:1611–1624
1615
Table 1 Antimicrobial activity of the final 5a–k scaffolds
R
12
11
6
7
10
1N
N5
8
9
2
4
N
NH
O
13
3
25
19
16
23
18
17
22
21
14
15
O
O
20
24
Compound
In vitro antibacterial and antifungal activity zone of inhibition in mm (MIC in lg/ml)
The final scaffolds containing
4-hydroxy coumarin 5(R)
Gram ?ve bacterial strains
Gram -ve bacterial strains
Fungal strains
S. aureus
B. subtilis
E. coli
P. aeruginosa
A. niger
C. albicans
5a (N-Methyl piperazine)
16 (100)
17 (100)
21 (50)
20 (100)
20 (50)
16 (100)
15 (100)
22 (25)
17 (100)
18 (100)
23 (25)
14 (100)
17 (100)
20 (50)
20 (12.5)
21 (12.5)
21 (6.25)
15 (100)
18 (100)
21 (25)
20 (12.5)
19 (12.5)
–
17 (100)
19 (100)
23 (12.5)
22 (12.5)
20 (100)
19 (100)
16 (100)
20 (50)
17 (100)
21 (25)
22 (12.5)
–
5b (N-Ethyl piperazine)
5c (1-{3-Chlorophenyl}piperazine)
21 (25)
5d (1-{2,3-Dichlorophenyl Piperazine})
5e (Piperidine)
22 (25)
23 (12.5)
20 (50)
21 (50)
23 (12.5)
16 (100)
17 (100)
15 (100)
22 (50)
19 (100)
19 (100)
17 (100)
23 (25)
22 (25)
5f (Morpholine)
16 (100)
17 (100)
20 (100)
18 (50)
22 (25)
5g (N-Phenyl piperazine)
5h (N-Acetyl piperazine)
5i (N-Isopropyl piperazine)
5j (1-{2-Pyridyl} piperazine)
5k (1-{2-Pyrimidyl}piperazine)
Ciprofloxacin (100 lg/disc)
Ketoconazole (100 lg/disc)
DMSO
16 (100)
22 (12.5)
18 (100)
20 (25)
20 (100)
23 (12.5)
23 (12.5)
29 (3.125)
18 (100)
20 (50)
21 (25)
22 (12.5)
29 (3.125)
21 (50)
20 (50)
32 (3.125)
33 (3.125)
30 (6.25)
–
33 (3.125)
–
–
–
–
–
Note The MIC values were evaluated at concentration range, 3.125–100 lg/ml. The table shows the corresponding zone of inhibition in
millimetre and MIC values in lg/ml
Milestone GmbH, 50–60 Hz). The rotation of the rotor,
irradiation time and power were monitored with the ‘‘Easy
Control-640’’ software package. Melting points were
measured in open capillary on Veego (Model: VMP-D)
electronic apparatus and are uncorrected. The IR spectra
(4,000–400 cm-1) of synthesized compounds were recor-
ded on Shimadzu 8400-S FT-IR spectrophotometer with
KBr. Thin layer chromatography was performed on
microscopic glass slides (2 9 7.5 cm) coated with silica
gel-G, using appropriate mobile phase system and spots
were visualized under UV radiation. Nuclear magnetic
resonance spectra were recorded on Varian 400 MHz
model spectrometer using CDCl3 as a solvent and TMS as
internal standard (Chemical shifts in d ppm). All new
compounds were subjected to elemental analysis and the
results were in acceptable range.
(4,6-Dichloro-[1,3,5,]triazin-2-yl)-phenyl-amine (1)
To a stirred solution of 2,4,6-trichloro-1,3,5-triazine (15 g,
0.081 mol) in anhydrous THF (150 ml), aniline (7.97 g,
123

1616
Med Chem Res (2012) 21:1611–1624
Table 2 Antimicrobial activity of the final 6a–k scaffolds
19
O
1
N
13
O
9
17
R
O
10
11
2
8
7
6
5
14
15
N
N
3
4
20
16
12
25
NH
26
CH3
18
21
22
24
23
Compound
In vitro antibacterial and antifungal activity zone of inhibition in mm (MIC in lg/ml)
The final scaffolds containing
7-hydroxy-4-methyl coumarin 6(R)
Gram ?ve bacterial strains
Gram -ve bacterial strains
Fungal strains
S. aureus
B. subtilis
E. coli
P. aeruginosa
A. niger
C. albicans
6a (N-Methyl piperazine)
19 (100)
17 (100)
22 (25)
21 (100)
21 (50)
16 (100)
16 (100)
22 (25)
20 (100)
21 (100)
24 (12.5)
24 (12.5)
21 (100)
17 (100)
15 (100)
23 (25)
16 (100)
20 (100)
23 (25)
23 (12.5)
22 (12.5)
21 (50)
17 (100)
21 (50)
19 (100)
23 (12.5)
22 (25)
–
20 (100)
20 (100)
25 (12.5)
25 (12.5)
22 (50)
22 (50)
18 (100)
25 (25)
19 (100)
23 (25)
24 (25)
–
6b (N-Ethyl piperazine)
6c (1-{3-Chlorophenyl}piperazine)
23 (50)
6d (1-{2,3-Dichlorophenyl Piperazine})
6e (Piperidine)
24 (25)
25 (12.5)
19 (100)
20 (100)
20 (100)
23 (50)
23 (12.5)
22 (25)
21 (50)
6f (Morpholine)
20 (100)
17 (100)
22 (25)
22 (50)
6g (N-Phenyl piperazine)
6h (N-Acetyl piperazine)
6i (N-Isopropyl piperazine)
6j (1-{2-Pyridyl} piperazine)
6k (1-{2-Pyrimidyl}piperazine)
Ciprofloxacin (100 lg/disc)
Ketoconazole (100 lg/disc)
DMSO
17 (100)
23 (12.5)
18 (100)
22 (25)
19 (100)
23 (12.5)
24 (6.25)
29 (3.125)
18 (100)
24 (12.5)
24 (12.5)
29 (3.125)
18 (100)
22 (50)
21 (25)
23 (50)
32 (3.125)
33 (3.125)
30 (6.25)
–
33 (3.125)
–
–
–
–
–
0.081 mol) was added drop wise at 0–5°C. The resulting
reaction mixture was stirred at this temperature for 2 h,
then triethyl amine (8.28 g, 0.081 mol) was added in the
reaction mixture and stirring was continued for another 4 h.
