Synthesis of 3-{4-[4-dimethylamino-6-(4-methyl-2-oxo-2Hchromen-7-yloxy)-[1, 3,5]triazin-2-ylamino]-phenyl}-2-phenyl-5- (4-pyridin-2-yl-piperazin-1-ylmethyl) -thiazolidin-4-one and their biological evaluation

Article abstract of DOI:10.1007/s00044-011-9822-y

A novel series of thiazolidinone derivatives namely 3-{4-[4-dimethylamino- 6-(4-methyl-2-oxo-2Hchromen- 7-yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2- phenyl-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-thiazolidin- 4-one have been synthesized from the intermed

Full text of DOI:10.1007/s00044-011-9822-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2926–2944
DOI 10.1007/s00044-011-9822-y
ORIGINAL RESEARCH
Synthesis of 3-{4-[4-dimethylamino-6-(4-methyl-2-oxo-2H-
chromen-7-yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-phenyl-5-
(4-pyridin-2-yl-piperazin-1-ylmethyl)-thiazolidin-4-one and their
biological evaluation
•
Divyesh Patel Premlata Kumari Navin Patel
•
Received: 19 August 2011 / Accepted: 19 October 2011 / Published online: 3 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A novel series of thiazolidinone derivatives
namely 3-{4-[4-dimethylamino-6-(4-methyl-2-oxo-2H-
multidrug resistant microbial strains proliferate, the necessity
for effectivetherapy has stimulated research onthesynthesis of
novel antimicrobial molecules (Saleh et al., 2010).
chromen-7-yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-
phenyl-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-thiazolidin-
4-one have been synthesized from the intermediate
7-[4-(4-amino-phenylamino)-6-dimethylamino-[1,3,5]triazin-
2-yloxy]-4-methyl-chromen-2-one (7). Condensation reac-
tion of compound 7 with different aldehyde derivatives
were performed to give Schiff base derivatives, which after
cyclization gave thiazolidinones and they were incorpo-
rated with 1-pyridin-2-yl-piperazine to get target com-
pounds. The newly synthesized compounds were evaluated
for their antimicrobial activity against eight bacteria
(S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumo-
niae, S. typhi, P. vulgaris, and S. flexneria) and four fungi
(A. niger, C. albicans, A. fumigatus, and A. clavatus).
1,3,5-triazine derivatives have been known for a long
period of time. From the literature survey we found that
1,3,5-triazines showed biological activities such as antimi-
crobial (Madhukar et al., 1988), antitumor (Matsuno et al.,
2000), anticancer (Saczewski et al., 2006), antimalarial
(David et al., 2011), and antiviral (Chen et al., 2009). So, we
started our work by taking 2,4,6-trichloro-[1,3,5]-triazine as
a starting material. In our continuation work on 1,3,5-triazine
derivatives (Divyesh et al., 2011), here we have report 1,3,
5-triazine-based some novel thiazolidinone derivatives.
Thiazolidinones are an important class of heterocyclic
compounds known for their potential pharmaceutical appli-
cations (Verma and Saraf, 2008). In this study, we have
synthesized intermediate 7-[4-(4-amino-phenylamino)-6-
dimethylamino-[1,3,5]triazin-2-yloxy]-4-methyl-chromen-2-
one (7) which contain coumarin derivative. The coumarin
moiety is distributed widely in nature. A number of natural
products and synthetic analogs featuring coumarin structural
motif display wide-ranging biological properties and they
are used as antibacterial (Khan et al., 2004), antifungal (Nida
et al., 2011), anticancer (Federica et al., 2010), antiHIV
(Luis et al., 2005), antioxidant (Khan et al., 2002, Garazd
et al., 2007), anti-inflammatory (Koneni et al., 2011), anti-
biotics (Hussain et al., 2003), anticoagulant (Manolov and
Danchev, 1995), and antitumor (Al-Soud et al., 2006) agents.
Coumarin derivatives are also used as optical whiteners,
luminescence dyes (Yi-Feng et al., 2010), active media for
lasers (Zabradnik, 1992). Among the various coumarin
derivatives 4-substituted coumarins are important due to their
biological applications (Nenad et al., 2010, Zeba et al.,
2011). For example 7-hydroxy-4-methylcoumarin is used as
spasmolytic drug in several European countries (Kultti et al.,
Keywords 7-Hydroxy-4-methyl coumarin Á Piperazine Á
Thiazolidinone Á Antimicrobial
Introduction
The increasing incidence of infection caused by the rapid
development of microbial resistance to most of the known
antibiotics is a serious health problem. There are a number of
factors responsible for mutations in the microbial genomes. As
D. Patel Á P. Kumari (&)
Department of Applied Chemistry, S.V. National Institute
of Technology, Surat 395007, India
e-mail: premlatakumari1@gmail.com
N. Patel
Department of Chemistry, V.N. South Gujarat University,
Surat 395007, India
123

Med Chem Res (2012) 21:2926–2944
2927
2009). So, compound 7 seems to be a good candidate to fulfill
our objective via its condensation with different aldehydes to
afford Schiff base and further cyclization to get thiazolidi-
nones. The piperazine ring is found in a number of biologi-
cally active compounds, including several marketed drugs
(Bruce et al., 1994) and it is considered to be a privileged
structure in drug discovery (Duglas et al., 2003). From the
Literature survey we found that mannich reaction for thia-
zolidinone derivatives is important and these types of
derivatives possess significant biological activities (Bahgat
et al., 2005). In light of these considerations, we synthesized
thiazolidinone derivatives attached with 1-pyridin-2-yl-
piperazine. All the novel derivatives were screened for their
antibacterial and antifungal activity.
Results and discussion
Chemistry
The synthetic strategy adopted to obtain the target compounds
isdepictedinScheme 1. 2,4,6-Trichloro-[1,3,5]triazine (1) on
H3C
CH3
N
Cl
THF
N
N
NH(CH3)2
+
N
N
Et3N
Cl
Cl
Cl
Cl
N
N
3
2
1
H3C
CH3
N
CH3
N
N
THF
NaH
O
O
3
+
O
Cl
N
HO
O
O
5
CH3
4
H3C
CH3
N
N
N
N
O
NH2
O
O
NH
NH2
1,4-dioxane
K2CO3
+
5
H2N
7
6
CH3
H3C
CH3
N
N
N
N
O
O
CH
Ar
N
O
NH
Ar CHO
ethanol
piperidine
7
+
(a-n)
8a-n
CH3
H3C
CH3
N
Ar
N
N
N
S
O
O
O
NH
benzene
N
8a-n
HSCH2COOH
+
9
10a-n
O
CH3
Scheme 1 Synthesis of thiazolidinone derivatives
123

2928
Med Chem Res (2012) 21:2926–2944
H3C
CH3
10a-n
N
N
Ar
N
N
N
+
S
N
O
O
N
ethanol
paraformladehyde
O
NH
N
N
HN
N
11
12a-n
O
CH3
Ar (a-n) - Aromatic aldehydes
h
i
a
CHO
CHO
O2N
CHO
b
Cl
CHO
HO
Cl
Br
c
j
Cl
CHO
CHO
Cl
COOH
d
H3C
CHO
CHO
k
l
CHO
e
F
CHO
H3CO
H3CO
CHO
f
CHO
m
F
H3CO
OH
g
n
Cl
CHO
HO
CHO
Scheme 1 continued
reaction with dimethylamine (2) at 0–5°C yielded (4,
6-dichloro-[1,3,5]triazin-2-yl)-dimethylamine (3). Com-
pound 3 was then reacted with 7-hydroxy-4-methylcoum-
arin (4) to yield 7-(4-chloro-6-dimethylamino-[1,3,5]
triazin-2-yloxy)-4-methyl-chromen-2-one (5). The inter-
compounds 12a–n were prepared by the reaction of
10a–n with a mixture of paraformaldehyde and 1-pyridin-
2-yl-piperazine in absolute ethanol.
The structures of the synthesized compounds were con-
firmed by spectral data, elemental analysis and they were in
1
full agreement with the proposed structures. In H NMR
mediate
7-[4-(4-amino-phenylamino)-6-dimethylamino-
[1,3,5]triazin-2-yloxy]-4-methyl-chromen-2-one (7) was
prepared by condensation of compound 5 with p-phenyl-
enediamine. Hydrazones 8a–n were prepared by reaction
between Compound 7 and different aromatic aldehydes.
Cyclization of hydrazones with mercaptoacetic acid led
to the formation of thiazolidinones 10a–n. The target
spectra of compound 3, singlet signal appeared at 3.10 ppm
due to –CH3. The formation of compound 5 bearing cou-
1
marin moiety was confirmed by H NMR spectra which
indicate signal at d 2.45 ppm for –CH3 of coumarin. Protons
corresponding to the coumarin moiety resonated at
6.15–7.76 ppm. In IR spectra, the band at 1,678 cm-1 (C=O
123

Med Chem Res (2012) 21:2926–2944
2929
of coumarin) also confirmed the formation of compound 5.
Moreover, a characteristic band appeared at 1,263 cm-1
corresponded to the C–O–C linkage, while disappearance of
the –OH peak at 3600–3650 cm-1, belonging to the
7-hydroxy-4-methylcoumarin, gave correction to the for-
mation of intermediate 5.
Table 1 In vitro (gram-positive) antibacterial activity of newly
synthesized compounds
Compound
Zone of inhibition in mm (MIC in lg/ml)
(100 lg/disk)
Gram-positive
S. aureus
B. cereus
The formation of compound 7 was supported by the
appearance of singlet signal at d 11.82 for –NH2 and d 9.63
for –NH in 1H NMR spectrum and in IR spectrum for NH2
band at 3,415 cm-1, 3,324 for –NH also confirmed the
formation of compound 7. Compound 7 when treated with
aromatic aldehydes gave the corresponding hydrazones
8a–n. Compound 8a which did not show signal for NH2 but
showed the presence of a signal at d 7.84 for one proton of
N=CH–Ph. Hydrazones 8a–n on further treatment with
mercaptoacetic acid gave thiazolidinones 10a–n. Com-
pound 10a showed the presence of doublet signals at d
3.61, 3.55 for two protons of S–CH2 and at d 6.12 for S–
CH–N in 1H NMR spectra, which confirm the formation of
thiazolidinone ring. Compound 10a showed a characteristic
absorption for the cyclic carbonyl group at 1,719 cm-1 in
8a
11 (100)
14 (100)
13 (100)
16 (100)
20 (25)
13 (100)
17 (50)
\10 (100)
20 (25)
13 (100)
13 (100)
15 (100)
16 (50)
20 (12.5)
12 (100)
17 (50)
16 (100)
18 (50)
23 (25)
17 (50)
18 (50)
13 (100)
22 (12.5)
17 (50)
16 (100)
18 (50)
17 (50)
22 (12.5)
14 (100)
22 (25)
19 (50)
20 (25)
28 (6.25)
19 (25)
21 (25)
16 (100)
27 (6.25)
20 (50)
19 (50)
21 (25)
20 (25)
26 (6.25)
30 (1.0)
–
10 (100)
17 (50)
15 (100)
17 (50)
18 (50)
16 (50)
14 (100)
\10 (100)
18 (50)
16 (50)
11 (100)
13 (100)
12 (100)
18 (25)
13 (100)
19 (50)
18 (50)
19 (25)
20 (25)
19 (50)
16 (100)
11 (100)
20 (12.5)
20 (50)
14 (100)
16 (100)
14 (100)
20 (25)
16 (100)
23 (12.5)
21 (25)
22 (12.5)
23 (12.5)
21 (12.5)
18 (50)
13 (100)
25 (6.25)
22 (25)
17 (50)
19 (25)
17 (50)
23 (12.5)
31 (1.0)
–
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
1
10a
the IR spectra. The H NMR spectra of compounds 12a–n
10b
revealed the absence of the –CH2 absorption signal of
thiazolidinone ring and appeared the broad singlet signal of
the methylene (4CH2) of 1-pyridin-2-yl-piperazine.
10c
10d
10e
The synthesized compounds 8a–n, 10a–n, and 12a–n
were evaluated for in vitro antibacterial and antifungal
activity against various gram-positive, gram-negative bac-
teria, and fungal strains. The results are shown in Tables 1,
2, 3. Standard antibacterial Ciprofloxacin and antifungal
Ketoconazole were also tested for comparison with syn-
thesized compounds 8a–n, 10a–n, and 12a–n. From the
antimicrobial studies (Tables 1, 2, and 3) we found final
compounds 12a–n showed higher activity than the Schiff
base derivatives 8a–n and thiazolidinone derivatives 10a–n.
When 1-pyridin-2-yl-piperazine incorporated with thiazo-
lidinone derivatives 10a–n and converts to final derivatives
12a–n then all the final derivatives showed increased
antimicrobial activity. The MIC values of 12a–n exhibited
varied range (6.25–100 lg/ml) against both bacterial and
fungal strains.
10f
10g
10h
10i
10j
10k
10l
10m
10n
12a
12b
12c
12d
12e
12f
The compound 12a having aryl ring on thiazolidinone
moiety attached with 1-pyridin-2-yl-piperazine showed
MIC value in the range of 50–100 lg/ml against all the
bacterial strains. Compound 12b which were having elec-
tron withdrawing chloro substituents at the ortho-para
position of aryl ring attached at thiazolidinone moiety
shows effective inhibitory effect in terms of MIC =
12.5 lg/ml against B. cereus and P. vulgaris. Compound
12c which were having chloro substituents at meta-para
position of aryl ring found less active compared to 12b
against gram-positive bacteria S. aureus and B. cereus.
Compound 12d having electron donating methyl group on
12g
12h
12i
12j
12k
12l
12m
12n
Ciprofloxacin (100 lg/disk)
DMSO
Note Each value is the mean of three independent experiments
123

