Synthesis and biological evaluation of some thiazolidinones as antimicrobial agents

Article abstract of DOI:10.1016/j.ejmech.2011.11.041

A novel series of thiazolidinone derivatives namely 4-(4-dimethylamino-6- {4-[5-(4-ethylpiperazin-1-ylmethyl)-4-oxo-2-phenylthiazolidin-3-yl]-phenylamino} -[1,3,5]triazin-2-yloxy)-1-methyl-1H-quinolin-2-one have been synthesized from the key intermediate

Full text of DOI:10.1016/j.ejmech.2011.11.041

European Journal of Medicinal Chemistry 48 (2012) 354e362
Contents lists available at SciVerse ScienceDirect
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journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and biological evaluation of some thiazolidinones
as antimicrobial agents
,
b
Divyesh Patel a, Premlata Kumari a , Navin Patel
*
a Applied Chemistry Department, S.V. National Institute of Technology, Surat 395007, India
b Department of Chemistry, V.N. South Gujarat University, Surat 395007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of thiazolidinone derivatives namely 4-(4-dimethylamino-6-{4-[5-(4-ethylpiperazin-1-
ylmethyl)-4-oxo-2-phenylthiazolidin-3-yl]-phenylamino}-[1,3,5]triazin-2-yloxy)-1-methyl-1H-quinolin-
2-one have been synthesized from the key intermediate 4-[4-(4-aminophenylamino)-6-dimethylamino-
[1,3,5]triazin-2-yloxy]-1-methyl-1H-quinolin-2-one (7). Condensation reaction of compound 7 with
different aldehyde derivatives were performed to obtain Schiff base derivatives, which after cyclization
gave thiazolidinones and finally they were reacted with N-ethylpiperazine to get target compounds. The
newly synthesized compounds were evaluated for their antimicrobial activity against eight bacterial
strains (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneu-
moniae, Salmonella typhi, Proteus vulgaris, Shigella flexneri) and four fungal strains (Aspergillus niger,
Candida albicans, Aspergillus fumigatus, Aspergillus clavatus).
Received 23 June 2011
Received in revised form
25 November 2011
Accepted 28 November 2011
Available online 7 December 2011
Keywords:
Thiazolidinones
Antibacterial activity
Antifungal activity
Structureeactivity relationship
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
applications of 1,3,5-triazines and quinolones, the intermediate
compound 7 seems to be a good candidate to fulfill our objective via
The increasing incidence of infection caused by the rapid
development of microbial resistance to most of the known antibi-
otics is a serious health problem. There are number of factors
responsible for mutations in the microbial genomes. As multidrug
resistant microbial strains proliferate, the necessity for effective
therapy has stimulated research on the synthesis of novel antimi-
crobial molecules [1].
The advent of 1,3,5-triazines, associated with diverse biological
activities such as antimicrobial [2,3], antiprotozoal [4], anticancer
[5], antimalarial [6] and antiviral [7] activity accelerated the rate of
progress of 1,3,5-triazine derivatives. Thiazolidinones are an
important class of heterocyclic compounds known for their
potential pharmaceutical applications [8]. In the development of an
efficient procedure for the synthesis of some new thiazolidinone
derivatives, we reported herein synthesis of key intermediate 4-[4-
(4-aminophenylamino)-6-dimethylamino-[1,3,5]triazin-2-yloxy]-
1-methyl-1H-quinolin-2-one (7) which contain quinolone deriva-
tive. Quinolone derivatives are used as anticancer [9], anti-HIV [10],
antitumor [11], antioxidant, anti-inflammatory [12] and anti-
thyroid agents [13]. On account of the prominent biological
its condensation with different aldehydes to afford Schiff base and
further cyclization to get thiazolidinones. Piperazines and
substituted piperazines are important family of heterocyclic
compounds as they have attracted significant interest in medicinal
chemistry [14e16]. Literature survey ascribes that Mannich reac-
tion for thiazolidinone derivatives are important and these types of
derivatives possess significant biological activities [17]. In view of
these conceptions, we reported the synthesis of thiazolidinone
derivatives attached with N-ethylpiperazine. All the novel deriva-
tives were screened for their antimicrobial activity and their results
are discussed.