The resulted reaction mixture was then treated with cru-
shed ice, followed by neutralization by dilute HCl and then
filtered, dried and recrystallized from acetone to afford
pure 16.99 g (yield: 87%) of 1 as white colored amorphous
solid, m.p. 191–194°C, FT-IR (KBr): 3,296.45 cm1 (NH).
After the completion of the reaction, it was treated with
crushed ice, filtered, dried and recrystallized from acetone to
afford pure 15.04 g (yield: 82%) of 3a as off white colored
amorphous solid, m.p. 250–253°C; FT-IR (KBr): 1,697.21
(C=O), 1,254–1,257 cm-1 (C–O–C).
7-(4-Chloro-6-phenylamino-[1,3,5]triazin-2-yloxy)-4-
methyl-chromen-2-one (3b)
To a stirred solution of 7-hydroxy-4-methyl coumarin (8 g,
0.045 mol) and 60% NaH (1.05 g, 0.045 mol) in anhydrous
THF (150 ml), compound 1 (10.95 g, 0.045 mol) was added
into the reaction mixture and stirred for 2 h at room tem-
perature and then stirring was continued for another 14 h at
45–50°C. After completion of the reaction, it was treated
with crushed ice, filtered, dried and recrystallized from
acetone to afford pure 13.53 g (yield: 79%) of 3b as off
white colored amorphous solid, m.p. 264–267°C; FT-IR
4-(4-Chloro-6-phenylamino-[1,3,5]triazin-2-yloxy)-
chromen-2-one (3a)
To a stirred solution of 4-hydroxy coumarin (8 g, 0.050 mol)
and 60% NaH (1.19 g, 0.050 mol) in anhydrous THF
(150 ml), compound 1 (11.89 g, 0.050 mol) was added into
the reaction mixture and stirred for 2 h at room temperature
and then stirring was continued for another 14 h at 45–50°C.
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Med Chem Res (2012) 21:1611–1624
1617
Table 3 Data of synthesized compound 5a–k
Entry
Solvent
R
Microwave method
Conventional method
Reaction
time (min)
Yield (%)
Reaction
time (h)
Yield (%)
5a
5b
5c
5d
5e
5f
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
N-Methyl piperazine
N-Ethyl piperazine
2
4
3
3
2
5
4
3
6
2
3
75
72
80
88
78
83
79
77
86
82
75
8
10
10
12
8
71
65
72
85
70
77
72
60
80
78
69
1-{2-Chlorophenyl}piperazine
1-{2,3-Dichlorophenyl Piperazine}
Piperidine
Morpholine
9
5g
5h
5i
N-Phenyl piperazine
N-Acetyl piperazine
N-Isopropyl piperazine
1-{2-Pyridyl} piperazine
1-{2-Pyrimidyl}piperazine
11
10
13
11
10
5j
5k
Table 4 Data of synthesized compound 6a–k
Entry
Solvent
R
Microwave method
Conventional method
Reaction
time (min)
Yield (%)
Reaction
time (h)
Yield (%)
6a
6b
6c
6d
6e
6f
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
1,4,-Dioxane
N-Methyl piperazine
N-Ethyl piperazine
3
3
2
4
3
2
6
5
4
3
2
83
80
86
72
80
85
81
74
91
94
85
9
79
76
81
64
71
78
75
65
85
88
79
8
1-{2-Chlorophenyl}piperazine
1-{2,3-Dichlorophenyl Piperazine}
Piperidine
11
11
9
Morpholine
12
12
11
12
12
11
6g
6h
6i
N-Phenyl piperazine
N-Acetyl piperazine
N-Isopropyl piperazine
1-{2-Pyridyl} piperazine
1-{2-Pyrimidyl}piperazine
6j
6k
(KBr): 1,697.40 (C=O), 1,465.70 (CH3), 1,255–1,257 cm-1
(C–O–C).
(yield: 71%) of 5a, as white colored compound. Same
procedure was used for synthesis of compounds 5b–k and
6a–k.
General procedures for the preparation of compounds
(5a–k) and (6a–k)
Microwave method
To testify whether microwave irradiation speeds up the
final nucleophilic substitution reactions the same reaction
were carried out in the same scale and same solvent, i.e.,
1,4-dioxane under microwave irradiation. The reaction
time was found to be dramatically reduced for each sub-
stitution from 10 to 15 h (conventional heating method) to
2–6 min under microwave irradiation. Microwave assisted
reactions were conducted in septum-sealed reaction vessels
in microwave reactor. The final condensation of compound
3a and 3b with various substituted piperazines was carried
out under microwave irradiation. For example, compound
Conventional method
To a solution of 3a (3.68 g, 0.01 mol) in 1, 4-dioxane
(30 ml), N-methyl piperazine 4a (1.00 g, 0.01 mol) was
added and the reaction mixture was refluxed for 10–15 h as
per TLC monitoring. Potassium carbonate was used for the
neutralization of the reaction mixture. After completion of
the reaction, it was treated with crushed ice, neutralized by
dilute HCl. The precipitates thus obtained was filtered,
dried and recrystallized from THF (15 ml) to give 3.05 g
123

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Med Chem Res (2012) 21:1611–1624
3b (3.89 g, 0.01 mol) in 1 equivalent of K2CO3 (1.41 g)
was condensed with N-ethyl piperazine 4b (1.14 g,
0.01 mol) using 1,4-dioxane (30 ml) as a solvent under
microwave irradiation at 400 W power for 2–8 min and the
reaction was heated until completion as determined by
TLC analysis. After completion of the reaction the solvent
was recovered by using vacuum solvent recovery module,
the remaining reaction mixture were treated with crushed
ice, neutralized by dil. HCl and the precipitates thus
obtained were filtered by Buchner funnel by applying
vacuum and dried and recrystallized from THF to give
3.48 g (yield: 76%) of 6b as off white colored compound.
Same procedure was used for synthesis of other final
compounds also. The optimized reaction condition in
respect to reaction time and yield is described in Table 4
for each final nucleophilic reaction.
C=O at coumarin), 154.21 (C-23, C–O–C at coumarin),
152.48–116.10 (13C,–Ar–C), 110.55 (C-22, O=C–C
of coumarin), 51.27 (N–CH2 at piperazine linkage),
50.46–43.20 (4C, piperazine ring carbons), 16.45 (CH2–
CH3 of piperazine); Anal. Calcd. for C24H24N6O3: C,
64.85; H, 5.44; N, 18.91. Found: 64.82; H, 5.46; N, 18.90.