2930
Med Chem Res (2012) 21:2926–2944
Table 2 In vitro (gram-negative) antibacterial activity of newly synthesized compounds
Compound
(100 lg/disk)
Zone of inhibition in mm (MIC in lg/ml)
Gram-negative
E. coli
P. aeruginosa
K. pneumoniae
S. typhi
P. vulgaris
S. flexneria
8a
\10 (100)
13 (100)
11 (100)
\10 (100)
16 (50)
12 (100)
12 (100)
16 (50)
18 (50)
20 (50)
17 (100)
11 (100)
–
–
\10 (100)
14 (100)
14 (100)
17 (50)
15 (50)
18 (25)
19 (25)
13 (100)
19 (50)
\10 (100)
–
–
–
8b
17 (50)
12 (100)
10 (100)
\10 (100)
16 (50)
15 (100)
\10 (100)
11 (100)
\10 (100)
\10 (100)
14 (100)
–
16 (50)
12 (100)
11 (100)
17 (50)
14 (100)
17 (50)
–
14 (100)
15 (100)
18 (50)
14 (100)
19 (50)
21 (25)
\10 (100)
17 (100)
–
8c
8d
8e
8f
20 (50)
8g
16 (100)
\10 (100)
20 (25)
8h
8i
18 (50)
18 (50)
11 (100)
12 (100)
10 (100)
17 (50)
15 (100)
16 (50)
19 (50)
20 (50)
22 (25)
19 (50)
15 (100)
11 (100)
21 (25)
20 (50)
14 (100)
15 (100)
12 (100)
18 (50)
19 (50)
18 (50)
21 (25)
22 (50)
26 (6.25)
21 (25)
18 (50)
13 (100)
23 (12.5)
22 (25)
18 (50)
18 (100)
15 (100)
20 (25)
33 (1.0)
–
19 (50)
13 (100)
–
8j
14 (100)
–
8k
11 (100)
10 (100)
13 (100)
18 (100)
12 (100)
17 (50)
18 (50)
20 (25)
18 (50)
22 (25)
24 (12.5)
11 (100)
19 (50)
10 (100)
14 (100)
13 (100)
17 (50)
23 (25)
15 (100)
20 (25)
19 (50)
22 (25)
21 (25)
25 (12.5)
27 (6.25)
14 (100)
22 (25)
15 (100)
17 (100)
17 (100)
19 (50)
26 (6.25)
32 (B3)
–
8l
10 (100)
\10 (100)
18 (25)
18 (50)
12 (100)
18 (50)
11 (100)
16 (100)
18 (50)
19 (25)
17 (50)
20 (25)
21 (25)
16 (100)
23 (12.5)
12 (100)
\10 (100)
19 (50)
14 (100)
24 (12.5)
14 (100)
18 (50)
20 (50)
21 (25)
19 (50)
23 (25)
24 (12.5)
18 (50)
27 (6.25)
14 (100)
11 (100)
22 (25)
17 (50)
28 (6.25)
30 (1.0)
–
16 (50)
\10 (100)
17 (50)
10 (100)
18 (50)
17 (100)
14 (100)
20 (25)
17 (50)
20 (25)
\10 (100)
21 (12.5)
16 (50)
11 (100)
18 (50)
12 (100)
19 (50)
13 (100)
21 (12.5)
20 (25)
18 (50)
22 (12.5)
21 (50)
25 (12.5)
10 (100)
25 (12.5)
19 (50)
15 (100)
20 (50)
15 (100)
22 (25)
31 (1.0)
–
8m
8n
19 (50)
\10 (100)
19 (50)
15 (100)
15 (100)
15 (100)
18 (50)
18 (50)
12 (100)
15 (100)
13 (100)
12 (100)
17 (50)
\10 (100)
22 (25)
13 (100)
21 (25)
19 (50)
19 (50)
18 (50)
20 (50)
22 (25)
15 (100)
19 (25)
17 (50)
15 (100)
19 (50)
11 (100)
27 (6.25)
33 (1.0)
–
10a
14 (100)
17 (50)
10b
10c
14 (100)
13 (100)
17 (50)
10d
10e
10f
23 (25)
10g
20 (50)
10h
13 (100)
24 (12.5)
17 (100)
\10 (100)
12 (100)
11 (100)
20 (25)
10i
10j
10k
10l
10m
10n
12a
16 (100)
19 (25)
12b
12c
18 (50)
12d
18 (50)
12e
20 (25)
12f
28 (6.25)
23 (50)
12g
12h
16 (100)
30 (6.25)
20 (50)
12i
12j
12k
13 (100)
16 (100)
13 (100)
23 (12.5)
32 (1.0)
–
12l
12m
12n
Ciprofloxacin (100 lg/disk)
DMSO
Note Each value is the mean of three independent experiments
– indicates compound is not active at higher concentration of 100 lg/ml
123

Med Chem Res (2012) 21:2926–2944
2931
Table 3 In vitro antifungal activity of newly synthesized compounds
Compound
(100 lg/disk)
Zone of inhibition in mm (MIC in lg/ml)
A. niger
A. fumigatus
A. clavatus
C. albicans
8a
\10 (100)
11 (100)
\10 (100)
17 (50)
–
\10 (100)
17 (50)
–
8b
13 (100)
12 (100)
15 (100)
14 (100)
14 (100)
16 (50)
\10 (100)
18 (50)
20 (25)
\10 (100)
13 (100)
–
12 (100)
10 (100)
17 (50)
21 (25)
13 (100)
18 (50)
–
8c
15 (100)
16 (100)
19 (50)
8d
8e
20 (50)
8f
18 (50)
17 (50)
8g
12 (100)
\10 (100)
20 (50)
18 (50)
8h
13 (100)
14 (100)
18 (50)
8i
16 (100)
19 (50)
–
8j
15 (100)
10 (100)
16 (50)
8k
\10 (100)
11 (100)
\10 (100)
15 (100)
13 (100)
19 (50)
8l
17 (50)
–
8m
8n
12 (100)
14 (100)
11 (100)
14 (100)
12 (100)
20 (25)
18 (25)
–
20 (25)
10 (100)
16 (100)
13 (100)
20 (50)
24 (12.5)
18 (50)
22 (25)
\10 (100)
19 (50)
21 (25)
–
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
17 (50)
15 (100)
18 (50)
18 (50)
17 (50)
18 (50)
13 (100)
21 (12.5)
23 (25)
10 (100)
17 (50)
\10 (100)
21 (25)
\10 (100)
19 (50)
18 (50)
20 (25)
21 (12.5)
19 (25)
21 (12.5)
18 (50)
25 (6.25)
27 (6.25)
13 (100)
20 (25)
13 (100)
23 (12.5)
29 (1.0)
18 (50)
19 (50)
25 (12.5)
20 (25)
22 (25)
21 (25)
15 (100)
12 (100)
24 (12.5)
19 (100)
12 (100)
19 (50)
21 (25)
17 (100)
18 (50)
20 (50)
13 (100)
16 (100)
13 (100)
19 (50)
20 (50)
\10 (100)
22 (12.5)
12 (100)
20 (50)
17 (100)
24 (12.5)
27 (6.25)
21 (12.5)
26 (6.25)
13 (100)
23 (12.5)
25 (12.5)
\10 (100)
23 (25)
\10 (100)
27 (6.25)
33 (1.0)
15 (100)
18 (50)
14 (100)
18 (50)
16 (100)
23 (25)
16 (100)
23 (12.5)
29 (6.25)
23 (12.5)
18 (50)
20 (50)
22 (25)
26 (6.25)
25 (12.5)
25 (12.5)
20 (50)
15 (100)
27 (6.25)
25 (25)
21 (25)
23 (12.5)
15 (100)
19 (50)
15 (100)
22 (25)
19 (50)
17 (50)
21 (25)
22 (12.5)
31 (1.0)
Ketoconazole
(100 lg/disk)
30 (B3)
DMSO
–
–
–
–
Note Each value is the mean of three independent experiments
– indicates compound is not active at higher concentration of 100 lg/ml
123

2932
Med Chem Res (2012) 21:2926–2944
para position of aryl ring showed good ability to inhibit
B. cereus with MIC = 12.5 lg/ml. Compounds 12e and
12f which were having electron withdrawing fluoro sub-
stitution on para and meta position of aryl ring, respec-
tively, attached to thiazolidinone moiety incorporated with
1-pyridin-2-yl-piperazine exerted excellent activity with a
MIC value in the range of 6.25–50 lg/ml against all the
tested bacterial strains. Para substituted fluorinated Com-
pound 12e showed the highest activity (MIC = 6.25 lg/
ml, 28 mm inhibitory zone) to inhibit S. aureus. Compound
12e also found most potent against P. aeruginosa in terms
of MIC = 6.25 lg/ml and inhibitory zone 26 mm among
all the final compounds. Meta substituted fluorinated
Compound 12f showed good activity against E. coli in
terms of MIC = 6.25 lg/ml. Compound 12g having mono-
chloro substitution at aryl ring indicates similar
MIC = 12.5 lg/ml against S. typhi and P. vulgaris. Same
compound displayed maximum inhibitory zone 27 mm
with excellent MIC = 6.25 lg/ml against S. flexneria
among all the synthesized compounds. Thiazolidinone
12 h with –NO2 gr. substituted at aryl ring showed same
MIC = 100 lg/ml against all the bacterial strains except
against S. typhi with MIC = 50 lg/ml. Compound 12i
having para hydroxy substituent at aryl ring on thiazolid-
inone incorporated with 1-pyridin-2-yl-piperazine exhib-
ited the greatest activity against S. aureus, B. cereus,
E. coli, and S. typhi in terms of MIC = 6.25 lg/ml. Com-
pound 12i found equipotent in terms of MIC = 6.25 lg/ml
with 12e against S. aureus but 12i indicates quite reduced
inhibitory zone (27 mm) compared to 12e. Strong inhibi-
tory effect was observed by compound 12i against
B. cereus, E. coli, and S. typhi with MIC = 6.25 lg/ml and
showed maximum inhibitory zones among all the synthe-
sized compounds. Besides compound 12f showed similar
MIC = 6.25 lg/ml against E. coli with quite reduced
inhibitory zone (28 mm) compared to 12i. Compound 12j
and 12 k bromo and –COOH substituent on aryl ring,
respectively, possess MIC values in the range of
25–100 lg/ml against both gram-positive and gram-nega-
tive bacterial strains. Compound 12 l having electron
donating group –OCH3 at para position of aryl ring
exhibited higher activity against all bacterial strains except
against S. flexneria compared to 12 m which contain
–OCH3 group on meta-para position of aryl ring. Com-
pound 12n which were having disubstituted hydroxy group
on aryl ring showed the highest zone of inhibition 27 mm
with excellent MIC = 6.25 lg/ml against K. pneumoniae.
Compound 12n also found most active against S. typhi with
MIC = 6.25 lg/ml along with compound 12i, but 12i
possess reduced inhibition zone compared to 12 m.
data of antifungal tests are depicted in Table 3. Compound
12a–n possesses higher activity than 8a–n and 10a–n.
A close analysis of the MIC in lg/ml values indicates
that all the final compounds 12a–n exhibited a varied
range (6.25–100 lg/ml) of antifungal activity against all
the tested fungal strains. Compound 12a showed
MIC = 100 lg/ml against all fungal strains. Same com-
pound showed poor activity in terms of inhibitory zone
(\10 mm) against A. fumigatus. Compound 12d exerted
good activity against A. niger and C. albicans with
MIC = 12.5 lg/ml. Similar MIC value was found for
compound 12f, 12i, and 12j against C. albicans. But
compound 12j possess slight higher zone of inhibition as
compared to 12d, 12f, and 12j. A significant inhibition was
observed for compound 12e towards A. niger and
A. clavatus with 6.25 lg/ml of MIC with 29 and 26 mm
inhibitory zones, respectively. Compound 12f, 12 g, 12j,
and 12n found half active in terms of MIC = 12.5 lg/ml
against A. clavatus compare to compound 12e. Compound
12e also exhibited the greatest activity (MIC = 6.25 lg/ml,
27 mm zone of inhibition) against C. albicans along with
compound 12n. Besides, one compound 12 g was found to
have same MIC value against C. albicans with slight
reduced inhibitory zone (26 mm). Compounds 12j act as the
most potent inhibitors of the growth of A. fumigatus fungi
(MIC = 6.25 lg/ml, inhibitory zone-27 mm), while com-
pound 12i was found to display similar MIC = 6.25 lg/ml
and quite reduced inhibition zone (25 mm). Compound 12e,
12g, and 12n found half active in terms of MIC (12.5 lg/ml)
against A. fumigatus compare to the most potent compounds
12i and 12j. All the remaining final thiazolidinone deriva-
tives exerted good to moderate activity.
Conclusion
The objective of this study was to synthesize and investigate
the antimicrobial activities of a new series of thiazolidinones
attached to 1-pyridin-2-yl-piperazine with the hope of dis-
covering new structure leads serving as antimicrobial agents.
Some of the newly synthesized compound containingelectron
withdrawing group like mono-chloro, mono-fluoro as sub-
stituentonaryl ring atthiazolidinone moiety 12e, 12f, and 12g
showed very good activity against both the gram-positive as
well as gram-negative bacteria. Compound 12i and 12n
having hydroxy group as substituents on aryl ring alsoshowed
excellent activity against both bacterial strains (gram-positive
and gram-negative). From the antifungal result we found that
compounds 12e and 12i showed excellent activity against all
fungal strains. From the biological study we can conclude that
antimicrobial activity may be associated with the nature of
tested bacterial and fungal strains and it also depends upon
substituent on aryl ring at thiazolidinone moiety.
The in vitro antifungal activity of compounds 8a–n,
10a–n, 12a–n were studied against the fungal strains viz.,
A. niger, A. fumigatus, A. clavatus, and C. albicans. The
123