2. Chemistry
The synthetic strategy adopted to obtain the target compounds
is depicted in Scheme 1. 2,4,6-Trichloro-[1,3,5]triazine (1) on
reaction with dimethylamine (2) at 0e5 ꢀC yielded (4,6-dichloro-
[1,3,5]triazin-2-yl)-dimethylamine (3). Further on reaction with 4-
hydroxy-N-methylquinolone
(4)
yielded
4-(4-chloro-6-
dimethylamino-[1,3,5]triazin-2-yloxy)-1-methyl-1H-quinolin-2-
one (5). The key intermediate 4-[4-(4-aminophenylamino)-6-
dimethylamino-[1,3,5]triazin-2-yloxy]-1-methyl-1H-quinolin-2-
one (7) was prepared in an excellent yield by condensation of
compound 5 with p-phenylenediamine (6). Compound 7 when
* Corresponding author. Tel.: þ91 9904003863.
E-mail address: premlatakumari1@gmail.com (P. Kumari).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.11.041

D. Patel et al. / European Journal of Medicinal Chemistry 48 (2012) 354e362
355
Scheme 1. Synthesis approach.

356
D. Patel et al. / European Journal of Medicinal Chemistry 48 (2012) 354e362
Table 1
7'
8'
9'
7
6
H3C
CH3
In vitro (gram-positive) antibacterial activity of newly synthesized compounds.
N
8
5
m
g/mL)a
Ar
2'
Compound (100
m
g/disc)
Zone of inhibition in mm (MIC in
Gram-positive
14"
10"
13"
12'
14'
2"
1'
N
N
3'
11'
10
4
9
CH2
3"
4"
S
10'
N
13
9"
8"
1"
H3C
N
NH
11"
O
N
4'
6'
11
13'
1
16'
15'
S. aureus
B. cereus
16 (100)
19 (12.5)
17 (12.5)
24 (50)
N
N
CH3
12"
5'
5"
15"
2
3
7"
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
12q
12r
14 (100)
25 (6.25)
15 (25)
O
O
6"
12
26 (50)
Fig. 1. General structure and numeration of thiazolidinone derivatives 12aer.
27 (6.25)
20 (12.5)
26 (6.25)
22 (50)
28 (6.25)
23 (6.25)
28 (6.25)
22 (50)
treated with aromatic aldehydes (aer) gave the corresponding
hydrazones 8aer. Cyclization of hydrazones with mercaptoacetic
acid (9) led to the formation of thiazolidinones 10aer. Finally the
target compounds 12aer were prepared by the reaction of 10aer
with a mixture of paraformaldehyde and N-ethylpiperazine (11) in
absolute ethanol (Fig. 1).
13 (100)
23 (25)
17 (50)
20 (50)
15 (100)
<10 (100)
21 (100)
26 (25)
28 (6.25)
23 (25)
15 (100)
<10 (100)
30 (1.0)
e
18 (100)
13 (100)
21 (50)
23 (12.5)
27 (6.25)
24 (12.5)
17 (100)
12 (100)
31 (1.0)
e
3. Result and discussion
The structures of the synthesized compounds were confirmed
by spectral data and elemental analysis and they were in full
agreement with the proposed structures. A C3N3 stretching in the s-
triazine ring was observed at 825e840 cmꢁ1 in IR spectrum. The
formation of compound 3 was confirmed by the appearance of
a singlet signal at
formation of compound 5 bearing quinolone moiety was confirmed
by 1H NMR spectra which indicate signal at
3.55 ppm for eCH3 of
Ciprofloxacin (100 mg/disc)
DMSO
a
Each value is the mean of three independent experiments.
d
3.10 ppm due to eCH3 in 1H NMR spectra. The
their minimum inhibitory concentration (MIC) values were
summarized in Tables 1 and 2. A close investigation of the MIC
values indicates that all the compounds exhibited a varied range
d
quinolone. Protons corresponding to the quinolone moiety reso-
nated at 6.05e8.31 ppm, in which doublet of doublet signal was
observed at 8.31 ppm due to C-5 proton of quinoline ring of
compound 5. Furthermore, in the IR spectra, the band at 1666 cmꢁ1
(C]O of quinolone) also confirmed the formation of compound 5.