4-{4-[4-(3-Chloro-phenyl)-piperazine-1-yl]-6-
phenylamino-[1,3,5]triazin-2-yloxy}-chromen-2-one (5c)
Yield: 72%, m.p. 225–227°C; IR (KBr, cm-1): 3,297.10
(N–H str.), 1,696.54 (C=O of coumarin), 1,268.17 (C–O–
1
C), 813.99 (–Cl), 810.17 (s-triazine C–N str.); H NMR
(400 MHz, CDCl3) d 10.19 (s, 1H, –NH at aniline linkage),
7.82 (d, J = 7.1 Hz, 1H at C-19 of coumarin), 7.78–7.29
(m, 9H, Ar–H), 7.13–6.65 (m, 3H, 3H of coumarin), 5.91
(s, 1H, 1H at C-22 of coumarin), 3.57 (br s, 8H, piperazine
ring); 13C NMR 165.45 (C-2, C–O–C at coumarin linkage),
162.11 (C-4, C–NH at aniline linkage), 158.22 (C-21,
C=O at coumarin), 153.98 (C-23,C–O–C at coumarin),
152.70–115.09 (19C, Ar–C), 110.51 (C-22, O=C–C of
coumarin), 50.44–43.15 (4C, piperazine ring carbons);
Anal. Calcd. for C28H23ClN6O3: C, 63.82; H, 4.40; N,
15.95. Found: 63.82; H, 4.42; N, 15.92.
Characterization data of synthesized compound 5a–k
and 6a–k
4-[4-4(4-Methyl-piperazin-1-yl)-6-phenylamino-
[1,3,5]triazine-2-yloxy]-chromen-2-one (5a)
Yield: 71%, m.p. 257–261°C; IR (KBr, cm-1): 3,296.45
(N–H str.), 1,693.41 (C=O of coumarin), 1,454.38 (-CH3),
1
1,258.29 (C–O–C), 808.12 (s-triazine C–N str.); H NMR
4-{4-[4-(2,3-Dichloro-phenyl)-piperazine-1-yl]-6-
phenylamino-[1,3,5]triazine-2-yloxy}-chromen-2-one (5d)
(400 MHz, CDCl3) d 10.17 (s, 1H, -NH at aniline linkage),
7.70 (d, J = 7.4 Hz, 1H at C-19 of coumarin), 7.65–7.34
(m, 5H, Ar–H), 7.29–7.03 (m, 3H, 3H of coumarin), 5.95
(s, 1H, 1H at C-22 of coumarin), 3.57 (br s, 8H, piperazine
ring), 13C NMR 167.20 (C-2, C–O–C at coumarin linkage),
162.10 (C-4, C-NH at aniline linkage), 158.20 (C-21,
–C=O at coumarin), 154.25 (C-23, C–O–C at coumarin),
151.50–115.40 (13C, Ar–C), 110.75 (C-22, O=C–C of
coumarin), 50.44–43.16 (4C, piperazine ring carbons),
42.70 (N–CH3 at piperazine linkage); Anal. Calcd. for
C23H22N6O3: C, 64.17; H, 5.15; N, 19.52. Found: 64.16; H,
5.15; N, 19.48.
Yield: 85%, m.p. 229°C; IR (KBr, cm-1): 3,298.38 (N–H
str.), 1,697.41 (C=O of coumarin), 1,261.49 (C–O–C),
808.20 (–Cl), 812.06 (s-triazine C–N str.); 1H NMR
(400 MHz, CDCl3) d 10.17 (s, 1H, –NH at aniline linkage),
7.63 (d, J = 7.6 Hz, 1H at C-19 of coumarin), 7.57–7.22
(m, 8H, Ar–H), 7.08–6.55 (m, 3H, 3H of coumarin), 5.93
(s, 1H, 1H at C-22 of coumarin), 3.57 (br s, 8H, piperazine
ring); 13C NMR 165.16 (C-2, C–O–C at coumarin linkage),
162.10 (C-4, C–NH at aniline linkage), 158.59 (C-21,
–C=O at coumarin), 154.18 (C-23, C–O–C at coumarin),
153.87–115.68 (19C, Ar–C), 110.77 (C-22, O=C–C of
coumarin), 50.43–43.16 (4C, piperazine ring carbons);
Anal. Calcd. for C26H22Cl2N6O3: C, 59.90; H, 3.95; N,
14.97. Found: 59.90; H, 3.93; N, 14.96.
4-[4-(4-Etrhyl-piperazine-1-yl)-6-phenylamino-
[1,3,5]triazin-2-yloxy]-chromen-2-one (5b)
Yield: 65%, m.p. 248–252°C; IR (KBr, cm-1) : 3,296.43
(N–H str.), 1,693.39 (C=O of coumarin), 1,496.34
(–CH2CH3), 1,258.27 (C–O–C), 816.19 (s-triazine C–N
4-(4-Phenylamino-6-piperidin-1-yl-[1,3,5]triazine-2-
yloxy)-chromen-2-one (5e)
1
str.); H NMR (400 MHz, CDCl3) d 10.17 (s, 1H, –NH at
aniline linkage), 7.62 (d, J = 7.7 Hz, 1H at C-19 of cou-
marin), 7.59–7.31 (m, 5H, Ar–H), 6.51–7.10 (m, 3H, 3H of
coumarin), 5.95 (s, 1H, 1H at C-22 of coumarin), 3.55 (br s,
8H, piperazine ring), 2.95 (q, J = 6.4 Hz, 2H, –CH2 of
piperazine), 1.93 (t, J = 6.7 Hz, 3H,–CH3 of piperazine);
13C NMR 166.97 (C-2, C–O–C at coumarin linkage),
162.15 (C-4, C–NH at aniline linkage), 158.20 (C-21,
Yield: 70%, m.p. 253–257°C; IR (KBr, cm-1): 3,298.42
(N–H str.), 1,697.35 (C=O of coumarin), 1,261.47 (C–O–
C), 814.41 (s-triazine C–N str.); 1H NMR (400 MHz,
CDCl3) d 10.17 (s, 1H, –NH at aniline linkage), 7.86 (d,
J = 7.2 Hz, 1H at C-19 of coumarin), 7.82–7.36 (m, 5H,
Ar–H), 7.25–6.96 (m, 3H, 3H of coumarin), 5.95 (s, 1H, 1H
at C-22 of coumarin), 3.87 (t, J = 4.9 Hz, 4H, piperidine),
123

Med Chem Res (2012) 21:1611–1624
1619
3.61 (t, J = 5.7 Hz, 4H, piperidine), 1.62–1.67 (m, 2H,
piperidine); 13C NMR 165.12 (C-2, C–O–C at coumarin
linkage), 158.59 (C-21, –C=O at coumarin), 154.15 (C-23,
C–O–C at coumarin), 153.80–115.62 (13C, Ar–C), 110.75
(C-22, O=C–C of coumarin), 46.67–23.16 (5C, piperidine
ring carbons); Anal. Calcd. for C23H21N5O3: C, 66.49; H,
5.09; N, 16. 86. Found: 66.48; H, 5.10; N, 16.84.