Med Chem Res (2012) 21:2926–2944
2933
Experimental section
1 h at room temperature and then it 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 compound 5, 20.88 g, Yield, 86%. mp
153–155°C; IR (KBr, cm-1): 1,678 (C=O of coumarin), 1,454
(–CH3 of coumarin), 1,263 (C–O–C), 812 (–Cl), 808 (s–tri-
Chemicals and solvents were obtained from commercial
sources and used as received throughout the investigation.
Melting points were determined in open capillaries on a
Veego electronic apparatus VMP-D (Veego Instrument
Corporation, Mumbai, India) and are uncorrected. IR spectra
(4000–400 cm-1) of synthesized compounds were recorded
on a Shimadzu 8400-S FT-IR spectrophotometer (Shimadzu
India Pvt. Ltd., Mumbai, India) using KBr pellets. Thin layer
chromatography was performed on object glass slides
(2 9 7.5 cm) coated with silica gel-G and spots were visu-
alized under UV irradiation. 1H NMR and 13C NMR spectra
were recorded on a Varian 400 MHz model spectrometer
(Varian India Pvt. Ltd., Mumbai, India) using DMSO as a
1
azine, C–N str.); H NMR (DMSO-d6, d, ppm): 7.76 (d,
J = 7.7 Hz, Hcu), 6.72–6.51 (m, 2H, Hcu), 6.15 (s, 1H, Hcu),
3.09 (s, 6H, 2CH3), 2.31 (d, J = 1.1 Hz, 3H, Hcu); 13C NMR
(DMSO-d6, d, ppm): 169.20 (C–Cl), 162.58 (C–N–(CH3)2),
162.11 (C=O of coumarin), 161.01 (C–O–C), 155.25 (C–O–C
of coumarin), 154.21 (C–CH3 at coumarin), 153.41–105.32
(6C, Ar–C), 37.79 (CH3–N–CH3), 22.56 (–CH3 of coumarin);
Anal. Calcd for C15H13ClN4O3: C, 54.14; H, 3.94; N, 16.84.
Found C, 54.22; H, 3.87; N, 16.89.
1
solvent and TMS as internal standard with H resonant fre-
quency of 400 MHz and 13C resonant frequency of 100 MHz.
The 1H NMR and 13C NMR chemical shifts were reported as
parts per million (ppm) downfield from TMS (Me4Si) and
were performed at centre for excellence, Vapi, India. The
splitting patterns are designated as follows; s, singlet; br s,
broad singlet; d, doublet; t, triplet; q, quartet; m, multiplet. All
new compounds were subjected to elemental analysis using a
Heraeus Carlo Erba 1180 CHN analyzer (Hanau, Germany).
Synthesis of 7-[4-(4-Amino-phenylamino)-6-
dimethylamino-[1,3,5]triazin-2-yloxy]-4-methyl-
chromen-2-one (7)
To a solution of compound 5 (15.0 g, 0.045 mol) in 1,
(4.87 g,
4-dioxane (150 ml), p-phenylenediamine
6
0.045 mol) was added and the reaction mixture was refluxed in
water bath at 70–80°C for 6–8 h. The progress of the reaction
was monitored by TLC using acetone/toluene (9:1) as eluent.
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 pre-
cipitates thus obtained were filtered and dried. During the
reactiondimercompoundwasformedalongwith compound7,
so it was treated by column chromatography using n-hexane:
ethyl acetate as eluent system to obtained pure compound 7.
Yield: 11.86 g, 79%. mp 202–205°C; IR (KBr, cm-1):
3,415.72 (–NH2), 3,324.29 (–NH), 1,681 (C=O of coumarin),
1,459 (–CH3 of coumarin), 812 (s-triazine, C–N str.); 1H NMR
(DMSO-d6, d, ppm): 11.82 (s, 2H, –NH2), 9.63 (s, 1H, –NH),
7.79 (d, J = 7.4 Hz, Hcu), 7.11–6.87 (m, 4H, Ar–H),
6.77–6.55 (m, 2H, Hcu), 6.19 (s, 1H, Hcu), 3.13 (s, 6H, 2CH3),
2.36 (d, J = 1.2 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
162.88 (C–N–(CH3)2), 162.49 (C=O of coumarin), 161.22 (C–
O–C), 155.53 (C–O–C of coumarin), 154.69 (C–CH3 at cou-
marin), 153.13–105.34 (12C, Ar–C), 37.85 (CH3–N–CH3),
22.73 (–CH3 of coumarin); Anal. Calcd for C21H20N6O3: C,
62.37; H, 4.98; N, 20.78. Found C, 62.32; H, 4.95; N, 20.83.
Synthesis of (4,6-dichloro-[1,3,5]triazin-2-yl)-
dimethylamine (3)
To a stirred solution of 2,4,6-trichloro-1,3,5-triazine 1
(20.0 g, 0.10 mol) in anhydrous THF (150 ml), dimethyl-
amine 2 (4.89 g, 0.10 mol) was added drop wise at 0–5°C.
The resulting reaction mixture was stirred at this temperature
for 2 h, then triethylamine (10.97 g, 0.10 mol) was added in
the reaction mixture and stirring was continued for another
4 h. The resulted reaction mixture was then treated with
crushed ice, followed by neutralization by dilute HCl, then
filtered and dried. In above process a very minor di-substi-
tuted compound was also formed, thus compound 3 was
purified by column chromatography over silica gel using n-
hexane: ethyl acetate as eluent system. Yield: 14.86 g, 77%.
mp 126–128°C; IR (KBr, cm-1): 806 (s-triazine, C–N str.);
1H NMR (DMSO-d6, d, ppm): 3.10 (s, 6H, 2CH3); 13C NMR
(DMSO-d6, d, ppm): 166.97, 163.41 (2C, Ar–C), 37.44
(H3C–N–CH3); Anal. Calcd for C5H6Cl2N4: C 31.11; H,
3.13; N, 29.02. Found: C 31.17; H, 3.06; N, 29.06.
General procedure for the synthesis of schiff bases 8a–n
Synthesis of 7-(4-chloro-6-dimethylamino-
[1,3,5]triazin-2-yloxy)-4-methyl-chromen-2-one (5)
Synthesis of 7-{4-[4-(benzylidene-amino)-phenylamino]-6-
dimethylamino-[1,3,5]triazin-2-yloxy}-4-methyl-chromen-
2-one (8a)
To a stirred solution of 7-hydroxy-4-methylcoumarin 4
(13.0 g, 0.073 mol) and 60% NaH (1.78 g, 0.074 mol) in
anhydrous THF (150 ml), compound 3 (14.25 g, 0.073 mol)
was added into the reaction mixture and first it was stirred for
To a solution of compound 7 (3.0 g; 0.007 mol) in absolute
ethanol (50 ml), containing
a
catalytic amount of
123

2934
Med Chem Res (2012) 21:2926–2944
piperidine, equimolecular amount of benzaldehyde (0.78 g;
0.007 mol) was added. The reaction mixture was refluxed for
5–6 h. It was then cooled at room temperature, poured into
crushed ice, filtered, washed, dried, and recrystallized from
DMF to yield 7-{4-[4-(benzylidene-amino)-phenylamino]-6-
dimethylamino-[1,3,5]triazin-2-yloxy}-4-methyl-chromen-2-
one (8a), 2.44 g, Yield:71%. mp 223–225°C; IR (KBr, cm-1):
3,326 (–NH), 1,674 (C=O of coumarin), 1,457 (–CH3 of
coumarin), 807 (s-triazine, C–N str.); 1H NMR (DMSO-d6, d,
ppm): 9.85 (s, 1H, –NH), 7.84 (s, 1H, N=CH–Ph), 7.73 (d,
J = 7.1 Hz, Hcu), 7.42–6.91 (m, 9H, Ar–H), 6.75–6.58 (m,
2H, Hcu), 6.31 (s, 1H, Hcu), 3.07 (s, 6H, 2CH3), 2.38 (d,
J = 1.2 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm): 163.31
(C–N–(CH3)2), 162.45 (C=O of coumarin), 161.34 (C–O–C),
155.46 (C–O–C of coumarin), 154.32 (C–CH3 at coumarin),
143.56 (C=N of Schiff base), 153.25–105.52 (18C, Ar–C),
37.21 (CH3–N–CH3), 22.46 (–CH3 of coumarin); Anal. Calcd
for C28H24N6O3: C, 68.28; H, 4.91; N, 17.06. Found: C, 68.33;
H, 4.86; N, 17.11. Other Schiff bases 8b–n were obtained in
similar manner.
164.49 (C–N–(CH3)2), 163.25 (C=O of coumarin), 161.45
(C–O–C), 155.75 (C–O–C of coumarin), 154.18 (C–CH3 at
coumarin), 142.58 (C=N of Schiff base), 134.39 (C–Cl),
133.46 (C–Cl), 152.21–108.54 (16C, Ar–C), 38.43 (CH3–
N–CH3), 22.61 (–CH3 of coumarin); Anal. Calcd for
C28H22Cl2N6O3: C, 59.90; H, 3.95; N, 14.97. Found: C,
59.97; H, 3.92; N, 14.94.
7-(4-Dimethylamino-6-{4-[(4-methyl-benzylidene)-amino]-
phenylamino}-[1,3,5]triazin-2-yloxy)-4-methyl-chromen-2-
one (8d)
Yield: 68%. mp 174–176°C; IR (KBr, cm-1): 3,342 (–NH),
1,662 (C=O of coumarin), 1,459 (–CH3 of coumarin), 812
1
(s-triazine, C–N str.); H NMR (DMSO-d6, d, ppm): 9.77
(s, 1H, –NH), 7.87 (s, 1H, N=CH–Ph), 7.75 (d, J = 7.3 Hz,
Hcu), 7.38–6.91 (m, 8H, Ar–H), 6.81–6.62 (m, 2H, Hcu),
6.12 (s, 1H, Hcu), 3.11 (s, 6H, 2CH3), 2.26 (d, J = 1.1 Hz,
3H, Hcu), 2.19 (s, 3H, ph-CH3); 13C NMR (DMSO-d6, d,
ppm): 164.20 (C–N–(CH3)2), 163.10 (C=O of coumarin),
161.65 (C–O–C), 156.14 (C–O–C of coumarin), 154.67
(C–CH3 at coumarin), 144.19 (C=N of Schiff base), 138.89
(C–CH3 of phenyl), 152.30–106.23 (17C, Ar–C), 37.63
(CH3–N–CH3), 22.34 (–CH3 of coumarin), 21.45 (C–CH3
of phenyl); Anal. Calcd for C29H26N6O3: C, 68.76; H, 5.17;
N, 16.59. Found: C, 68.71; H, 5.22; N, 16.65.
Characterization data of 8b–n
7-(4-{4-[(2,4-Dichloro-benzylidene)-amino]-
phenylamino}-6-dimethylamino-[1,3,5]triazin-2-yloxy)-4-
methyl-chromen-2-one (8b)
Yield: 73%. mp 207–209°C; IR (KBr, cm-1): 3,334 (–NH),
1,667 (C=O of coumarin), 1,440 (–CH3 of coumarin), 811
7-(4-Dimethylamino-6-{4-[(4-fluoro-benzylidene)-amino]-
phenylamino}-[1,3,5]triazin-2-yloxy)-4-methyl-chromen-2-
one (8e)
1
(s-triazine, C–N str.), 787 (–Cl); H NMR (DMSO-d6, d,
ppm): 9.82 (s, 1H, –NH), 7.86 (s, 1H, N=CH–Ph), 7.69 (d,
J = 7.3 Hz, Hcu), 7.43–7.10 (m, 7H, Ar–H), 6.68–6.56 (m,
2H, Hcu), 6.32 (s, 1H, Hcu), 3.17 (s, 6H, 2CH3), 2.39 (d,
J = 1.1 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
164.53 (C–N–(CH3)2), 163.11 (C=O of coumarin), 161.32
(C–O–C), 156.46 (C–O–C of coumarin), 154.22 (C–CH3 at
coumarin), 144.27 (C=N of Schiff base), 134.56 (C–Cl),
133.25 (C–Cl), 153.13–107.68 (16C, Ar–C), 37.25 (CH3–
N–CH3), 22.74 (–CH3 of coumarin); Anal. Calcd for
C28H22Cl2N6O3: C, 59.90; H, 3.95; N, 14.97. Found: C,
59.95; H, 3.91; N, 14.92.
Yield: 65%. mp 183–186°C; IR (KBr, cm-1): 3,348 (–NH),
1,665 (C=O of coumarin), 1,442 (–CH3 of coumarin),
1
1,159 (C–F), 813 (s-triazine, C–N str.); H NMR (DMSO-
d6, d, ppm): 9.83 (s, 1H, –NH), 7.85 (s, 1H, N=CH–Ph),
7.78 (d, J = 7.5 Hz, Hcu), 7.45–7.05 (m, 8H, Ar–H),
6.74–6.59 (m, 2H, Hcu), 6.16 (s, 1H, Hcu), 3.15 (s, 6H,
2CH3), 2.31 (d, J = 1.1 Hz, 3H, Hcu); 13C NMR (DMSO-
d6, d, ppm): 168.43 (C–F), 164.37 (C–N–(CH3)2), 163.50
(C=O of coumarin), 162.10 (C–O–C), 157.30 (C–O–C of
coumarin), 155.44 (C–CH3 at coumarin), 142.27 (C=N of
Schiff base), 153.17–107.49 (17C, Ar–C), 38.30 (CH3–N–
CH3), 23.16 (–CH3 of coumarin); Anal. Calcd for
C28H23FN6O3: C, 65.87; H, 4.54; N, 16.46. Found: C,
65.92; H, 4.57; N, 16.41.
7-(4-{4-[(3,4-Dichloro-benzylidene)-amino]-
phenylamino}-6-dimethylamino-[1,3,5]triazin-2-yloxy)-4-
methyl-chromen-2-one (8c)
Yield: 71%. mp 221–224°C; IR (KBr, cm-1): 3,339 (–NH),
1,664 (C=O of coumarin), 1,437 (–CH3 of coumarin), 813
7-(4-Dimethylamino-6-{4-[(3-fluoro-benzylidene)-amino]-
phenylamino}-[1,3,5]triazin-2-yloxy)-4-methyl-chromen-2-
one (8f)
1
(s-triazine, C–N str.), 792 (–Cl); H NMR (DMSO-d6, d,
ppm): 9.81 (s, 1H, –NH), 7.80 (s, 1H, N=CH–Ph), 7.66 (d,
J = 7.4 Hz, Hcu), 7.41–7.06 (m, 7H, Ar–H), 6.71–6.52 (m,
2H, Hcu), 6.28 (s, 1H, Hcu), 3.19 (s, 6H, 2CH3), 2.36 (d,
J = 1.1 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
Yield: 67%. mp 214–216°C; IR (KBr, cm-1): 3,353 (–NH),
1,666 (C=O of coumarin), 1,445 (–CH3 of coumarin), 1,162
1
(C–F), 811 (s-triazine, C–N str.); H NMR (DMSO-d6, d,
123