Moreover, a characteristic band appeared at 1256 cmꢁ1 corre-
sponded to the CeOeC linkage, while disappearance of the eOH
peak at 3600e3650 cmꢁ1, belonging to the 4-hydroxy-N-methyl-
quinolone, gave correction to the formation of intermediate
compound 5.
(6.25e100 mg/mL) of antibacterial activity against all the tested
bacterial strains. Compound 12a without any substituent at ortho,
meta and para position of the phenyl group on thiazolidinone ring
showed MIC ¼ 100
strains, also depicted MIC ¼ 25
MIC ¼ 100 g/mL against all other gram-negative bacterial strains.
mg/mL against studied gram-positive bacterial
mg/mL against Escherichia coli and
m
In case of compounds 12b and 12c, which were having electron
withdrawing chloro substituent, respectively at the orthoepara for
compound 12b and metaepara for compound 12c position of
phenyl ring attached at thiazolidinone ring shows effective inhib-
itory effect against all bacterial strains. Compound 12b exhibited
The formation of key intermediate compound 7 was supported
by the appearance of singlet signals at
d
d
11.48 ppm for eNH2 and
equipotent
Staphylococcus aureus along with compounds 12e, 12g and 12o.
g/
mL with 12n with slight reduced inhibition zone (26 mm) against
Shigella flexneri. Compound 12d which has electron donating
methyl group on para position of phenyl ring showed good ability
in
terms
of
MIC ¼ 6.25
m
g/mL
against
9.73 ppm for eNH in 1H NMR spectrum and IR spectrum for NH
and NH2 at 3370 and 3480 cmꢁ1 respectively also confirmed the
formation of compound 7. Absence of a CeCl stretching band at
700e760 cmꢁ1 in the IR spectra confirmed the formation of
compound 7 by condensation of p-phenylenediamine with s-
triazine ring. Compound 7 when treated with aromatic aldehydes
gave the corresponding hydrazones 8aer. For example when
compound 7 treated with benzaldehyde (a) gave compound 8a
which did not show signals for NH2 but showed the presence of
Same compound 12b found equipotent in terms of MIC ¼ 6.25
m
(MIC ¼ 50
m
g/mL) to inhibit S. aureus and Bacillus cereus. The best
activity for compound 12d (MIC ¼ 6.25
mg/mL) was observed
against Pseudomonas aeruginosa and Proteus vulgaris among all the
synthesized compounds. Compounds 12e, 12f and 12g, which were
having electron withdrawing fluoro and chloro substituents on
phenyl ring attached to thiazolidinone moiety exerted significant
a signal at
d 7.58 ppm for one proton of N]CHePh. The signal
observed at 9.77 ppm in the 1H NMR spectra of compound 8a was
attributed to eNH group. The 1H NMR spectra of compound 10a
activity with MIC value in the range of 6.25e50
the tested bacterial strains. Compounds 12e and 12g showed the
g/mL
mg/mL against all
showed the presence of doublet signals at
d 3.66, 3.76 ppm for two
protons of SeCH2 and singlet at 5.12 ppm for SeCHeN, which
d
highest zone of inhibition 28 mm with excellent MIC ¼ 6.25
m
confirm the formation of the thiazolidinone ring. Compound 10a
showed a characteristic absorption for the cyclic carbonyl group at
1722 cmꢁ1 in the IR spectra. The 1H NMR spectra of compounds
12aer showed the absence of doublet signal for eCH2 of thiazoli-
dinone ring and showed the signal for methylene (4CH2) of N-
ethylpiperazine. The newly obtained derivatives were evaluated for
their in vitro antimicrobial activity against different types of
bacterial strains and fungal strains and the results are summarized
in Tables 1e3.