10.19 (s, 1H, –NH at aniline linkage), 7.87 (d, J = 7.5 Hz,
1H at C-19 of coumarin), 7.83–7.35 (m, 5H, Ar–H),
7.31–7.04 (m, 3H, 3H of coumarin), 5.91 (s, 1H, 1H at
C-22 of coumarin), 3.57 (br s, 8H, piperazine ring), 2.14 (s,
3H, COCH3 at piperazine); 13C NMR 165.45 (C-2, C–O–C
at coumarin linkage), 163.40 (C-33, C=O of COCH3),
162.18 (C-4, C–NH at aniline linkage), 158.56 (C-21,
–C=O at coumarin), 154.18 (C-23, C–O–C at coumarin),
151.13–116.10 (13C, Ar–C), 110.65 (C-22, O=C–C of
coumarin), 50.35–44.19 (4C, piperazine ring carbons),
23.50 (C-34 of C–CH3); Anal. Calcd. for C24H22N6O4: C,
62.87; H, 4. 84; N, 18.33. Found : C, 62.85; H, 4. 84; N,
18.31.
4-(4-Morpholin-4-yl-6-phenylamino-[1,3,5]triazine-2-
yloxy)-chromen-2-one (5f)
Yield: 77%, m.p. 215–219°C; IR (KBr, cm-1): 3,296.58
(N–H str.), 1,695.67 (C=O of coumarin), 1,260.23 (C–O–
C), 811.21 (s-triazine C–N str.); 1H NMR (400 MHz,
CDCl3) d 10.20 (s, 1H, –NH at aniline linkage), 7.83 (d,
J = 7.7 Hz, 1H at C-19 of coumarin), 7.79–7.33 (m, 5H,
Ar–H), 7.26–7.04 (m, 3H, 3H of coumarin), 5.89 (s, 1H, 1H
at C-22 of coumarin), 2.40–2.35 (m, 4H, morpholine),
1.83–1.75 (m, 2H, –CH2, morpholine), 1.29–1.23 (m, 2H,
–CH2, morpholine); 13C NMR 165.12 (C-2, C–O–C at
coumarin linkage), 162.18 (C-4, C–NH at aniline linkage),
158.59 (C-21, –C=O at coumarin), 154.12 (C-23, C–O–C
at coumarin), 154.06–116.21 (13C, Ar–C), 110.78 (C-22,
O=C–C of coumarin), 49.77–46.90 (4C, morpholine ring
carbons); Anal. Calcd. for C22H19N5O4: C, 63.30; H, 4.59;
N, 16.78. Found: 63.32; H, 4.56; N, 16.74.
4-[4-(4-Isopropyl-piperazine-1-yl)-6-phenylamino-
[1,3,5]triazine-2-yloxy]-chromen-2-one (5i)
Yield: 80%, m.p. 241–244°C; IR (KBr, cm-1): 3,296.97
(N–H str.), 1,696.53 (C=O of coumarin), 1,489.43 (–CH3),
1
1,261.26 (C–O–C), 809.61 (s-triazine C–N str.); H NMR
(400 MHz, CDCl3) d 10.17 (s, 1H, –NH at aniline linkage),
7.83 (d, J = 7.1 Hz, 1H at C-19 of coumarin), 7.75–7.38
(m, 5H, Ar–H), 7.35–7.02 (m, 3H, 3H of coumarin), 5.93
(s, 1H, 1H at C-22 of coumarin), 3.60 (br s, 8H, piperazine
ring), 2.10 (d, J = 5.9 Hz, 6H, CH3–C–CH3 at piperazine);
13C NMR 166.15 (C-2, C–O–C at coumarin linkage),
162.32 (C-4, C–NH at aniline linkage), 158.58 (C-21,
–C=O at coumarin), 153.25 (C-23, C–O–C at coumarin),
152.19–115.07 (13C, Ar–C), 110.56 (C-22, O=C–C of
coumarin), 50.57–45.30 (4C, piperazine ring carbons),
23.50 (C-33, C-34 of CH3–C–CH3); Anal. Calcd. for
C25H26N6O3: C, 65.49; H, 5.72; N, 18.33. Found; C, 65.50;
H, 5.74; N, 18.31.
4-[4-Phenylamino-6-(4-phenyl-piperazine-1-yl)-
[1,3,5]triazine-2-yloxy]-chromen-2-one (5g)
Yield: 72%, m.p. 234–237°C; IR (KBr, cm-1): 3,297.48
(N–H str.), 1,696.54 (C=O of coumarin), 1,260.21 (C–O–
C), 815.10 (s-triazine C–N str.); 1H NMR (400 MHz,
CDCl3) d 10.17 (s, 1H, –NH at aniline linkage), 7.85 (d,
J = 7.7 Hz, 1H at C-19 of coumarin), 7.80–7.19 (m, 10H,
Ar–H), 7.11–6.80 (m, 3H, 3H of coumarin), 5.93 (s, 1H, 1H
at C-22 of coumarin), 3.54 (br s, 8H, piperazine ring); 13C
NMR 165.30 (C-2, C–O–C at coumarin linkage), 162.28
(C-4, C–NH at aniline linkage), 158.66 (C-21, –C=O
at coumarin), 153.88 (C-23, C–O–C at coumarin),
153.15–115.60 (19C, Ar–C), 110.78 (C-22, O=C–C of
coumarin), 50.19–43.90 (4C, piperazine ring carbons);
Anal. Calcd. for C28H24N6O3: C, 68.33; H, 4. 91; N, 17.06.
Found: 68.32; H, 4.91; N, 17.04.