Med Chem Res (2012) 21:2926–2944
2935
ppm): 9.76 (s, 1H, –NH), 7.82 (s, 1H, N=CH–Ph), 7.76 (d,
J = 7.1 Hz, Hcu), 7.40–6.91 (m, 8H, Ar–H), 6.83–6.64 (m,
2H, Hcu), 6.19 (s, 1H, Hcu), 3.11 (s, 6H, 2CH3), 2.27 (d,
J = 1.2 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm): 169.42
(C–F), 164.28 (C–N–(CH3)2), 162.71 (C=O of coumarin),
162.10 (C–O–C), 157.30 (C–O–C of coumarin), 155.31
(C–CH3 at coumarin), 143.56 (C=N of Schiff base),
152.24–109.69 (17C, Ar–C), 38.43 (CH3–N–CH3), 22.58
(–CH3 of coumarin); Anal. Calcd for C28H23FN6O3: C, 65.87;
H, 4.54; N, 16.46. Found: C, 65.94; H, 4.59; N, 16.43.
coumarin), 806 (s-triazine, C–N str.); 1H NMR (DMSO-d6,
d, ppm): 9.78 (s, 1H, –NH), 7.89 (s, 1H, N=CH–Ph), 7.76
(d, J = 7.1 Hz, Hcu), 7.36–6.96 (m, 8H, Ar–H), 6.65–6.49
(m, 2H, Hcu), 6.28 (s, 1H, Hcu), 4.56 (s, 1H, –OH), 3.14 (s,
6H, 2CH3), 2.24 (d, J = 1.4 Hz, 3H, Hcu); 13C NMR
(DMSO-d6, d, ppm): 164.62 (C–N–(CH3)2), 162.34 (C=O
of coumarin), 161.40 (C–O–C), 158.67 (C–OH), 155.69
(C–O–C of coumarin), 153.76 (C–CH3 at coumarin),
142.13 (C=N of Schiff base), 153.18–107.33 (17C, Ar–C),
37.65 (CH3–N–CH3), 22.53 (–CH3 of coumarin); Anal.
Calcd for C28H24N6O4: C, 66.13; H, 4.76; N, 16.53. Found:
C, 66.18; H, 4.71; N, 16.58.
7-(4-{4-[(4-Chloro-benzylidene)-amino]-phenylamino}-6-
dimethylamino-[1,3,5]triazin-2-yloxy)-4-methyl-chromen-
2-one (8g)
7-(4-{4-[(2-Bromo-benzylidene)-amino]-phenylamino}-6-
dimethylamino-[1,3,5]triazin-2-yloxy)-4-methyl-chromen-
2-one (8j)
Yield: 69%. mp 211–213°C; IR (KBr,cm-1): 3,342 (–NH),
1,661 (C=O of coumarin), 1,445 (–CH3 of coumarin), 806 (s-
triazine, C–N str.), 783 (–Cl); 1H NMR (DMSO-d6, d, ppm):
9.80 (s, 1H, –NH), 7.80 (s, 1H, N=CH–Ph), 7.72 (d,
J = 7.5 Hz, Hcu), 7.37–6.92 (m, 8H, Ar–H), 6.69–6.51 (m,
2H, Hcu), 6.21 (s, 1H, Hcu), 3.12 (s, 6H, 2CH3), 2.27 (d,
J = 1.3 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
164.87, 164.47 (C–N–(CH3)2), 162.59 (C=O of coumarin),
162.26 (C–O–C), 156.47 (C–O–C of coumarin), 154.13 (C–
CH3 at coumarin), 143.48 (C=N of Schiff base), 133.68 (C–
Cl), 153.60–106.54(17C, Ar–C), 38.43(CH3–N–CH3), 22.56
(–CH3 of coumarin); Anal. Calcd for C28H23ClN6O3: C,
63.82; H, 4.40; N, 15.95. Found: C, 63.87; H, 4.35; N, 15.90.
Yield: 66%. mp 216–218°C; IR (KBr, cm-1): 3,350 (–NH),
1,664 (C=O of coumarin), 1,455 (–CH3 of coumarin), 808
1
(s-triazine, C–N str.), 735 (–Br); H NMR (DMSO-d6, d,
ppm): 9.73 (s, 1H, –NH), 7.79 (s, 1H, N=CH–Ph), 7.69 (d,
J = 7.6 Hz, Hcu), 7.41–6.98 (m, 8H, Ar–H), 6.63–6.46 (m,
2H, Hcu), 6.30 (s, 1H, Hcu), 3.27 (s, 6H, 2CH3), 2.31 (d,
J = 1.2 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
164.39 (C–N–(CH3)2), 163.11 (C=O of coumarin), 162.34
(C–O–C), 155.39 (C–O–C of coumarin), 154.21 (C–CH3 at
coumarin), 143.29 (C=N of Schiff base), 121.65 (C–Br),
152.43 –107.25 (17C, Ar–C), 38.45 (CH3–N–CH3), 22.36
(–CH3 of coumarin); Anal. Calcd for C28H23BrN6O3: C,
58.85; H, 4.06; N, 14.71. Found: C, 58.81; H, 4.13; N,
14.76.
7-(4-Dimethylamino-6-{4-[(4-nitro-benzylidene)-amino]-
phenylamino}-[1,3,5]triazin-2-yloxy)-4-methyl-chromen-2-
one (8h)
Yield: 63%. mp 195–197°C; IR (KBr, cm-1): 3,346 (–NH),
1,664 (C=O of coumarin), 1,539 (N=O str.), 1,442 (–CH3 of
coumarin), 809 (s-triazine, C–N str.); 1H NMR (DMSO-d6, d,
ppm): 9.71 (s, 1H, –NH), 7.82 (s, 1H, N=CH–Ph), 7.74 (d,
J = 7.2 Hz, Hcu), 7.40–6.95 (m, 8H, Ar–H), 6.72–6.59 (m,
2H, Hcu), 6.24 (s, 1H, Hcu), 3.10 (s, 6H, 2CH3), 2.37 (d,
J = 1.1 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm): 164.67
(C–N–(CH3)2), 162.43 (C=O of coumarin), 161.59 (C–O–C),
157.13 (C–O–C of coumarin), 154.29 (C–CH3 at coumarin),
148.35 (C–NO2), 145.32 (C=N of Schiff base),
152.36–106.31 (17C, Ar–C), 37.78 (CH3–N–CH3), 22.48
(–CH3 of coumarin); Anal. Calcd for C28H23N7O5: C, 62.56;
H, 4.31; N, 18.24. Found: C, 62.63; H, 4.35; N, 18.19.
2-({4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-
7-yloxy)-[1,3,5]triazin-2-ylamino]-phenylimino}-methyl)-
benzoic acid (8k)
Yield: 60%. mp 233–235°C; IR (KBr, cm-1): 3,353 (–NH),
1,745 (–COOH), 1,670 (C=O of coumarin), 1,451 (–CH3 of
coumarin), 814 (s-triazine, C–N str.); 1H NMR (DMSO-d6,
d, ppm): 9.78 (s, 1H, –NH), 7.83 (s, 1H, N=CH–Ph), 7.65
(d, J = 7.2 Hz, Hcu), 7.33–6.92 (m, 8H, Ar–H), 6.68–6.49
(m, 2H, Hcu), 6.23 (s, 1H, Hcu), 3.21 (s, 6H, 2CH3), 2.35
(d, J = 1.5 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
169.15 (C=O of COOH), 164.44 (C–N–(CH3)2), 162.29
(C=O of coumarin), 161.47 (C–O–C), 154.65 (C–O–C of
coumarin), 154.19 (C–CH3 at coumarin), 143.57 (C=N of
Schiff base), 131.20 (C–COOH), 153.11–106.45 (17C, Ar–
C), 38.56 (CH3–N–CH3), 22.14 (–CH3 of coumarin); Anal.
Calcd for C29H24N6O5: C, 64.92; H, 4.51; N, 15.66. Found:
C, 64.96; H, 4.46; N, 15.71.
7-(4-Dimethylamino-6-{4-[(4-hydroxy-benzylidene)-
amino]-phenylamino}-[1,3,5]triazin-2-yloxy)-4-methyl-
chromen-2-one (8i)
Yield: 75%. mp 198–199°C; IR (KBr, cm-1): 3,355 (–NH),
3,244 (–OH), 1,670 (C=O of coumarin), 1,446 (–CH3 of
123

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Med Chem Res (2012) 21:2926–2944
7-(4-Dimethylamino-6-{4-[(4-methoxy-benzylidene)-
amino]-phenylamino}-[1,3,5]triazin-2-yloxy)-4-methyl-
chromen-2-one (8l)
coumarin), 154.11 (C–CH3 at coumarin), 142.25 (C=N of
Schiff base), 152.14–105.69 (16C, Ar–C), 38.13 (CH3–N–
CH3), 22.42 (–CH3 of coumarin); Anal. Calcd for
C28H24N6O5 : C, 64.11; H, 4.61; N, 16.02. Found: C,
64.14; H, 4.66; N, 16.07.
Yield: 74%. mp 202–204°C; IR (KBr, cm-1): 3,355 (–NH),
1,673 (C=O of coumarin), 1,444 (–CH3 of coumarin), 1,278
(–OCH3), 810 (s-triazine, C–N str.); 1H NMR (DMSO-d6, d,
ppm): 9.82 (s, 1H, –NH), 7.89 (s, 1H, N=CH–Ph), 7.72 (d,
J = 7.4 Hz, Hcu), 7.43–6.87 (m, 8H, Ar–H), 6.65–6.44 (m,
2H, Hcu), 6.19 (s, 1H, Hcu), 3.83 (s, 3H, –OCH3), 3.17 (s,
General procedure for the synthesis of thiazolidinones
10a–n
Synthesis of 3-{4-[4-dimethylamino-6-(4-methyl-2-oxo-2H-
chromen-7-yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-
phenyl-thiazolidin-4-one (10a)
6H, 2CH3), 2.25 (d, J = 1.3 Hz, 3H, CH3 of coumarin); 13
C
NMR (DMSO-d6, d, ppm): 164.34 (C–N–(CH3)2), 162.29
(C=O of coumarin), 161.17 (C–O–C), 160.21 (C–OCH3),
155.26 (C–O–C of coumarin), 154.19 (C–CH3 at couma-
rin), 142.34 (C=N of Schiff base), 152.29–107.68 (17C, Ar–
C), 55.92 (–OCH3), 38.46 (CH3–N–CH3), 22.54 (–CH3 of
coumarin); Anal. Calcd for C29H26N6O4: C, 66.66; H, 5.02;
N, 16.08. Found: C, 66.62; H, 5.07; N, 16.12.
A mixture of compound 8a (2.0 g; 0.004 mol) and thiogly-
colic acid (0.74 g; 0.008 mol) in dry benzene (40 ml) was
refluxed for 6 h. Water formed during the reaction was
removed azeotropically by Dean-Stark apparatus. Progress
of the reaction the reaction was checked by TLC using
benzene-ether as eluent. After the completion of reaction
benzene was removed by distillation to give solid, which was
dissolved in methanol (20 ml). This solution was warmed
and treated with sodium bicarbonate solution to remove
unreacted acid. The solid obtained was filtered, washed with
ether and purified by crystallization from methanol to form
3-{4-[4-dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-phenyl-thiazo-
lidin-4-one (10a), Yield: 73%. mp 249–251°C; IR
(KBr,cm-1): 3,331 (–NH), 1,719 (C=O of thiazolidinone),
1,671 (C=O of coumarin), 1,452 (–CH3 of coumarin), 807 (s-
triazine, C–N str.); 1H NMR (DMSO-d6, d, ppm): 9.87 (s, 1H,
–NH), 7.61 (d, J = 7.7 Hz, Hcu), 7.40–6.89 (m, 9H, Ar–H),
6.87–6.74 (m, 2H, Hcu), 6.20 (s, 1H, Hcu), 6.12 (N–CH–S),
3.61 (d, J = 12.6, 1H of thiazolidinone), 3.55 (d, J = 12.3,
1H of thiazolidinone), 3.06 (s, 6H, 2CH3), 2.49 (d,
J = 1.1 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
171.26 (C=O of thiazolidinone), 162.43 (C–N–(CH3)2),
162.21 (C=O of coumarin), 161.53 (C–O–C), 155.68 (C–O–
C of coumarin), 154.77 (C–CH3 at coumarin), 152.89–
106.21 (18C, Ar–C), 66.54 (N–C–S), 37.49 (CH3–N–CH3),
32.40 (–CH2 of thiazolidinone), 22.68 (-CH3 of coumarin);
Anal. Calcd for C30H26N6O4S: C, 63.59; H, 4.62; N, 14.83.
Found: C, 63.54; H, 4.67; N, 14.87. Similarly, other com-
pounds 10b–n has been synthesized.
7-(4-{4-[(3,4-Dimethoxy-benzylidene)-amino]-
phenylamino}-6-dimethylamino-[1,3,5]triazin-2-yloxy)-4-
methyl-chromen-2-one (8m)
Yield: 77%. mp 219–221°C; IR (KBr, cm-1): 3,351 (–NH),
1,666 (C=O of coumarin), 1,449 (–CH3 of coumarin),
1,275 (–OCH3), 811 (s-triazine, C–N str.); 1H NMR
(DMSO-d6, d, ppm): 9.79 (s, 1H, –NH), 7.77 (s, 1H,
N=CH–Ph), 7.74 (d, J = 7.2 Hz, Hcu), 7.30–6.91 (m, 7H,
Ar–H), 6.69–6.54 (m, 2H, Hcu), 6.39 (s, 1H, Hcu), 3.86 (s,
3H, –OCH3), 3.83 (s, 3H, –OCH3) 3.11 (s, 6H, 2CH3), 2.23
(d, J = 1.1 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
164.40 (C–N–(CH3)2), 162.47 (C=O of coumarin), 161.64
(C–O–C), 160.35 (C–OCH3), 159.46 (C–OCH3), 155.96
(C–O–C of coumarin), 155.14 (C–CH3 at coumarin),
144.31 (C=N of Schiff base), 152.45–104.77 (16C, Ar–C),
56.87 (–OCH3), 37.55 (CH3–N–CH3), 22.38 (–CH3 of
coumarin); Anal. Calcd for C30H28N6O5: C, 65.21; H, 5.11;
N, 15.21. Found: C, 65.25; H, 5.17; N, 15.17.
7–(4-{4-[(2,4-Dihydroxy-benzylidene)-amino]-
phenylamino}-6-dimethylamino-[1,3,5]triazin-2-yloxy)-4-
methyl-chromen-2-one (8n)
Yield: 75%. mp 231–233°C; IR (KBr, cm-1): 3,347 (–NH),
3,274 (–OH), 1,669 (C=O of coumarin), 1,451 (–CH3 of
coumarin), 810 (s-triazine, C–N str.); 1H NMR (DMSO–d6,
d, ppm): 9.84 (s, 1H, –NH), 8.49 (s, 1H, –OH), 7.85 (s, 1H,
N=CH–Ph), 7.77 (d, J = 7.5 Hz, Hcu), 7.47–7.11 (m, 7H,
Ar–H), 6.71–6.57 (m, 2H, Hcu), 6.25 (s,1H, Hcu), 4.65
(s,1H, –OH) 3.06 (s, 6H, 2CH3), 2.34 (d, J = 1.1 Hz, 3H,
Hcu); 13C NMR (DMSO-d6, d, ppm): 164.86 (C–N–
(CH3)2), 162.37 (C=O of coumarin), 161.85 (C–O–C),
157.78 (C–OH), 156.23 (C–OH), 155.63 (C–O–C of
Characterization data of 10b–n
2-(2,4-Dichloro-phenyl)-3-{4-[4-dimethylamino-6-(4-
methyl-2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-
ylamino]-phenyl}-thiazolidin-4-one (10b)
Yield: 68%. mp 242–245°C; IR (KBr, cm-1): 3,339 (–NH),
1,741 (C=O of thiazolidinone), 1,660 (C=O of coumarin),
1,432 (–CH3 of coumarin), 812 (s-triazine, C–N str.), 780
123