against B. cereus along with compound 12f with reduced inhibition
zone (23 mm). Compound 12e exhibited the greatest activity
against E. coli and Salmonella typhi at MIC ¼ 6.25
mg/mL. Besides,
compound 12f was found to have inhibitory effect with the same
MIC value against E. coli and S. typhi with slight reduced in inhib-
itory zones (23 mm and 24 mm respectively). Compound 12g found
to be superior in inhibiting the growth (26 mm of zone of inhibi-
tion) of Klebsiella pneumoniae (MIC ¼ 6.25
12h and 12i, with eNO2 group substituted at phenyl ring on para
and ortho position respectively exhibit similar MIC ¼ 50 g/mL
against B. cereus and MIC ¼ 100 g/mL against E. coli, P. aeruginosa
mg/mL). Thiazolidinones
The antibacterial potency of the synthesized compounds was
compared with broad spectrum antibiotic namely ciprofloxacin and
m
m

D. Patel et al. / European Journal of Medicinal Chemistry 48 (2012) 354e362
357
Table 2
In vitro (gram-negative) antibacterial activity of newly synthesized compounds.
Compound (100
m
g/disc)
Zone of inhibition in mm (MIC in
Gram-negative
m
g/mL)a
E. coli
22 (25)
24 (12.5)
17 (25)
P. aeruginosa
K. pneumoniae
S. typhi
P. vulgaris
S. flexneri
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
12q
12r
13 (100)
21 (25)
23 (25)
26 (6.25)
25 (12.5)
20 (50)
23 (50)
18 (100)
16 (100)
14 (100)
16 (100)
14 (100)
13 (100)
22 (25)
25 (12.5)
24 (12.5)
17 (100)
11 (100)
33 (1.0)
e
<10 (100)
23 (25)
19 (12.5)
24 (50)
25 (25)
22 (25)
26 (6.25)
23 (50)
15 (100)
19 (50)
19 (100)
12 (100)
16 (50)
26 (12.5)
25 (25)
23 (50)
16 (100)
16 (100)
33 (1.0)
e
16 (50)
15 (50)
12 (50)
23 (50)
27 (6.25)
24 (6.25)
20 (50)
22 (100)
15 (100)
17 (50)
17 (100)
12 (100)
13 (100)
22 (50)
26 (6.25)
25 (25)
14 (100)
14 (100)
30 (1.0)
e
15 (100)
20 (12.5)
19 (25)
27 (6.25)
22 (25)
19 (50)
25 (25)
25 (50)
17 (100)
16 (100)
17 (100)
15 (100)
12 (100)
25 (12.5)
21 (50)
23 (50)
14 (100)
13 (100)
31 (1.0)
e
12 (100)
26 (6.25)
22 (12.5)
24 (50)
24 (25)
28 (6.25)
23 (6.25)
27 (12.5)
24 (100)
14 (100)
16 (50)
19 (100)
<10 (100)
18 (50)
27 (6.25)
27 (6.25)
24 (25)
15 (100)
<10 (100)
32 (1.0)
e
19 (25)
25 (12.5)
26 (12.5)
22 (50)
14 (100)
13 (100)
15 (100)
11 (100)
15 (100)
27 (6.25)
26 (6.25)
22 (50)
16 (100)
<10 (100)
32 (ꢂ3)
e
Ciprofloxacin (100 mg/disc)
DMSO
a
Each value is the mean of three independent experiments.