4-[4-Phenylamino-6-(4-pyridine-2-yl-piperazine-1-yl)-
[1,3,5]triazine-2-yloxy]-chromen-2-one (5j)
Yield: 78%, m.p. 270–275°C; IR (KBr, cm-1): 3,297.15
(N–H str.), 1,696.51 (C=O of coumarin), 1,260.92 (C–O–
C), 818.09 (s-triazine C–N str.); 1H NMR (400 MHz,
CDCl3) d 10.17 (s, 1H, –NH at aniline linkage), 8.08 (d,
J = 6.9 Hz, 1H at C-19 of coumarin), 7.87–7.32 (m, 9H,
Ar–H), 7.13–6.74 (m, 3H, 3H of coumarin), 5.96 (s, 1H, 1H
at C-22 of coumarin), 3.62 (br s, 8H, piperazine ring); 13C
NMR 165.23 (C-2, C–O–C at coumarin linkage), 162.20
(C-4, C–NH at aniline linkage), 160.12 (C-32, N–C at
piperazine with pyridine linkage), 158.62 (C-21, –C=O
at coumarin), 154.20 (C-23, C–O–C at coumarin),
151.14–116.20 (17C, Ar–C), 110.70 (C-22, O=C–C of
coumarin), 51.55–46.13 (4C, piperazine ring carbons);
Anal. Calcd. for C25H26N6O3: C, 65.71; H, 4.70; N, 19.87.
Found; C, 65.69; H, 4.72; N, 19.87.
4-[4-(4-Acetyl-piperazine-1-yl)-6-phenylamno-
[1,3,5]triazine-2-yloxy]-chromen-2-one (5h)
Yield: 60%, m.p. 264–269°C; IR (KBr, cm-1): 3,297.40
(N–H str.), 1,696.39 (C=O of coumarin), 1,690.10 (C=O of
COCH3), 1,488.45 (–CH3 of COCH3), 1,260.20 (C–O–C),
810.91 (s-triazine C–N str.); 1H NMR (400 MHz, CDCl3) d
123

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Med Chem Res (2012) 21:1611–1624
1.80 (t, J = 6.9 Hz, 3H, –CH3 of piperazine); 13C NMR
165.17 (C-2, C–O–C at coumarin linkage), 164.34 (C-4,
C–NH at aniline linkage), 162.10 (C-14, –C=O at couma-
rin), 159.18 (C-8, C–O–C at coumarin), 153.88–96.35
(13C, Ar–C), 110.76 (C-15, O=C–C of coumarin), 50.17
(N–CH2 at piperazine linkage), 49.43–43.22 (4C, pipera-
zine ring carbons), 22.27 (C-18, C–CH3 of coumarin),
16.45 (C-33, CH2–CH3 of piperazine); Anal. Calcd. for
C25H26N6O3: C, 65.49; H, 5.72; N, 18.33. Found; C, 65.47;
H, 5.71; N, 18.30.
4-[4-Phenylamino-6-(4-pyrimidin-2-yl-piperazine-1-yl)-
[1,3,5]triazine-2-yloxy]-chromen-2-one (5k)
Yield: 69%, m.p. 218–221°C; IR (KBr, cm-1): 3,298.45
(N–H str.), 1,697.13 (C=O of coumarin), 1,261.44 (C–O–C),
812.23 (s-triazine C–N str.); 1H NMR (400 MHz, CDCl3) d
10.17 (s, 1H, –NH at aniline linkage), 8.45 (d, J = 7.5 Hz,
1H at C-19 of coumarin), 8.45–7.79 (m, 8H, Ar–H),
7.18–6.87 (m, 3H, 3H of coumarin), 5.19 (s, 1H, 1H at
C-22 of coumarin), 3.57 (br s, 8H, piperazine ring); 13C
NMR 166.05 (C-2, C–O–C at coumarin linkage), 162.24
(C-4, C–NH at aniline linkage), 158.60 (C-21, –C=O at
coumarin), 158.31 (C-32, N–C at piperazine with pyr-
imidine linkage), 154.32 (C-23, C–O–C at coumarin),
154.25–116.18 (17C, –Ar–C), 110.77 (C–22, O=C–C of
coumarin), 49.13–47.62 (4C, piperazine ring carbons);
Anal. Calcd. for C26H22N8O3: C, 63.15; H, 4.48; N, 22.66.
Found; C, 63.17; H, 4.48; N, 22.62.
7-{4-[4-(3-Chloro-phenyl)-piperazin-1-yl]-6-phenylamino-
[1,3,5]triazin-2-yloxy}-4-methyl-chromen-2-one (6c)
Yield: 81%, m.p. 235–240°C; IR (KBr, cm-1): 3,285.63
(N–H str.), 1,702.40 (C=O of coumarin), 1,447.52 (–CH3
of coumarin), 1,277.44 (C–O–C), 820.21 (–Cl), 816.27
1
(s-triazine C–N str.); H NMR (400 MHz, CDCl3) d 10.19
(s, 1H, –NH at aniline linkage), 7.74 (d, J = 7.2 Hz, 1H at
C-12 of coumarin), 7.62–7.37 (m, 8H, Ar–H), 6.97–6.66
(m, 2H, 2H of coumarin), 6.28 (s, 1H, 1H at C-15 of
coumarin), 3.62 (br s, 8H, piperazine ring), 2.43 (d,
J = 1.6 Hz, 3H, –CH3 of coumarin); 13C NMR 165.24
(C-2, C–O–C at coumarin linkage), 164.39 (C-4, C–NH at
aniline linkage), 162.13 (C-14, –C=O at coumarin), 159.24
(C-8, C–O–C at coumarin), 154.80–96.31 (19C, Ar–C),
110.77 (C-15, O=C–C of coumarin), 50.04–43.25 (4C,
piperazine ring carbons), 22.27 (C-18, C–CH3 of couma-
rin); Anal. Calcd. for C29H25ClN6O3: C, 64.38; H, 4.66; N,
15.53. Found; C, 64.36; H, 4.64; N, 15.54.
4-Methyl-7-[4-(4-methyl-piperazine-1-yl)-6-phenylamino-
[1,3,5]triazine-2-yloxy]-chromen-2-one (6a)
Yield: 79%, m.p. 258–263°C; IR (KBr, cm-1): 3,284.88
(N–H str.), 1,700.31 (C=O of coumarin), 1,448.54 (–CH3
of coumarin), 1,278.85 (C–O–C), 815.14 (s-triazine C–N
1
str.); H NMR (400 MHz, CDCl3) d 10.21 (s, 1H, –NH at
aniline linkage), 7.75 (d, J = 7.4 Hz, 1H at C-12 of cou-
marin), 7.71–7.37 (m, 5H, Ar–H), 7.02–6.84 (m, 2H, 2H of
coumarin), 6.30 (s, 1H, 1H at C-15 of coumarin), 3.60 (br s,
8H, piperazine ring), 2.40 (d, J = 1.1 Hz, 3H, –CH3 of
coumarin); 13C NMR 165.10 (C-2, C–O–C at coumarin
linkage), 164.41 (C-4, C–NH at aniline linkage), 162.062
(C-14, –C=O at coumarin), 159.20 (C-8, C–O–C at cou-
marin), 110.77 (C-15, O=C–C of coumarin), 153.90 96.30
(13C, Ar–C), 49.40–43.18 (4C, piperazine ring carbons),
42.06 (C-33, N–CH3 of piperazine), 22.25 (C-18, C–CH3
of coumarin); Anal. Calcd. for C24H24N6O3: C, 64.85; H,
5.44; N, 18.91. Found; C, 64.87; H, 5.42; N, 18.90.