Med Chem Res (2012) 21:2926–2944
2937
1
(–Cl); H NMR (DMSO-d6, d, ppm): 9.85 (s, 1H, –NH),
(N–C–S), 37.88 (CH3–N–CH3), 33.57 (–CH2 of thiazolidi-
none), 22.53 (–CH3 of coumarin), 21.65 (C–CH3 of phenyl);
Anal. Calcd for C31H28N6O4S: C, 64.12; H, 4.86; N, 14.47.
Found: C, 64.06; H, 4.92; N, 14.53.
7.59 (d, J = 7.2 Hz, Hcu), 7.41–7.12 (m, 7H, Ar–H),
6.63–6.53 (m, 2H, Hcu), 6.33 (s, 1H, Hcu), 6.14 (s, 1H, N–
CH–S), 3.66 (d, J = 12.6, 1H of thiazolidinone), 3.54 (d,
J = 12.4, 1H of thiazolidinone), 3.16 (s, 6H, 2CH3), 2.38
(d, J = 1.1 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
170.33 (C=O of thiazolidinone), 164.43 (C–N–(CH3)2),
161.35 (C=O of coumarin), 161.10 (C–O–C), 155.14 (C–
O–C of coumarin), 154.21 (C–CH3 at coumarin), 134.22
(C–Cl), 133.30 (C–Cl), 152.26–107.16 (16C, Ar–C), 68.29
(N–C–S), 37.13 (CH3–N–CH3), 31.56 (–CH2 of thiazolid-
inone), 22.27 (–CH3 of coumarin); Anal. Calcd for
C30H24Cl2N6O4S: C, 56.70; H, 3.81; N, 13.22. Found: C,
56.75; H, 3.77; N, 13.26.
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-(4-fluoro-
phenyl)-thiazolidin-4-one (10e)
Yield: 60%. mp 236–238°C; IR (KBr, cm-1): 3,344 (–NH),
1,742 (C=O of thiazolidinone), 1,659 (C=O of coumarin),
1
1,427 (–CH3 of coumarin), 810 (s-triazine, C–N str.); H
NMR (DMSO-d6, d, ppm): 9.86 (s, 1H, –NH), 7.79 (d,
J = 7.4 Hz, Hcu), 7.41–7.09 (m, 8H, Ar–H), 6.63–6.49 (m,
2H, Hcu), 6.13 (s, 1H, Hcu), 6.11 (s, 1H, N–CH–S), 3.63
(d, J = 12.4,1H of thiazolidinone), 3.53 (d, J = 12.2, 1H
of thiazolidinone), 3.06 (s, 6H, 2CH3), 2.32 (d, J = 1.3 Hz,
3H, Hcu); 13C NMR (DMSO-d6, d, ppm): 170.43 (C=O of
thiazolidinone), 167.31 (C–F), 163.40 (C–N–(CH3)2),
162.29 (C=O of coumarin), 161.66 (C–O–C), 155.31 (C–
O–C of coumarin), 154.19 (C–CH3 at coumarin),
152.65–107.39 (17C, Ar–C), 67.88 (N–C–S), 38.11 (CH3–
N–CH3), 32.49 (–CH2 of thiazolidinone), 22.43 (–CH3 of
coumarin); Anal. Calcd for C30H25FN6O4S: C, 61.63; H,
4.31; N, 14.38. Found: C, 61.67; H, 4.28; N, 14.31.
2-(3,4-Dichloro-phenyl)-3-{4-[4-dimethylamino-6-(4-
methyl-2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-
ylamino]-phenyl}-thiazolidin-4-one (10c)
Yield: 65%. mp 259–261°C; IR (KBr, cm-1): 3,346 (–NH),
1,736 (C=O of thiazolidinone), 1,664 (C=O of coumarin),
1,425 (–CH3 of coumarin), 811 (s-triazine, C–N str.), 788
(–Cl); 1H NMR (DMSO-d6, d, ppm): 9.83 (s, 1H, –NH), 7.55
(d, J = 7.4 Hz, Hcu), 7.44–6.98 (m, 7H, Ar–H), 6.67–6.51
(m, 2H, Hcu), 6.31 (s, 1H, Hcu), 6.10 (s, 1H, N–CH–S), 3.63
(d, J = 12.1, 1H of thiazolidinone), 3.52 (d, J = 12.2, 1H of
thiazolidinone), 3.13 (s, 6H, 2CH3), 2.35 (d, J = 1.3 Hz, 3H,
Hcu); 13C NMR (DMSO–d6, d, ppm): 171.45 (C=O of
thiazolidinone), 164.33 (C–N–(CH3)2), 162.32 (C=O of
coumarin), 161.23 (C–O–C), 155.29 (C–O–C of coumarin),
154.33 (C–CH3 at coumarin), 135.15 (C–Cl), 134.27 (C–Cl),
152.34–107.59 (16C, Ar–C), 68.11 (N–C–S), 37.40 (CH3–
N–CH3), 33.20 (–CH2 of thiazolidinone), 22.58 (–CH3 of
coumarin); Anal. Calcd for C30H24Cl2N6O4S: C, 56.70; H,
3.81; N, 13.22. Found: C, 56.73; H, 3.75; N, 13.29.
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-(3-fluoro-
phenyl)-thiazolidin-4-one (10f)
Yield: 64%. mp 245–247°C; IR (KBr, cm-1): 3,358 (–NH),
1,745 (C=O of thiazolidinone), 1,656 (C=O of coumarin),
1
1,431 (–CH3 of coumarin), 813 (s-triazine, C–N str.); H
NMR (DMSO-d6, d, ppm): 9.80 (s, 1H, –NH), 7.76 (d,
J = 7.3 Hz, Hcu), 7.44–6.98 (m, 8H, Ar–H), 6.60–6.45 (m,
2H, Hcu), 6.10 (s, 1H, Hcu), 6.14 (s, 1H, N–CH–S), 3.65
(d, J = 12.2, 1H of thiazolidinone), 3.51 (d, J = 12.5, 1H
of thiazolidinone), 3.10 (s, 6H, 2CH3), 2.28 (d, J = 1.6 Hz,
3H, Hcu); 13C NMR (DMSO-d6, d, ppm): 170.55 (C=O of
thiazolidinone), 168.46 (C–F), 164.19 (C–N–(CH3)2),
162.36 (C=O of coumarin), 161.60 (C–O–C), 155.38 (C–
O–C of coumarin), 154.25 (C–CH3 at coumarin),
152.55–107.33 (17C, Ar–C), 68.12 (N–C–S), 38.26 (CH3–
N–CH3), 31.54 (–CH2 of thiazolidinone), 22.67 (–CH3 of
coumarin); Anal. Calcd for C30H25FN6O4S: C, 61.63; H,
4.31; N, 14.38. Found: C, 61.69; H, 4.25; N, 14.34.
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-p-tolyl-
thiazolidin-4-one (10d)
Yield: 63%. mp 231–233°C; IR (KBr, cm-1): 3,345 (–NH),
1,733 (C=O of thiazolidinone), 1,661 (C=O of coumarin),
1
1,446 (–CH3 of coumarin), 806 (s–triazine, C–N str.); H
NMR (DMSO–d6, d, ppm): 9.81 (s, 1H, –NH), 7.74 (d,
J = 7.2 Hz, Hcu), 7.41–6.95 (m, 8H, Ar–H), 6.68–6.55 (m,
2H, Hcu), 6.14 (s, 1H, Hcu), 6.08 (s, 1H, N–CH–S), 3.61 (d,
J = 12.2, 1H of thiazolidinone), 3.55 (d, J = 12.1, 1H of
thiazolidinone), 3.10 (s, 6H, 2CH3), 2.26 (d, J = 1.1 Hz, 3H,
Hcu), 2.17 (s, 3H, ph-CH3); 13C NMR (DMSO-d6, d, ppm):
173.11 (C=O of thiazolidinone), 163.45 (C–N–(CH3)2),
162.21 (C=O of coumarin), 160.86 (C–O–C), 155.47 (C–O–
C of coumarin), 154.23 (C–CH3 at coumarin), 139.17
(C–CH3 of phenyl), 152.11–106.21 (17C, Ar–C), 65.77
2-(4-Chloro-phenyl)-3-{4-[4-dimethylamino-6-(4-methyl-
2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-ylamino]-
phenyl}-thiazolidin-4-one (10g)
Yield: 66%. mp 228–230°C; IR (KBr, cm-1): 3,348 (–NH),
1,739 (C=O of thiazolidinone), 1,661 (C=O of coumarin),
123