and S. typhi. Compound 12h having para substituted eNO2 group
on phenyl ring depicted higher zone of inhibition against all the
bacterial strains as compared to 12i. Compound 12j, with eOH
group on phenyl ring at para position displayed better activity in
terms of MIC and zone of inhibition as well against both gram-
positive bacteria compared to compounds 12q and 12r, possess-
ing dihydroxy substituent at phenyl ring. Compounds 12q and 12r
MIC ¼ 6.25
with similar efficacy of compounds 12e and 12f in terms of
MIC ¼ 6.25 g/mL against the same bacterial strains. Same
g/mL with
27 mm and 26 mm zone of inhibition respectively, which were
found most potent among all the synthesized compounds against
S. flexneri. Compound 12o was also found equipotent as 12e and 12f
in terms of MIC with 26 mm diameter of inhibition zone against
S. typhi. Compound 12o exhibited the greatest activity against
mg/mL (27 mm zone of inhibition) against E. coli along
m
compounds, 12n and 12o showed similar MIC ¼ 6.25
m
showed weak inhibitory activity at 100 mg/mL of MIC against all
bacterial strains. In addition, a close survey of inhibition zones of
compound 12q against E. coli, P. aeruginosa and S. flexneri were
found higher than compound 12r. Antibacterial activity of electron
withdrawing bromo substituted compounds 12k and 12i showed
S. aureus at 6.25 mg/mL of MIC. Besides, two compounds 12e and
12g were found to have inhibitory effect with the same MIC value
against S. aureus with slight reduced inhibitory zones (27 mm and
26 mm respectively). Compound 12p also showed effective action
against all bacterial strains in terms of MIC in the range of
lesser activity in terms of MIC ¼ 100
mg/mL compared to fluoro and
chloro substituted compounds 12e, 12f and 12g. Strong inhibitory
effect was shown by final derivatives 12n and 12o with
12.5e50 mg/mL.
The in vitro antifungal activities of compounds 12aer were
studied against the fungal strains viz., Aspergillus niger,
Aspergillus fumigatus, Aspergillus clavatus and Candida albicans.
Ketoconazole was used as a standard drug. The data of antifungal
Table 3
In vitro antifungal activity of newly synthesized compounds.
Compound(100
m
g/disc)
Zone of inhibition in mm (MIC in
A. niger A. fumigatus A. clavatus C. albicans
12 (100) <10 (100)
m
g/mL)a
tests are depicted in Table 3. A close survey of the MIC in
values indicates that all the compounds 12aer exhibited a varied
g/mL) of antifungal activity against all the
mg/mL
range (MIC ¼ 6.25e100
m
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
12q
12r
<10 (100)
25 (12.5)
19 (50)
14 (100)
28 (12.5)
23 (25)
28 (6.25)
21 (25)
17 (25)
16 (50)
tested fungal strains. Compound 12a which has no substituent at
ortho, meta and para position of the phenyl ring to thiazolidinone
21 (100)
26 (12.5)
25 (12.5)
26 (25)
24 (50)
28 (12.5)
24 (50)
26 (12.5)
20 (100)
13 (100)
21 (50)
26 (25)
25 (25)
24 (50)
23 (12.5)
21 (100)
15 (100)
21 (100)
16 (100)
23 (50)
25 (25)
25 (25)
27 (12.5)
17 (100)
19 (100)
19 (100)
12 (100)
ring showed MIC ¼ 100
mg/mL against all fungal strains. Compound
12b which has electron withdrawing chloro substituent at the ortho
and para position of phenyl ring exerted excellent activity against
23 (50)
A. niger at MIC ¼ 6.25
significant inhibition was also observed toward A. clavatus and
C. albicans at 12.5 g/mL of MIC with 25 mm and 28 mm inhibitory
zones respectively. Similar minimum inhibitory concentration level
g/mL) observed against the same fungi for
mg/mL with 28 mm of zone of inhibition. A
<10 (100)
18 (100)
14 (100)
m
14 (100)
<10 (100) <10 (100)
13 (100) <10 (100)
15 (100)
27 (25)
25 (12.5)
21 (100)
11 (100)
<10 (100)
30 (ꢂ3)
e
11 (100)
20 (50)
27 (12.5)
26 (25)
15 (100)
13 (100)
29 (1.0)
17 (100)
23 (50)
24 (12.5)
24 (50)
17 (100) <10 (100)
12 (100) <10 (100)
31 (1.0)
17 (100)
25 (100)
26 (12.5)
23 (50)
(MIC ¼ 12.5
m
compounds 12g and 12o with slightly reduced inhibition zone.
Compound 12e having electron withdrawing fluoro substituent at
para position of phenyl ring exerted activity in the range of
MIC ¼ 12.5e25
m
g/mL against all fungi. Compound 12e exhibited
Ketoconazole (100
DMSO
mg/disc)
33 (1.0)
the greatest activity against A. fumigatus at 12.5
mg/mL of MIC.
e
e
e
Besides, two compounds 12g and 12o were found to have same MIC
value against A. fumigatus with marginally reduced inhibitory
a
Each value is the mean of three independent experiments.