7-{4-[4-(2,3-Dichloro-phenyl)-piperazine-1-yl]-6-
phenylamino-[1,3,5]triazin-2-yloxy}-4-methyl-chromen-2-
one (6d)
Yield: 64%, m.p. 223–226°C; IR (KBr, cm-1): 3,284.83
(N–H str.), 1,700.10 (C=O of coumarin), 1,277.53 (C–O–
C), 1,448.12 (–CH3 of coumarin), 817.52 (–Cl), 810.54
1
(s-triazine C–N str.); H NMR (400 MHz, CDCl3) d 10.28
7-[4-(4-Ethyl-piperazin-1-yl)-6-phenylamino-
[1,3,5]triazin-2-yloxy]-4-methyl-chromen-2-one (6b)
(s, 1H, –NH at aniline linkage), 7.70 (d, J = 7.9 Hz, 1H at
C-12 of coumarin), 7.65–7.31 (m, 8H, Ar–H), 6.54–6.92
(m, 2H, 2H of coumarin), 6.21 (s, 1H, 1H at C-15 of
coumarin), 3.59 (br s, 8H, piperazine ring), 2.41 (d,
J = 1.3 Hz, 3H, –CH3 of coumarin); 13C NMR 165.29
(C-2, C–O–C at coumarin linkage), 164.33 (C-4, C–NH at
aniline linkage), 163.18 (C-14, –C=O at coumarin), 160.04
(C-8, C–O–C at coumarin), 154.80–96.31 (19C, Ar–C),
110.74 (C-15, O=C–C of coumarin), 50.16–44.55 (4C,
piperazine ring carbons), 22.30 (C-18, C–CH3 of couma-
rin); Anal. Calcd. for C29H24Cl2N6O3: C, 60.53; H, 4.20;
N, 14.60. Found; C, 60.55; H, 4.20; N, 14.57.
Yield: 76%, m.p. 249–253°C; IR (KBr, cm-1): 3,286.57
(N–H str.), 1,702.29 (C=O of coumarin), 1,275.49 (C–O–
C), 1,448.55 (–CH3 of coumarin), 811.19 (s-triazine C–N
1
str.); H NMR (400 MHz, CDCl3) d 10.26 (s, 1H, –NH at
aniline linkage), 7.70 (d, J = 7.6 Hz, 1H at C-12 of cou-
marin), 7.66–7.32 (m, 5H, Ar–H), 7.10–6.83 (m, 2H, 2H of
coumarin), 6.22 (s, 1H, 1H at C-15 of coumarin), 3.57 (br s,
8H, piperazine ring), 2.50 (q, J = 6.6 Hz, 2H, –CH2 of
piperazine), 2.44 (d, J = 1.4 Hz, 3H, –CH3 of coumarin),
123

Med Chem Res (2012) 21:1611–1624
1621
4-Methyl-7-(4-phenylamino-6-piperidin-1-yl-
[1,3,5]triazin-2-yloxy)-chromen-2-one (6e)
of coumarin), 6.29 (s, 1H, 1H at C-15 of coumarin), 3.57
(br s, 8H, piperazine ring), 2.37 (d, J = 1.7 Hz, 3H, –CH3
of coumarin); 13C NMR 165.13 (C-2, C–O–C at coumarin
linkage), 164.41 (C-4, C–NH at aniline linkage), 162.06
(C-14, –C=O at coumarin), 159.26 (C-8, C–O–C at cou-
marin), 153.93–96.35 (19C, Ar–C), 110.77 (C-15, O=C–C
of coumarin), 49.42–43.16 (4C, piperazine ring carbons),
22.25 (C-18, C–CH3 of coumarin); Anal. Calcd. for
C29H26N6O3: C, 68.76; H, 5.17; N, 16.59. Found; C, 68.78;
H, 5.17; N, 16.57.