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Med Chem Res (2012) 21:2926–2944
1,442 (–CH3 of coumarin), 813 (s-triazine, C–N str.), 785
1
thiazolidinone), 164.17 (C–N–(CH3)2), 162.34 (C=O of
coumarin), 160.24 (C–O–C), 158.55 (C–OH), 155.30
(C–O–C of coumarin), 154.46 (C–CH3 at coumarin),
153.16–106.27 (17C, Ar–C), 64.33 (N–C–S), 37.19 (CH3–
N–CH3), 32.17 (–CH2 of thiazolidinone), 22.54 (–CH3 of
coumarin); Anal. Calcd for C30H26N6O5S: C, 61.84; H,
4.50; N, 14.42. Found: C, 61.78; H, 4.56; N, 14.37.
(–Cl); H NMR (DMSO-d6, d, ppm): 9.82 (s, 1H, –NH),
7.71 (d, J = 7.1 Hz, Hcu), 7.40–6.86 (m, 8H, Ar–H),
6.59–6.44 (m, 2H, Hcu), 6.19 (s, 1H, Hcu), 6.13 (s, 1H, N–
CH–S), 3.61 (d, J = 12.1, 1H of thiazolidinone), 3.52 (d,
J = 12.3, 1H of thiazolidinone), 3.15 (s, 6H, 2CH3), 2.28
(d, J = 1.1 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
172.19 (C=O of thiazolidinone), 164.12 (C–N–(CH3)2),
161.23 (C=O of coumarin), 161.45 (C–O–C), 155.23 (C–
O–C of coumarin), 154.46 (C–CH3 at coumarin), 133.21
(C–Cl), 152.11–105.43 (17C, Ar–C), 66.10 (N–C–S), 38.15
(CH3–N–CH3), 34.56 (–CH2 of thiazolidinone), 22.11
(–CH3 of coumarin); Anal. Calcd for C30H25ClN6O4S: C,
59.95; H, 4.19; N, 13.98. Found: C, 59.89; H, 4.24; N,
13.92.
2-(2-Bromo-phenyl)-3-{4-[4-dimethylamino-6-(4-methyl-2-
oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-ylamino]-
phenyl}-thiazolidin-4-one (10j)
Yield: 63%. mp 245–246°C; IR (KBr, cm-1): 3,355 (–NH),
1,741 (C=O of thiazolidinone), 1,658 (C=O of coumarin),
1,453 (–CH3 of coumarin), 806 (s-triazine, C–N str.), 731
1
(–Br); H NMR (DMSO-d6, d, ppm): 9.79 (s, 1H, –NH),
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-(4-nitro-
phenyl)-thiazolidin-4-one (10h)
7.61 (d, J = 7.4 Hz, Hcu), 7.36– 7.02 (m, 8H, Ar–H),
6.60–6.45 (m, 2H, Hcu), 6.34 (s, 1H, Hcu), 6.20 (s, 1H, N–
CH–S), 3.63 (d, J = 12.3, 1H of thiazolidinone), 3.54 (d,
J = 12.1, 1H of thiazolidinone), 3.28 (s, 6H, 2CH3), 2.30
(d, J = 1.1 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
173.21 (C=O of thiazolidinone), 164.84 (C–N–(CH3)2),
162.27 (C=O of coumarin), 162.11 (C–O–C), 155.35 (C–
O–C of coumarin), 154.19 (C–CH3 at coumarin), 121.53
(C–Br), 152.11–107.13 (17C, Ar–C), 67.21 (N–C–S),
38.40 (CH3–N–CH3), 31.23 (–CH2 of thiazolidinone),
22.59 (–CH3 of coumarin); Anal. Calcd for C30H25BrN6
O4S: C, 55.82; H, 3.90; N, 13.02. Found: C, 55.87; H, 3.84;
N, 13.09.
Yield: 61%. mp 222–224°C; IR (KBr, cm-1): 3,352 (–NH),
1,729 (C=O of thiazolidinone), 1,663 (C=O of coumarin),
1,542 (N=O str.), 1,447 (–CH3 of coumarin), 810 (s-tri-
azine, C–N str.); 1H NMR (DMSO-d6, d, ppm): 9.77 (s, 1H,
–NH), 7.67 (d, J = 7.5 Hz, Hcu), 7.36–6.89 (m, 8H, Ar–
H), 6.69–6.51 (m, 2H, Hcu), 6.23 (s, 1H, Hcu), 6.17 (s, 1H,
N–CH–S), 3.62 (d, J = 12.4, 1H of thiazolidinone), 3.55
(d, J = 12.1, 1H of thiazolidinone), 3.11 (s, 6H, 2CH3),
2.35 (d, J = 1.4 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d,
ppm): 171.65 (C=O of thiazolidinone), 164.69 (C–N–
(CH3)2), 162.27 (C=O of coumarin), 161.17 (C–O–C),
155.63 (C–O–C of coumarin), 154.22 (C–CH3 at couma-
rin), 148.20 (C–NO2), 150.64–105.65 (17C, Ar–C), 67.14
(N–C–S), 38.11 (CH3–N–CH3), 31.62 (–CH2 of thiazolid-
inone), 22.54 (–CH3 of coumarin); Anal. Calcd for
C30H25N7O6S: C, 58.91; H, 4.12; N, 16.03. Found: C,
58.94; H, 4.17; N, 16.06.
2-(3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-
chromen-7-yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-4-
oxo-thiazolidin-2-yl)-benzoic acid (10k)
Yield: 57%. mp 235–237°C; IR (KBr, cm-1): 3,351 (–NH),
1,747 (C=O of thiazolidinone), 1,743 (–COOH), 1,669
(C=O of coumarin), 1,451 (–CH3 of coumarin), 810 (s-
1
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-(4-hydroxy-
phenyl)-thiazolidin-4-one (10i)
triazine, C–N str.); H NMR (DMSO-d6, d, ppm): 9.82 (s,
1H, –NH), 7.65 (d, J = 7.5 Hz, Hcu), 7.36–6.83 (m, 8H,
Ar–H), 6.67–6.52 (m, 2H, Hcu), 6.22 (s, 1H, Hcu), 6.12 (s,
1H, N–CH–S), 3.60 (d, J = 12.6, 1H of thiazolidinone),
3.55 (d, J = 12.4, 1H of thiazolidinone), 3.20 (s, 6H,
2CH3), 2.26 (d, J = 1.2 Hz, 3H, Hcu); 13C NMR (DMSO-
d6, d, ppm): 171.26 (C=O of thiazolidinone), 170.14 (C=O
of COOH), 164.79 (C–N–(CH3)2), 162.78 (C=O of cou-
marin), 162.18 (C–O–C), 154.13 (C–O–C of coumarin),
153.79 (C–CH3 at coumarin), 131.25 (C–COOH),
153.41–106.29 (17C, Ar–C), 66.32 (N–C–S), 38.22 (CH3–
N–CH3), 33.45 (–CH2 of thiazolidinone), 22.45 (–CH3 of
coumarin); Anal. Calcd for C31H26N6O6S: C, 60.97; H,
4.29; N, 13.76. Found: C, 60.92; H, 4.34; N, 13.83.
Yield: 71%. mp 260–263°C; IR (KBr, cm-1): 3,359 (–NH),
3,244 (–OH), 1,753 (C=O of thiazolidinone), 1,670 (C=O
of coumarin), 1,439 (–CH3 of coumarin), 806 (s-triazine,
C–N str.); 1H NMR (DMSO-d6, d, ppm): 9.84 (s, 1H,
–NH), 7.77 (d, J = 7.4 Hz, Hcu), 7.39–7.04 (m, 8H, Ar–
H), 6.64–6.49 (m, 2H, Hcu), 6.29 (s, 1H, Hcu), 6.18 (s, 1H,
N–CH–S), 4.60 (s, 1H, –OH), 3.64 (d, J = 12.1, 1H of
thiazolidinone), 3.51 (d, J = 12.3, 1H of thiazolidinone),
3.19 (s, 6H, 2CH3), 2.23 (d, J = 1.2 Hz, 3H, Hcu);
13C NMR (DMSO-d6, d, ppm): 172.24 (C=O of
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Med Chem Res (2012) 21:2926–2944
2939
C–N str.); 1H NMR (DMSO-d6, d, ppm): 9.80 (s, 1H,
–NH), 8.54 (s, 1H, –OH), 7.78 (d, J = 7.1 Hz, Hcu),
7.43–7.06 (m, 7H, Ar–H), 6.61–6.42 (m, 2H, Hcu), 6.27 (s,
1H, Hcu), 6.15 (s, 1H, N–CH–S), 4.70 (s, 1H, –OH), 3.65
(d, J = 12.6,1H of thiazolidinone), 3.57 (d, J = 12.1, 1H
of thiazolidinone), 3.13 (s, 6H, 2CH3), 2.35 (d, J = 1.5 Hz,
3H, Hcu); 13C NMR (DMSO-d6, d, ppm): 173.11 (C=O of
thiazolidinone), 165.14 (C–N–(CH3)2), 162.43 (C=O of
coumarin), 162.27 (C–O–C), 158.23 (C–OH), 156.64
(C–OH), 155.16 (C–O–C of coumarin), 154.29 (C–CH3 at
coumarin), 151.79–106.13 (16C, Ar–C), 66.95 (N–C–S),
38.13 (CH3–N–CH3), 34.28 (–CH2 of thiazolidinone),
22.45 (–CH3 of coumarin); Anal. Calcd for C30H26N6O6S:
C, 60.19; H, 4.38; N, 14.04. Found: C, 60.23; H, 4.34; N,
14.09.
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-(4-methoxy-
phenyl)-thiazolidin-4-one (10l)
Yield: 71%. mp 270–273°C; IR (KBr, cm-1): 3,349 (–NH),
1,735 (C=O of thiazolidinone), 1,675 (C=O of coumarin),
1,446 (–CH3 of coumarin), 1,281 (–OCH3), 812 (s–triazine,
C–N str.); 1H NMR (DMSO-d6, d, ppm): 9.79 (s, 1H,
–NH), 7.71 (d, J = 7.2 Hz, Hcu), 7.41–6.93 (m, 8H, Ar–
H), 6.63–6.41 (m, 2H, Hcu), 6.20 (s, 1H, Hcu), 6.17 (s, 1H,
N–CH–S), 3.80 (s, 3H, –OCH3), 3.62 (d, J = 12.2, 1H of
thiazolidinone), 3.53 (d, J = 12.1, 1H of thiazolidinone),
3.11 (s, 6H, 2CH3), 2.24 (d, J = 1.1 Hz, 3H, Hcu); 13C
NMR (DMSO-d6, d, ppm): 172.11 (C=O of thiazolidi-
none), 164.32 (C–N–(CH3)2), 162.54 (C=O of coumarin),
162.10 (C–O–C), 160.26 (C–OCH3), 154.75 (C–O–C of
coumarin), 154.46 (C–CH3 at coumarin), 153.13–106.12
(17C, Ar–C), 67.83 (N–C–S), 56.64 (–OCH3), 38.55
(CH3–N–CH3), 31.24 (–CH2 of thiazolidinone), 22.47
(–CH3 of coumarin); Anal. Calcd for C31H28N6O5S: C,
62.40; H, 4.73; N, 14.09. Found: C, 62.45; H, 4.77; N,
14.03.
General procedure for the synthesis of target
compounds 12a–n
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-phenyl-5-(4-
pyridin-2-yl-piperazin-1-ylmethyl)-thiazolidin-4-one (12a)
2-(3,4-Dimethoxy-phenyl)-3-{4-[4-dimethylamino-6-(4-
methyl-2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-
ylamino]-phenyl}-thiazolidin-4-one (10m)
A mixture of paraformaldehyde (0.25 g; 0.0,025 mol) and
1-pyridin-2-yl-piperazine (0.81 g; 0.005 mol) in 30 ml of
absolute ethanol was refluxed for 30 min until complete
solubility of paraformaldehyde was achieved. A warmed
solution of compound 10a (5.0 g, 0.010 mol) in 50 ml of
ethanol was subsequently added to the reaction mixture.
The whole reaction mixture was refluxed for 10–11 h and
left at room temperature under stirring for 3 days, and after
that the volatile material was evaporated. The dry residue
was extracted with DMF to form 3-{4-[4-dimethylamino-
6-(4-methyl-2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-
ylamino]-phenyl}-2-phenyl-5-(4-pyridin-2-yl-piperazin-1-
ylmethyl)-thiazolidin-4-one (12a). Similarly, other final
compounds have been synthesized.
Yield: 70%. mp 278–280°C; IR (KBr, cm-1): 3,356 (–NH),
1,743 (C=O of thiazolidinone), 1,666 (C=O of coumarin),
1,449 (–CH3 of coumarin), 1,275 (–OCH3), 810 (s-triazine,
C–N str.); 1H NMR (DMSO-d6, d, ppm): 9.85 (s, 1H,
–NH), 7.65 (d, J = 7.3 Hz, Hcu), 7.39–6.95 (m, 7H, Ar–
H), 6.68–6.55 (m, 2H, Hcu), 6.42 (s, 1H, Hcu), 6.28 (s, 1H,
N–CH–S), 3.86 (s, 3H, –OCH3), 3.79 (s, 3H, –OCH3), 3.63
(d, J = 12.4, 1H of thiazolidinone), 3.51 (d, J = 12.3, 1H
of thiazolidinone), 3.09 (s, 6H, 2CH3), 2.30 (d, J = 1.2 Hz,
3H, Hcu); 13C NMR (DMSO–d6, d, ppm): 171.54 (C=O of
thiazolidinone), 164.27 (C–N–(CH3)2), 161.95 (C=O of
coumarin), 161.55 (C–O–C), 160.34 (C–OCH3), 159.70
(C–OCH3), 154.65 (C–O–C of coumarin), 154.40 (C–CH3
at coumarin), 152.10–105.57 (16C, Ar–C), 66.12 (N–C–S),
56.95 (–OCH3), 37.49 (CH3–N–CH3), 32.69 (–CH2 of
thiazolidinone), 22.15 (–CH3 of coumarin); Anal. Calcd for
C32H30N6O6S: C, 61.33; H, 4.83; N, 13.41. Found: C,
61.37; H, 4.76; N, 13.46.
Characterization data of final synthesized compounds
12a–n
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-phenyl-5-(4-
pyridin-2-yl-piperazin-1-ylmethyl)-thiazolidin-4-one (12a)
Yield: 64%. mp 256–258°C; IR (KBr, cm-1): 3,347 (–NH),
1,736 (C=O of thiazolidinone), 1,669 (C=O of coumarin),
2-(2,4-Dihydroxy-phenyl)-3-{4-[4-dimethylamino-6-(4-
methyl-2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-
ylamino]-phenyl}-thiazolidin-4-one (10n)
1
1,443 (–CH3 of coumarin), 806 (s-triazine, C–N str.); H
NMR (DMSO-d6, d, ppm): 9.92 (s, 1H, –NH), 7.72 (d,
J = 7.3 Hz, Hcu), 7.65–7.49 (m, 2H, HPy), 7.46–6.93 (m,
9H, Ar–H), 6.86 (dd, J = 7.3, 1.6 Hz, HPy), 6.83 (td,
J = 7.5, 1.3 Hz, HPy), 6.80–6.63 (m, 2H, Hcu), 6.22 (s,
1H, Hcu), 6.13 (s, 1H, N–CH–S), 4.34 (t, J = 7.1 Hz, 1H
Yield: 66%. mp 282–284°C; IR (KBr, cm-1): 3,351 (–NH),
3,266 (–OH), 1,733 (C=O of thiazolidinone), 1,669 (C=O
of coumarin), 1,450 (–CH3 of coumarin), 809 (s-triazine,
123