358
D. Patel et al. / European Journal of Medicinal Chemistry 48 (2012) 354e362
zones (26 mm and 27 mm respectively). Compound 12e and 12f
g/mL against A. niger. Compound 12o, which
were having electron donating methyl substituent at para position
of phenyl ring attached to thiazolidinone moiety shows admirable
antifungal activity against all the tested fungal strains at
above process a very minor di-substituted 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%. M.p. 126e128 ꢀC; IR (KBr, cmꢁ1): 806 (s-triazine, CeN
showed MIC ¼ 12.5
m
str.); 1H NMR (DMSO-d6): 3.10 (s, 6H, 2CH3); 13C NMR (DMSO-d6):
d
MIC ¼ 12.5
m
g/mL with significant inhibitory zone in the range of
d
166.97, 163.41 (2C, AreC), 37.44 (C-70, C-80). Anal. Calcd for
C5H6Cl2N4: C, 31.11; H, 3.13; N, 29.02%. Found: C, 31.17; H, 3.06; N,
29.06%.
24ee27 mm against all the fungal strains. All the remaining final
thiazolidinone derivatives exerted good to moderate activity.
4. Conclusion
5.2. Synthesis of 4-(4-chloro-6-dimethylamino-[1,3,5]triazin-2-
yloxy)-1-methyl-1H-quinolin-2-one (5)
From the antimicrobial study we ascertained that some of the
newly synthesized compound containing electron withdrawing
group like chloro, fluoro as substituent on phenyl ring at thiazoli-
dinone moiety 12b, 12e, 12f, and 12g showed significant activity
against both the gram-positive as well as gram-negative bacteria.
On the other hand, compound 12o having electron donating group
methoxy as substituent on phenyl ring also showed good activity
against both bacterial strains (gram-positive and gram-negative).
Antifungal screening was carried out on A. niger, A. fumigatus,
A. clavatus and C. albicans. Among the tested compounds 12b
To a stirred solution of 4-hydroxy-N-methylquinolone 4 (13.0 g,
0.074 mol) and 60% NaH (1.78 g, 0.074 mol) in anhydrous THF
(150 mL), compound 3 (14.28 g, 0.074 mol) was added into the
reaction mixture and first it was stirred for 1 h at room temperature
and then it was continued for another 14 h at 45e50 ꢀC. After
completion of the reaction, it was treated with crushed ice, filtered,
dried and recrystallized from acetone to afford compound 5. Yield:
20.59 g, 84%. M.p. 210e215 ꢀC; IR (KBr, cmꢁ1): 1666 (C]O of qui-
nolone), 1256 (CeOeC), 806 (s-triazine, CeN str.); 1H NMR (DMSO-
showed the highest inhibition against A. niger at 6.25
m
g/mL,
d6):
quinolone), 6.05 (s, 1H, H-3), 3.55 (s, 3H, H-11), 3.10 (s, 6H, 2CH3);
13C NMR (DMSO-d6): 170.96 (CeCl), 170.15 (C-60), 165.51 (C-20),
161.12 (C-2), 151.69 (C-4), 141.20, 131.97, 123.14, 122.52, 116.77,
115.84, 96.10 (7C, AreC), 37.15 (C-70, C-80), 32.66 (C-11). Anal. Calcd
for C15H14ClN5O2: C, 54.30; H, 4.25; N, 21.11%. Found: C, 54.22; H,
4.29; N, 21.05%.
d
8.31 (dd, J ¼ 7.4, 1.6 Hz, H-5), 8.05e7.61 (m, 3H, AreH of
A. clavatus and C. albicans at 12.5 g/mL respectively. Compounds
m
12e and 12o depicted significant activity against A. fumigatus
among all synthesized derivatives. The antimicrobial study of the
synthesized compounds permitted us to state that the variation of
antimicrobial activity may be associated with the nature of tested
bacterial and fungal strains and the substituent on phenyl ring at
thiazolidinone moiety. The results unfold the way for investigation
of new potential lead compounds for investigating antimicrobial
activity.