Yield: 71%, m.p. 242–247°C; IR (KBr, cm-1): 3,284.80
(N–H str.), 1,703.08 (C=O of coumarin), 1,447.42 (–CH3
of coumarin), 1,278.29 (C–O–C), 809.43 (s-triazine C–N
1
str.); H NMR (400 MHz, CDCl3) d 10.20 (s, 1H, –NH at
aniline linkage), 7.84 (d, J = 7.3 Hz, 1H at C-12 of cou-
marin), 7.79–7.34 (m, 5H, Ar–H), 7.04–6.83 (m, 2H, 2H of
coumarin), 6.15 (s, 1H, 1H at C-15 of coumarin), 2.46 (d,
J = 1.5 Hz, 3H, –CH3 of coumarin), 3.71 (t, J = 4.6 Hz,
4H, piperidine), 3.64 (t, J = 5.5 Hz, 4H, piperidine),
1.58–1.50 (m, 2H, piperidine); 13C NMR 165.35 (C-2,
C–O–C at coumarin linkage), 164.31 (C-4, C–NH at ani-
line linkage), 164.12 (C-14, –C=O at coumarin), 160.10
(C-8, C–O–C at coumarin), 154.75–96.12 (13C, Ar–C),
110.77 (C-15, O=C–C of coumarin), 46.11–23.50 (5C,
piperidine ring carbons), 22.38 (C-18, C–CH3 of couma-
rin); Anal. Calcd. for C24H23N5O3: C, 67.12; H, 5.40; N,
16.31. Found; C, 67.09; H, 5.38; N, 16.30.
7-[4-(4-Acetyl-piperazine-1-yl)-6-phenylamino-
[1,3,5]triazin-2-yloxy]-4-methyl-chromen-2-one (6h)
Yield: 65%, m.p. 268–273°C; IR (KBr, cm-1): 3,284.82 (N–
H str.), 1,704.17 (C=O of coumarin), 1,448.61 (–CH3 of
coumarin), 1,277.97 (C–O–C), 1,692.21 (C=O of COCH3),
811.32 (s-triazine C–N str.); 1H NMR (400 MHz, CDCl3) d
10.21 (s, 1H, –NH at aniline linkage), 7.65 (d, J = 7.4 Hz,
1H at C-12 of coumarin), 7.60–7.22 (m, 5H, Ar–H),
7.15–6.83 (m, 2H, 2H of coumarin), 6.27 (s, 1H, 1H at C-15
of coumarin), 3.65 (br s, 8H, piperazine ring), 2.45 (d,
J = 1.4 Hz, 3H, –CH3 of coumarin), 2.17 (s, 3H, COCH3 at
piperazine); 13C NMR 165.19 (C-2, C–O–C at coumarin
linkage), 164.85 (C-33, C=O of COCH3), 164.40 (C-4,
C–NH at aniline linkage), 163.16 (C-14, –C=O at couma-
rin), 159.22 (C-8, C–O–C at coumarin), 153.99–96.15 (13C,
Ar–C), 110.69 (C-15, O=C–C of coumarin), 47.36–44.26
(4C, piperazine ring carbons), 22.22 (C-18, C–CH3 of cou-
marin), 21.31 (C-35 of C–CH3); Anal. Calcd. for
C25H24N6O4: C, 63.55; H, 5.12; N, 17.79. Found; C, 63.53;
H, 5.11; N, 17.79.
4-Methyl-7-(4-morpholine-4-yl-6-phenylamino-
[1,3,5]triazin-2-yloxy)-chromen-2-one (6f)
Yield: 78%, m.p. 260–262°C; IR (KBr, cm-1): 3,284.85
(N–H str.), 1,700.13 (C=O of coumarin), 1,448.52 (–CH3
coumarin), 1,278.80 (C–O–C), 810.70 (s-triazine C–N str.);
1H NMR (400 MHz, CDCl3) d 10.21 (s, 1H, –NH at aniline
linkage), 7.69 (d, J = 7.7 Hz, 1H at C-12 of coumarin),
7.64–7.29 (m, 5H, Ar–H), 7.11–6.85 (m, 2H, 2H of cou-
marin), 6.29 (s, 1H, 1H at C-15 of coumarin), 2.39 (d,
J = 1.9 Hz, 3H, –CH3 of coumarin), 2.43–2.38 (m, 4H,
morpholine), 1.79–1.71 (m, 2H, –CH2, morpholine),
1.24–1.20 (m, 2H, –CH2, morpholine); 13C NMR 165.36
(C-2, C–O–C at coumarin linkage), 164.59 (C-4, C–NH at
aniline linkage), 164.45 (C-14, –C=O at coumarin), 159.26
(C-8, C–O–C at coumarin), 110.72 (C-15, O=C–C of
coumarin), 155.08–96.25 (13C, Ar–C), 49.75–46.50 (4C,
morpholine ring carbons), 22.27 (C-18, C–CH3 of cou-
marin); Anal. Calcd. for C23H21N5O4: C, 64.03; H, 4.91; N,
16.23. Found; C, 64.01; H, 4.92; N, 16.25.
7-[4-(4-Isopropyl-piperazin-1-yl)-6-phenylamino-
[1,3,5]triazin-2-yloxy]-4-methyl-chromen-2-one (6i)
Yield: 85%, m.p. 261–264°C; IR (KBr, cm-1): 3,285.10
(N–H str.), 1,700.19 (C=O of coumarin), 1,448.49 (–CH3
coumarin), 1,278.69 (C–O–C), 811.65 (s-triazine C–N str.);
1H NMR (400 MHz, CDCl3) d 10.25 (s, 1H, –NH at aniline
linkage), 7.79 (d, J = 7.1 Hz, 1H at C-12 of coumarin),
7.74–7.28 (m, 5H, Ar–H), 7.10–6.89 (m, 2H, 2H of cou-
marin), 6.23 (s, 1H, 1H at C-15 of coumarin), 3.62 (br s,
8H, piperazine ring), 2.42 (d, J = 1.6 Hz, 3H, –CH3 of
coumarin), 1.98 (d, J = 6.2 Hz, 6H, CH3–C–CH3 at
piperazine); 13C NMR 165.25 (C-2, C–O–C at coumarin
linkage), 164.48 (C-4, C–NH at aniline linkage), 162.46
(C-14, –C=O at coumarin), 159.30 (C-8, C–O–C at cou-
marin), 154.87–97.09 (13C, Ar–C), 110.71 (C-15, O=C–C
of coumarin), 51.13–46.16 (4C, piperazine ring carbons),
22.25 (C-18, C–CH3 of coumarin), 20.27 (C-34,C-35 of
4-Methyl-7-[4-phenylamino-6-(4-phenyl-pipearzni-1-yl)-
[1,3,5]triazin-2-yloxy)-chromen-2-one (6g)
Yield: 75%, m.p. 262–266°C; IR (KBr, cm-1): 3,284.88
(N–H str.), 1,700.31 (C=O of coumarin), 1,448.59 (–CH3
of coumarin), 1,278.85 (C–O–C), 813.99 (s-triazine C–N
1
str.); H NMR (400 MHz, CDCl3) d 10.24 (s, 1H, –NH at
aniline linkage), 7.58 (d, J = 7.9 Hz, 1H at C-12 of cou-
marin), 7.49–7.18 (m, 10H, Ar–H), 6.89–6.15 (m, 2H, 2H
123

1622
Med Chem Res (2012) 21:1611–1624
CH3–C–CH3); Anal. Calcd. for C26H28N6O3: C, 66.09; H,
5.97; N, 17.78. Found; C, 66.12; H, 5.99; N, 17.80.