2940
Med Chem Res (2012) 21:2926–2944
of S–CH–C=O), 3.59 (br-s, 8H, Piperazine), 3.44–3.21 (m,
2H, –CH2 between thiazolidinone ring and piperazine),
3.13 (s, 6H, 2CH3), 2.36 (d, J = 1.1 Hz, 3H, Hcu); 13C
NMR (DMSO-d6, d, ppm): 172.26 (C=O of thiazolidi-
none), 164.18 (C–N–(CH3)2), 162.55 (C=O of coumarin),
161.64 (C–O–C), 160.79 (C–N of 1-pyridin-2-yl-pipera-
zine), 155.78 (C–O–C of coumarin), 154.40 (C–CH3 at
coumarin), 153.37– 106.47 (22C, Ar–C), 65.72 (N–C–S),
62.89, 59.43 (4C-piperazine), 58.33 (–CH2 between thia-
zolidinone ring and piperazine), 58.20 (CH of thiazolidi-
none ring), 38.45 (CH3–N–CH3), 22.56 (CH3 of coumarin);
Anal. Calcd for C40H39N9O4S: C, 64.76; H, 5.30; N, 16.99.
Found: C, 64.79; H, 5.24; N, 16.94.
6.82 (td, J = 7.5, 1.3 Hz, HPy), 6.76–6.63 (m, 2H, Hcu),
6.44 (s, 1H, Hcu), 6.24 (s, 1H, N–CH–S), 4.36 (t,
J = 7.2 Hz, 1H of S–CH–C=O), 3.64 (br-s, 8H, Pipera-
zine), 3.38–3.21 (m, 2H, –CH2 between thiazolidinone ring
and piperazine), 3.17 (s, 6H, 2CH3), 2.39 (d, J = 1.3 Hz,
3H, Hcu); 13C NMR (DMSO-d6, d, ppm): 171.35 (C=O of
thiazolidinone), 165.18 (C–N–(CH3)2), 163.24 (C=O of
coumarin), 161.44 (C–O–C), 160.55 (C–N of 1-pyridin-2-
yl-piperazine), 155.49 (C–O–C of coumarin), 155.13 (C–
CH3 at coumarin), 134.89 (C–Cl), 134.37 (C–Cl),
152.31–107.62 (20C, Ar–C), 68.13 (N–C–S), 64.22, 61.54
(4C-piperazine), 60.29 (–CH2 between thiazolidinone ring
and piperazine), 58.21 (CH of thiazolidinone ring), 37.85
(CH3–N–CH3), 22.48 (–CH3 of coumarin); Anal. Calcd for
C40H37Cl2N9O4S: C, 59.26; H, 4.60; N, 15.55. Found: C,
59.31; H, 4.64; N, 15.47.
2-(2,4-Dichloro-phenyl)-3-{4-[4-dimethylamino-6-(4-
methyl-2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-
ylamino]-phenyl}-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-
thiazolidin-4-one (12b)
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-5-(4-pyridin-2-yl-
piperazin-1-ylmethyl)-2-p-tolyl-thiazolidin-4-one (12d)
Yield: 70%. mp 278–280°C; IR (KBr, cm-1): 3,344 (–NH),
1,747 (C=O of thiazolidinone), 1,662 (C=O of coumarin),
1,436 (–CH3 of coumarin), 810 (s-triazine, C–N str.), 784
Yield: 59%. mp 269–271°C; IR (KBr, cm-1): 3,351 (–NH),
1,740 (C=O of thiazolidinone), 1,665 (C=O of coumarin),
1
1,454 (–CH3 of coumarin), 808 (s-triazine, C–N str.); H
1
(–Cl); H NMR (DMSO-d6, d, ppm): 9.97 (s, 1H, –NH),
7.61 (d, J = 7.4 Hz, Hcu), 7.58–7.43 (m, 2H, HPy),
7.41–7.17 (m, 7H, Ar–H), 6.92 (dd, J = 7.4, 1.1 Hz, HPy),
6.85 (td, J = 7.2, 1.1 Hz, HPy), 6.70–6.59 (m, 2H, Hcu),
6.37 (s, 1H, Hcu), 6.18 (s, 1H, N–CH–S), 4.29 (t,
J = 7.5 Hz, 1H of S–CH–C=O), 3.62 (br-s, 8H, Pipera-
zine), 3.41–3.27(m, 2H, –CH2 between thiazolidinone ring
and piperazine), 3.22 (s, 6H, 2CH3), 2.42 (d, J = 1.3 Hz,
3H, Hcu); 13C NMR (DMSO-d6, d, ppm): 171.54 (C=O of
thiazolidinone), 164.79 (C–N–(CH3)2), 162.80 (C=O of
coumarin), 160.55 (C–O–C), 160.41 (C–N of 1-pyridin-2-
yl-piperazine), 155.23 (C–O–C of coumarin), 154.25
(C–CH3 at coumarin), 134.50 (C–Cl), 133.41 (C–Cl),
153.28–107.22 (20C, Ar–C), 69.54 (N–C–S), 62.76, 61.53
(4C-piperazine), 59.33 (–CH2 between thiazolidinone ring
and piperazine), 58.14 (CH of thiazolidinone ring), 37.19
(CH3–N–CH3), 22.76 (–CH3 of coumarin); Anal. Calcd for
C40H37Cl2N9O4S: C, 59.26; H, 4.60; N, 15.55. Found: C,
59.29; H, 4.65; N, 15.50.
NMR (DMSO-d6, d, ppm): 9.76 (s, 1H, –NH), 7.79 (d,
J = 7.1 Hz, Hcu), 7.62–7.45 (m, 2H, HPy), 7.41–7.03 (m,
8H, Ar–H), 6.89 (dd, J = 7.5, 1.3 Hz, HPy), 6.81 (td,
J = 7.2, 1.5 Hz, HPy), 6.71–6.56 (m, 2H, Hcu), 6.16 (s,
1H, Hcu), 6.11 (s, 1H, N–CH–S), 4.29 (t, J = 7.4 Hz, 1H
of S–CH–C=O), 3.63 (br-s, 8H, Piperazine), 3.41–3.23 (m,
2H, –CH2 between thiazolidinone ring and piperazine),
3.16 (s, 6H, 2CH3), 2.30 (d, J = 1.1 Hz, 3H, Hcu), 2.21 (s,
3H, ph-CH3); 13C NMR (DMSO-d6, d, ppm): 173.45 (C=O
of thiazolidinone), 164.24 (C–N–(CH3)2), 162.63 (C=O of
coumarin), 161.78 (C–O–C), 160.46 (C–N of 1–pyridin–2–
yl–piperazine), 156.13 (C–O–C of coumarin), 154.52
(C–CH3 at coumarin), 139.24 (C–CH3 of phenyl),
152.24–106.26 (21C, Ar–C), 66.40 (N–C–S), 63.65, 61.42
(4C-piperazine), 59.41 (–CH2 between thiazolidinone ring
and piperazine), 58.75 (CH of thiazolidinone ring), 38.41
(CH3–N–CH3), 22.63 (–CH3 of coumarin), 21.51 (–CH3 of
coumarin); Anal. Calcd for C41H41N9O4S: C, 65.15; H,
5.47; N, 16.68. Found: C, 65.11; H, 5.43; N, 16.72.
2–(3,4-Dichloro-phenyl)-3-{4-[4-dimethylamino-6-(4-
methyl-2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-
ylamino]-phenyl}-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-
thiazolidin-4-one (12c)
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-(4-fluoro-
phenyl)-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-
thiazolidin-4-one (12e)
Yield: 66%. mp 291–292°C; IR (KBr,cm-1): 3,356 (–NH),
1,740 (C=O of thiazolidinone), 1,665 (C=O of coumarin),
1,439 (–CH3 of coumarin), 813 (s-triazine, C–N str.), 797
Yield: 62%. mp 249–251°C; IR (KBr, cm-1): 3,339 (–NH),
1,748 (C=O of thiazolidinone), 1,663 (C=O of coumarin),
1,433 (–CH3 of coumarin), 1,167 (C–F), 810 (s-triazine, C–N
str.); 1H NMR (DMSO-d6, d, ppm): 9.73 (s, 1H, –NH), 7.81
1
(–Cl); H NMR (DMSO-d6, d, ppm): 9.88 (s, 1H, -NH),
7.74 (d, J = 7.3 Hz, Hcu), 7.67–7.48 (m, 2H, HPy),
7.43–7.06 (m, 7H, Ar–H), 6.89 (dd, J = 7.2, 1.4 Hz, HPy),
123

Med Chem Res (2012) 21:2926–2944
2941
(d, J = 7.6 Hz, Hcu), 7.72–7.53 (m, 2H, HPy), 7.49–7.11
(m, 8H, Ar–H), 6.85 (dd, J = 7.2, 1.3 Hz, HPy), 6.80 (td,
J = 7.1, 1.4 Hz, HPy), 6.69–6.52 (m, 2H, Hcu), 6.19 (s, 1H,
Hcu), 6.14 (s, 1H, N–CH–S), 4.36 (t, J = 7.2 Hz, 1H of S–
CH–C=O), 3.59 (br-s, 8H, Piperazine), 3.34–3.16 (m, 2H,
–CH2 between thiazolidinone ring and piperazine), 3.12 (s,
6H, 2CH3), 2.38 (d, J = 1.1 Hz, 3H, Hcu); 13C NMR
(DMSO-d6, d, ppm): 171.56 (C=O of thiazolidinone), 167.60
(C–F), 164.39 (C–N–(CH3)2), 162.57 (C=O of coumarin),
161.89 (C–O–C), 161.12 (C–N of 1-pyridin-2-yl-pipera-
zine), 156.29 (C–O–C of coumarin), 154.33 (C–CH3 at
coumarin), 153.41–108.35 (21C, Ar–C), 69.43 (N–C–S),
65.46, 62.34 (4C-piperazine), 60.19 (–CH2 between thiazo-
lidinone ring and piperazine), 57.63 (CH of thiazolidinone
ring), 38.61 (CH3–N–CH3), 22.51 (–CH3 of coumarin);
Anal. Calcd for C40H38FN9O4S: C, 63.23; H, 5.04; N, 16.59.
Found: C, 63.28; H, 5.09; N, 16.53.
(–Cl); 1H NMR (DMSO-d6, d, ppm): 9.75 (s, 1H, –NH), 7.66
(d, J = 7.5 Hz, Hcu), 7.60–7.44 (m, 2H, HPy), 7.36–6.92
(m, 8H, Ar–H), 6.85 (dd, J = 7.4, 1.3 Hz, HPy), 6.79 (td,
J = 7.4, 1.2 Hz, HPy), 6.65–6.54 (m, 2H, Hcu), 6.25 (s, 1H,
Hcu), 6.17 (s, 1H, N–CH–S), 4.31 (t, J = 7.5 Hz, 1H of
S–CH–C=O), 3.64 (br-s, 8H, Piperazine), 3.38–3.23 (m, 2H,
–CH2 between thiazolidinone ring and piperazine), 3.18 (s,
6H, 2CH3), 2.32 (d, J = 1.2 Hz, 3H, Hcu); 13C NMR
(DMSO-d6, d, ppm): 173.22 (C=O of thiazolidinone), 164.33
(C–N–(CH3)2), 162.69 (C=O of coumarin), 162.13 (C–O–C),
161.19 (C–N of 1-pyridin-2-yl-piperazine), 155.87 (C–O–C
of coumarin), 154.55 (C–CH3 at coumarin), 133.41 (C–Cl),
153.48–106.30 (21C, Ar–C), 66.12 (N–C–S), 61.64, 57.40
(4C-piperazine), 60.45 (–CH2 between thiazolidinone ring
and piperazine), 58.61 (CH of thiazolidinone ring), 38.27
(CH3–N–CH3), 22.64 (–CH3 of coumarin); Anal. Calcd for
C40H38ClN9O4S: C, 61.89; H, 4.93; N, 16.24. Found: C,
61.94; H, 4.88; N, 16.27.
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-(3-fluoro-
phenyl)-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-
thiazolidin-4-one (12f)
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-(4-nitro-
phenyl)-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-
thiazolidin-4-one (12h)
Yield: 65%. mp 263–266°C; IR (KBr, cm-1): 3,350 (–NH),
1,736 (C=O of thiazolidinone), 1,667 (C=O of coumarin),
1,427 (–CH3 of coumarin), 1,161 (C–F), 810 (s-triazine, C–N
str.); 1H NMR (DMSO-d6, d, ppm): 9.86 (s, 1H, –NH), 7.79
(d, J = 7.4 Hz, Hcu), 7.71–7.50 (m, 2H, HPy), 7.42–6.91
(m, 8H, Ar–H), 6.87 (dd, J = 7.1, 1.3 Hz, HPy), 6.83 (td,
J = 7.3, 1.2 Hz, HPy), 6.64–6.46 (m, 2H, Hcu), 6.22 (s, 1H,
Hcu), 6.16 (s, 1H, N–CH–S), 4.27 (t, J = 7.4 Hz, 1H of S–
CH–C=O), 3.63 (br-s, 8H, Piperazine), 3.39–3.18 (m, 2H,
–CH2 between thiazolidinone ring and piperazine), 3.04
(s, 6H, 2CH3), 2.35 (d, J = 1.4 Hz, 3H, Hcu); 13C NMR
(DMSO-d6, d, ppm): 172.10 (C=O of thiazolidinone), 167.43
(C–F), 164.47 (C–N–(CH3)2), 162.26 (C=O of coumarin),
162.11 (C–O–C), 161.34 (C–N of 1-pyridin-2-yl-pipera-
zine), 157.21 (C–O–C of coumarin), 154.24 (C–CH3 at
coumarin), 152.65–108.31 (21C, Ar–C), 68.82 (N–C–S),
63.16, 61.52 (4C-piperazine), 59.67 (–CH2 between thiazo-
lidinone ring and piperazine), 57.43 (CH of thiazolidinone
ring), 37.48 (CH3–N–CH3), 22.41 (–CH3 of coumarin);
Anal. Calcd for C40H38FN9O4S: C, 63.23; H, 5.04; N, 16.59.
Found: C, 63.26; H, 5.07; N, 16.54.
Yield: 57%. mp 261–263°C; IR (KBr, cm-1): 3,348 (–NH),
1,732 (C=O of thiazolidinone), 1,666 (C=O of coumarin),
1,545 (N = O str.), 1,454 (–CH3 of coumarin), 812 (s-tri-
azine, C–N str.); 1H NMR (DMSO-d6, d, ppm): 9.89 (s, 1H,
–NH), 7.71 (d, J = 7.5 Hz, Hcu), 7.67–7.50 (m, 2H, HPy),
7.45–6.90 (m, 8H, Ar–H), 6.88 (dd, J = 7.3, 1.4 Hz, HPy),
6.82 (td, J = 7.4, 1.2 Hz, HPy), 6.75–6.64 (m, 2H, Hcu),
6.29 (s, 1H, Hcu), 6.21 (s, 1H, N–CH–S), 4.25 (t,
J = 7.4 Hz, 1H of S–CH–C=O), 3.67 (br-s, 8H, Piperazine),
3.37–3.19 (m, 2H, –CH2 between thiazolidinone ring and
piperazine), 3.13 (s, 6H, 2CH3), 2.44 (d, J = 1.6 Hz, 3H,
Hcu); 13C NMR (DMSO-d6, d, ppm): 172.16 (C=O of thia-
zolidinone), 165.13 (C–N–(CH3)2), 162.56 (C=O of cou-
marin), 161.28 (C–O–C), 161.11 (C–N of 1-pyridin-2-yl-
piperazine), 156.10 (C–O–C of coumarin), 154.45 (C–CH3
at coumarin), 148.59 (C–NO2), 151.67–105.16 (21C, Ar–C),
67.25 (N–C–S), 63.52, 62.45 (4C-piperazine), 61.64 (–CH2
between thiazolidinone ring and piperazine), 57.66 (CH of
thiazolidinone ring), 38.27 (CH3–N–CH3), 22.76 (–CH3 of
coumarin); Anal. Calcd for C40H38N10O6S: C, 61.06; H,
4.87; N, 17.80. Found: C, 61.11; H, 4.89; N, 17.85.
2-(4-Chloro-phenyl)-3-{4-[4-dimethylamino-6-(4-methyl-
2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-ylamino]-
phenyl}-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-
thiazolidin-4-one (12g)
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-(4-hydroxy-
phenyl)-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-
thiazolidin-4-one (12i)
Yield: 65%. mp 285–287°C; IR (KBr, cm-1): 3,360 (–NH),
1,743 (C=O of thiazolidinone), 1,663 (C=O of coumarin),
1,446 (–CH3 of coumarin), 808 (s-triazine, C–N str.), 789
Yield: 73%. mp [300°C; IR (KBr, cm-1): 3,367 (–NH), 3,247
(–OH), 1,756 (C=O of thiazolidinone), 1,678 (C=O of
123

2942
Med Chem Res (2012) 21:2926–2944
coumarin), 1,443 (–CH3 of coumarin), 808 (s-triazine, C–N
str.); 1H NMR (DMSO-d6, d, ppm): 9.94 (s, 1H, –NH), 7.80 (d,
J = 7.1 Hz, Hcu), 7.72–7.55 (m, 2H, HPy), 7.35–6.96 (m, 8H,
Ar–H), 6.86 (dd, J = 7.6, 1.3 Hz, HPy), 6.80 (td, J = 7.5,
1.2 Hz, HPy), 6.67–6.52 (m, 2H, Hcu), 6.31 (s, 1H, Hcu), 6.20
(s, 1H, N–CH–S), 4.63 (s, 1H, –OH), 4.37 (t, J = 7.3 Hz, 1H of
S–CH–C=O), 3.54 (br-s, 8H, Piperazine), 3.47–3.30 (m, 2H,
–CH2 between thiazolidinone ring and piperazine), 3.22 (s, 6H,
2CH3), 2.27 (d, J = 1.3 Hz, 3H, Hcu); 13C NMR (DMSO-d6,
d, ppm): 172.59 (C=O of thiazolidinone), 164.37 (C–N–
(CH3)2), 162.43 (C=O of coumarin), 161.55 (C–O–C), 161.13
(C–N of 1-pyridin-2-yl-piperazine), 158.55 (C–OH), 155.71
(C–O–C of coumarin), 154.63 (C–CH3 at coumarin),
153.44–106.41 (21C, Ar–C), 65.24 (N–C–S), 63.49, 61.22 (4C-
piperazine), 60.39 (–CH2 between thiazolidinone ring and
piperazine), 57.26 (CH of thiazolidinone ring), 37.53 (CH3–N–
CH3), 22.62 (–CH3 of coumarin); Anal. Calcd for C40H39N9O5S:
C, 63.39; H, 5.19; N, 16.63. Found: C, 63.46; H, 5.15; N, 16.58.
str.);1H NMR (DMSO-d6, d, ppm): 9.90(s, 1H, –NH), 7.69(d,
J = 7.6 Hz, Hcu), 7.63–7.37 (m, 2H, HPy), 7.33–6.89 (m,
8H, Ar–H), 6.82(dd, J = 7.4, 1.4 Hz, HPy), 6.76(td,J = 7.3,
1.1 Hz, HPy), 6.70–6.55 (m, 2H, Hcu), 6.25 (s, 1H, Hcu), 6.16
(s, 1H, N–CH–S), 4.23 (t, J = 7.5 Hz, 1H of S–CH–C=O),
3.59 (br-s, 8H, Piperazine), 3.51–3.43 (m, 2H, –CH2 between
thiazolidinone ring and piperazine), 3.26 (s, 6H, 2CH3), 2.29
(d, J = 1.3 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
171.59 (C=O of thiazolidinone), 170.52 (C=O of COOH),
165.32 (C–N–(CH3)2), 163.10 (C=O of coumarin), 162.28
(C–O–C), 160.48 (C–N of 1-pyridin-2-yl-piperazine), 154.90
(C–O–C of coumarin), 154.43 (C–CH3 at coumarin), 131.33
(C–COOH), 154.32–105.49 (21C, Ar–C), 67.92 (N–C–S),
62.44, 59.36 (4C-piperazine), 58.89 (–CH2 between thiazo-
lidinone ring and piperazine), 58.25 (CH of thiazolidinone
ring), 38.30 (CH3–N–CH3), 22.58 (–CH3 of coumarin); Anal.
Calcd for C41H39N9O6S: C, 62.66; H, 5.00; N, 16.04. Found:
C, 62.61; H, 5.07; N, 16.01.
2-(2-Bromo-phenyl)-3-{4-[4-dimethylamino-6-(4-methyl-2-
oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-ylamino]-
phenyl}-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-
thiazolidin-4-one (12j)
3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-(4-methoxy-
phenyl)-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-
thiazolidin-4-one (12l)
Yield: 60%. mp 280–282°C; IR (KBr, cm-1): 3,359 (–NH),
1,743 (C=O of thiazolidinone), 1,662 (C=O of coumarin),
1,459 (–CH3 of coumarin), 806 (s-triazine, C–N str.), 737
(–Br); 1H NMR (DMSO-d6, d, ppm): 9.73 (s, 1H, –NH), 7.66
(d, J = 7.4 Hz, Hcu), 7.60–7.42 (m, 2H, HPy), 7.38–7.10 (m,
8H, Ar–H), 6.89(dd, J = 7.3, 1.5 Hz, HPy), 6.79(td,J = 7.6,
1.5 Hz, HPy), 6.68–6.49 (m, 2H, Hcu), 6.36 (s, 1H, Hcu), 6.24
(s, 1H, N–CH–S), 4.32 (t, J = 7.2 Hz, 1H of S–CH–C=O),
3.66 (br-s, 8H, Piperazine), 3.53–3.38 (m, 2H, –CH2 between
thiazolidinone ring and piperazine), 3.32 (s, 6H, 2CH3), 2.38
(d, J = 1.2 Hz, 3H, Hcu); 13C NMR (DMSO-d6, d, ppm):
173.34 (C=O of thiazolidinone), 165.11 (C–N–(CH3)2),
162.36 (C=O of coumarin), 162.15 (C–O–C), 160.28 (C–N of
1-pyridin-2-yl-piperazine), 155.63 (C–O–C of coumarin),
154.27 (C–CH3 at coumarin), 121.78 (C–Br), 152.62–107.19
(21C, Ar–C), 67.49 (N–C–S), 62.56, 60.32 (4C-piperazine),
59.44 (–CH2 between thiazolidinone ring and piperazine),
58.40 (CH of thiazolidinone ring), 38.17 (CH3–N–CH3),
22.46 (–CH3 of coumarin); Anal. Calcd for C40H38BrN9O4S:
C, 58.53; H, 4.67; N, 15.36. Found: 58.46; H, 4.70; N, 15.39.
Yield: 69%. mp[ 300°C; IR (KBr, cm-1): 3,353 (–NH),
1,739 (C=O of thiazolidinone), 1,678 (C=O of coumarin),
1,449 (–CH3 of coumarin), 1,284 (–OCH3), 813 (s-triazine,
C–N str.); 1H NMR (DMSO-d6, d, ppm): 9.87 (s, 1H, –NH),
7.75 (d, J = 7.4 Hz, Hcu), 7.66–7.45 (m, 2H, HPy),
7.42–6.90 (m, 8H, Ar–H), 6.85 (dd, J = 7.5, 1.4 Hz, HPy),
6.77 (td, J = 7.1, 1.3 Hz, HPy), 6.69–6.46 (m, 2H, Hcu), 6.23
(s, 1H, Hcu), 6.21(s, 1H, N–CH–S), 4.34 (t, J = 7.1 Hz,1Hof
S–CH–C=O), 3.87 (s, 3H, –OCH3), 3.60 (br-s, 8H, Pipera-
zine), 3.43–3.17 (m, 2H, –CH2 between thiazolidinone ring
and piperazine), 3.09 (s, 6H, 2CH3), 2.28 (d, J = 1.4 Hz, 3H,
Hcu); 13C NMR (DMSO-d6, d, ppm): 172.14 (C=O of thia-
zolidinone), 164.39 (C–N–(CH3)2), 163.10 (C=O of couma-
rin), 162.18 (C–O–C), 161.19 (C–N of 1-pyridin-2-yl-
piperazine),160.33(C–OCH3), 155.49(C–O–Cofcoumarin),
154.65 (C–CH3 at coumarin), 153.35–106.39 (21C, Ar–C),
68.17 (N–C–S), 64.79, 62.40 (4C-piperazine), 61.56 (–CH2
between thiazolidinone ring and piperazine), 58.71 (CH of
thiazolidinone ring), 56.85 (–OCH3), 38.59 (CH3–N–CH3),
22.51 (–CH3 of coumarin); Anal. Calcd for C41H41N9O5S: C,
63.80; H, 5.35; N, 16.33. Found: C, 63.76; H, 5.39; N, 16.40.
2-[3-{4-[4-Dimethylamino-6-(4-methyl-2-oxo-2H-
chromen-7-yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-4-
oxo-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-thiazolidin-2-
yl]-benzoic acid (12k)
2-(3,4-Dimethoxy-phenyl)-3-{4-[4-dimethylamino-6-(4-
methyl-2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-
ylamino]-phenyl}-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-
thiazolidin-4-one (12m)
Yield: 54%. mp 264–266°C; IR (KBr, cm-1): 3,343 (–NH),
1,752 (C=O of thiazolidinone), 1,748 (–COOH), 1,671 (C=O
of coumarin), 1,454 (–CH3 of coumarin), 811 (s-triazine, C–N
Yield: 73%. mp [ 300°C; IR (KBr, cm-1): 3,363 (–NH),
1,746 (C=O of thiazolidinone), 1,669 (C=O of coumarin),
123

Med Chem Res (2012) 21:2926–2944
2943
1,453 (–CH3 of coumarin), 1,277 (–OCH3), 811 (s-triazine,
C–N str.); 1H NMR (DMSO-d6, d, ppm): 9.75 (s, 1H,
–NH), 7.68 (d, J = 7.2 Hz, Hcu), 7.57–7.41 (m, 2H, HPy),
7.34–7.02 (m, 7H, Ar–H), 6.93 (dd, J = 7.1, 1.6 Hz, HPy),
6.84 (td, J = 7.5, 1.4 Hz, HPy), 6.72–6.54 (m, 2H, Hcu),
6.36 (s, 1H, Hcu), 6.39 (s, 1H, N–CH–S), 4.27 (t,
J = 7.5 Hz, 1H of S–CH–C=O), 3.89 (s, 3H, –OCH3), 3.81
(s, 3H, –OCH3), 3.55 (br-s, 8H, Piperazine), 3.40–3.24 (m,
2H, –CH2 between thiazolidinone ring and piperazine),
3.15 (s, 6H, 2CH3), 2.33 (d, J = 1.5 Hz, 3H, Hcu); 13C
NMR (DMSO-d6, d, ppm): 172.34 (C=O of thiazolidi-
none), 164.45 (C–N–(CH3)2), 162.67 (C=O of coumarin),
161.77 (C–O–C), 160.89 (C–N of 1-pyridin-2-yl-pipera-
zine), 160.21(C–OCH3), 159.66 (C–OCH3), 154.98 (C–O–
(S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumoniae,
S. typhi, P. vulgaris, and S. Flexneria) and fungi (A. niger, A.
fumigatus, A. clavatus, and C. albicans) species using paper
disk-diffusion technique (Gillespie, 1994). The sterilized
(autoclaved at 120°C for 30 min) medium (40–50°C) was
inoculated (1 ml/100 ml of medium) with the suspension
(105 cfu ml-1) of the micro-organism (matched to McFar-
land barium sulphate standard) and poured into a petridish to
give a depth of 3–4 mm. The paper impregnated with the test
compounds (lg ml-1) in dimethyl sulfoxide) was placed on
the solidified medium. The plates were pre-incubated for 1 h
at room temperature and incubated at 37°C for 24 and 48 h
for anti-bacterial and anti-fungal activities, respectively.
Ciprofloxacin (100 lg/disk) and Ketoconazole (100 lg/
disk) were used as standard for antibacterial and anti-fungal
activity, respectively. The observed zone of inhibition is
presented in Tables 1, 2, and 3. MIC of the compound was
determined by agar streak dilution method (Hawkey and
Lewis, 1994). A stock solution of the synthesized compound
(100 lg ml-1) in dimethyl sulfoxide was prepared and
graded quantities of the test compounds were incorporated in
specified quantity of molten sterile agar (nutrient agar for
anti-bacterial activity and sabouraud dextrose agar medium
for anti-fungal activity). A specified quantity of the medium
(40–50°C) containing the compound was poured into a pet-
ridish to give a depth of 3–4 mm and allowed to solidify.
Suspension of the microorganism was prepared to contain
approximately 105 cfu ml-1and applied to plates with seri-
ally diluted compounds in dimethyl sulfoxide to be tested
and incubated at 37°C for 24 and 48 h for bacteria and fungi,
respectively. The MIC was considered to be the lowest
concentration of the test substance exhibiting no visible
growth of bacteria or fungi on the plate. The observed MIC is
presented in Tables 1, 2, and 3.
C
of coumarin), 154.83 (C–CH3 at coumarin),
152.91–105.22 (20C, Ar–C), 66.23 (N–C–S), 62.49, 61.25
(4C-piperazine), 60.43 (–CH2 between thiazolidinone ring
and piperazine), 59.45 (CH of thiazolidinone ring), 57.13
(–OCH3), 37.54 (CH3–N–CH3), 22.32 (–CH3 of couma-
rin); Anal. Calcd for C42H43N9O6S: C, 62.91; H, 5.40; N,
15.72. Found: C, 62.96; H, 5.45; N, 15.65.
2-(2,4-Dihydroxy-phenyl)-3-{4-[4-dimethylamino-6-(4-
methyl-2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-
ylamino]-phenyl}-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-
thiazolidin-4-one (12n)
Yield: 72%. Mp[ 300°C; IR (KBr, cm-1): 3,372 (–NH),
3,271 (–OH), 1,738 (C=O of thiazolidinone), 1,673 (C=O of
coumarin), 1,455 (–CH3 of coumarin), 812 (s-triazine, C–N
str.); 1H NMR (DMSO-d6, d, ppm): 9.69 (s, 1H, –NH), 8.57 (s,
1H, –OH), 7.81 (d, J = 7.2 Hz, Hcu), 7.68–7.47 (m, 2H,
HPy), 7.42–7.11 (m, 7H, Ar–H), 6.91 (dd, J = 7.3, 1.5 Hz,
HPy), 6.84 (td, J = 7.1, 1.2 Hz, HPy), 6.64–6.42 (m, 2H,
Hcu), 6.28 (s, 1H, Hcu), 6.19 (s, 1H, N–CH–S), 4.77 (s, 1H,
–OH), 4.36(t, J = 7.1 Hz, 1HofS–CH–C=O), 3.53(br-s, 8H,
Piperazine), 3.47–3.21 (m, 2H, –CH2 between thiazolidinone
ring and piperazine), 3.11 (s, 6H, 2CH3), 2.38 (d, J = 1.3 Hz,
3H, Hcu); 13C NMR (DMSO-d6, d, ppm): 173.44 (C=O of
thiazolidinone), 165.21 (C–N–(CH3)2), 162.47 (C=O of cou-
marin), 162.25 (C–O–C), 160.39 (C–N of 1-pyridin-2-yl-
piperazine), 158.51 (C–OH), 156.77 (C–OH), 155.74 (C–O–
C of coumarin), 154.38 (C–CH3 at coumarin), 152.55–106.19
(20C, Ar–C), 67.53 (N–C–S), 65.52, 62.48 (4C-piperazine),
59.47 (–CH2 between thiazolidinone ring and piperazine),
58.42 (CH of thiazolidinone ring), 38.19 (CH3–N–CH3),
22.56 (–CH3 of coumarin); Anal. Calcd for C40H39N9O6S: C,
62.08; H, 5.08; N, 16.29. Found: C, 62.03; H, 5.14; N, 16.34.
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