strains, such as two Gram -ve bacteria (E. coli, P. aeru-
ginosa), two Gram ?ve bacteria (S. aureus, B. subtilis) and
two fungal species (C. albicans and A. niger) using disc
diffusion sensitivity test (Cruickshank et al. 1975). Muel-
ler–Hinton agar media were sterilized (autoclaved at 120°C
for 30 min) and allowed to pour at uniform depth of disc to
solidify and access of suspension was decanted, which was
then inoculated (1 ml/100 ml of medium) with the sus-
pension (105 CFU/ml) and turbidity of all the bacterial
cultures was adjusted to 0.5 McFarland Nephelometery
standard, which was streaked over the surface of media
using a sterile cotton swab (15 min at 180°C) to ensure
pronominal growth of organisms. The sterile plates previ-
ously soaked in a known concentration of the test com-
pounds in DMSO were placed on the solidified nutrient
agar medium that is previously inoculated with pathogenic
bacterial suspension for the sole purpose of producing
zones of inhibition in millimeter in the bacterial lawn at the
end of an incubation period of 24 h at 37 1°C if any,
around the disc. An additional control disc impregnated
with an equivalent amount of solvent (DMSO) was also
used in the assay without any sample, which did not reveal
any inhibition. Ciprofloxacin and ketoconazole were used
as standard control drugs for antibacterial and anti-fungal
activity, respectively at 100 lg/disc. Ciprofloxacin is
active against both Gram ?ve and Gram -ve bacteria by
functioning inhibition of DNA gyrase, a type II topoiso-
merase and topoisomerase IV, which is the necessary
enzyme to separate bacterial DNA, thereby inhibiting cell
division by binding these enzymes and prevent them from
decatenating replicating DNA. Therefore, in our study, we
selected ciprofloxacin as a standard drug control because it
is a broad-spectrum antibiotic. Each experiment was per-
formed in triplicate, and the results of this activity evalu-
ation are mentioned in Tables 1 and 2.
4-Methyl-7-[4-phenylamino-6-(4-pyrodine-2-yl-piperazin-
1-yl)-[1,3,5]triazin-2-yloxy]-chromen-2-one (6j)
Yield: 88%, m.p. 250–254°C; IR (KBr, cm-1): 3,284.81
(N–H str.), 1,700.30 (C=O of coumarin), 1,448.49 (–CH3
of coumarin), 1,278.38 (C–O–C), 814.36 (s-triazine C–N
1
str.); H NMR (400 MHz, CDCl3) d 10.19 (s, 1H, –NH at
aniline linkage), 7.96 (d, J = 6.9 Hz, 1H at C-12 of cou-
marin), 7.85–7.33 (m, 9H, Ar–H), 7.03–6.64 (m, 2H, 2H of
coumarin), 6.29 (s, 1H, 1H at C-15 of coumarin), 3.57 (br s,
8H, piperazine ring), 2.40 (d, J = 1.2 Hz, 3H, –CH3 of
coumarin); 13C NMR 165.33 (C-2, C–O–C at coumarin
linkage), 164.40 (C-4, C–NH at aniline linkage), 163.26
(C-14, –C=O at coumarin), 160.58 (C-33, N–C at pipera-
zine with pyridine linkage), 159.29 (C-8, C–O–C at cou-
marin), 155.10–96.15 (17C, –Ar–C), 110.65 (C-15, O=C–C
of coumarin), 49.74–47.17 (4C, piperazine ring carbons),
22.30 (C-18, C–CH3 of coumarin); Anal. Calcd. for
C28H25N7O3: C, 66.26; H, 4.96%; N, 19.32. Found; C,
66.26; H, 5.98%; N, 19.35.
4-Methyl-7-[4-phenylamino-6-(4-pyrimidin-2-yl-
piperazine-1-yl)-[1,3,5]triazin-2-yloxy]-chromen-2-one
(6k)
Yield: 79%, m.p. 258–263°C; IR (KBr, cm-1): 3,284.84
(N–H str.), 1,700.43 (C=O of coumarin), 1,448.42 (–CH3
coumarin), 1,278.19 (C–O–C), 816.25 (s-triazine C–N str.);
1H NMR (400 MHz, CDCl3) d 10.21 (s, 1H, –NH at aniline
linkage), 7.75 (d, J = 7.2 Hz, 1H at C-12 of coumarin),
7.71–7.30 (m, 8H, Ar–H), 7.11–6.83 (m, 2H, 2H of cou-
marin), 6.25 (s, 1H, 1H at C-15 of coumarin), 3.60 (br s,
8H, piperazine ring), 2.42 (d, J = 1.1 Hz, 3H, –CH3 of
coumarin); 13C NMR 165.10 (C-2, C–O–C at coumarin
linkage), 164.46 (C-4, C–NH at aniline linkage), 162.46
(C-14, –C=O at coumarin), 160.58 (C-33, N–C at pipera-
zine with pyridine linkage), 159.26 (C-8, C–O–C at cou-
marin), 158.32 (C-33,N–C at piperazine with pyrimidine
linkage), 154.19–96.35 (17C, Ar–C), 51.30–47.17 (4C,
piperazine ring carbons), 110.77 (C-15, O=C–C of cou-
marin), 22.35 (C-18, C–CH3 of coumarin); Anal. Calcd. for
C27H24N8O3: C, 63.77; H, 4.76; N, 22.03. Found C,
63.75%; H, 4.76%; N, 22.05%.
To determine minimum inhibitory concentration, a
stock solution of the synthesized compound (100 lg/ml)
in DMSO was prepared and appropriate respective quan-
tities of the test compounds were incorporated in the
specified quantity of molten sterile agar, in which, nutrient
agar and sabouraud dextrose agar medium was used for
anti-bacterial and anti-fungal activity evaluation, respec-
tively. The medium containing the test compound was
poured into a petridish at a depth of 4–5 mm and allowed
to solidify under aseptic conditions. Microorganism sus-
pension was prepared having approximately 105 CFU/ml
and applied to plates with diluted compounds in DMSO
and incubated at 37 1°C for 24 h for MIC determina-
tion for pathogenic bacteria and 48 h for fungi. The
lowest concentration of the substance, on the plate to be
tested, preventing the development of visible growth of
inoculated bacteria and fungi was recorded to represent
MIC expressed in lg/ml.
Antimicrobial activity
All the newly synthesized s-triazinyl piperazine and
piperidine scaffolds 5a–k and 6a–k were examined for
antimicrobial activity against several bacterial and fungal
123

Med Chem Res (2012) 21:1611–1624
1623
Acknowledgments The authors are thankful to S.V. National
Institute of Technology, Surat for the scholarship, encouragement and
facilities. Authors are also grateful to Catapharma, Enzal chemicals
Pvt. Ltd., Dr. Prem’s molecules Pvt. Ltd., Ami organics Pvt. Ltd.,
Modepro (India) Pvt. Ltd., Siddharth Interchem Pvt. Ltd., Mahr-
shee laboratories for providing valuable piperazine and piperidine
derivatives.
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