d
5.3. Synthesis of 4-[4-(4-aminophenylamino)-6-dimethylamino-
[1,3,5]triazin-2-yloxy]-1-methyl-1H-quinolin-2-one (7)
5. Experimental
To a solution of compound 5 (15.0 g, 0.045 mol) in 1,4-dioxane
(150 mL), p-phenylenediamine (4.88 g, 0.045 mol) was added and
the reaction mixture was refluxed for 10e15 h as per TLC moni-
toring. 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 precipitate thus
obtained was filtered and dried. During the reaction dimer
compound was formed along with compound 7, so it was treated by
column chromatography using n-hexane:ethyl acetate as eluent
system to obtained pure compound 7. Yield: 14.52 g, 80%. M.p.
198e203 ꢀC; IR (KBr, cmꢁ1): 3370 (eNH), 3480 (eNH2), 1666 (C]O
of quinolone), 806 (s-triazine, CeN str.); 1H NMR (DMSO-d6):
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 appa-
ratus VMP-D (Veego Instrument Corporation, Mumbai, India) and
are uncorrected. IR spectra (4000e400 cmꢁ1
) of synthesized
compounds were recorded on a Shimadzu 8400-S FT-IR spectro-
photometer (Shimadzu India Pvt. Ltd., Mumbai, India) using KBr
pellets. Thin layer chromatography was performed on object glass
slides (2 ꢃ 7.5 cm) coated with silica gel-G and spots were visual-
ized 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 solvent and TMS as
internal standard with 1H resonant frequency 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).
d
11.48 (s, 2H, eNH2), 9.73 (s, 1H, eNH), 8.35 (dd, 1H, J ¼ 7.6, 1.5 Hz,
H-5), 8.02e7.52 (m, 3H, AreH of quinolone), 7.27e6.80 (m, 4H,
AreH), 6.02 (s, 1H, H-3), 3.47 (s, 3H, H-11), 3.13 (s, 6H, 2CH3); 13C
NMR (DMSO-d6): 167.10 (C-60), 163.98 (C-40), 164.15 (C-20), 161.42
(C-2), 152.69 (C-4), 139.90, 138.49, 138.41, 132.77, 127.56, 127.44,
123.67, 123.53, 122.96, 122.69, 116.75, 115.68, 97.14 (13C, AreC),
37.19 (C-70, C-80), 32.71 (C-11). Anal. Calcd for C21H21N7O2: C, 62.52;
H, 5.25; N, 24.30%. Found: C, 62.46; H, 5.29; N, 24.36%.
5.4. General procedure for the synthesis of Schiff bases 8aer
5.1. Synthesis of (4,6-dichloro-[1,3,5]triazin-2-yl)-dimethylamine (3)
To a solution of compound 7 (2.0 g; 0.0049 mol) in absolute
ethanol (50 mL), containing a catalytic amount of piperidine,
equimolecular amount of the appropriate aldehydes (for e.g.
benzaldehyde (a) e 0.52 g; 0.0049 mol) was added. The reaction
mixture was refluxed for 5e6 h. It was then cooled at room
temperature, poured into crushed ice, filtered, washed, dried and
recrystallized from DMF to yield 4-{4-[4-(benzylidene-amino)-
phenylamino]-6-dimethylamino-[1,3,5]triazin-2-yloxy}-1-methyl-
1H-quinolin-2-one (8a). Yield: 1.75 g, 73%. M.p. 219e223 ꢀC; IR
(KBr, cmꢁ1): 3366 (eNH), 1666 (C]O of quinolone), 806 (s-triazine,
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), dimethylamine 2 (4.89 g,
0.10 mol) was added very slowly drop wise at 0e5 ꢀC. The resulting
reaction mixture was stirred at this temperature for 2 h, then
triethyl amine (10.97 g, 0.10 mol) was added subsequently into the
reaction mixture and stirring was continued for another 4 h. The
resulted reaction mixture was then treated with crushed ice, fol-
lowed by neutralization by dilute HCl and then filtered, dried. In

D. Patel et al. / European Journal of Medicinal Chemistry 48 (2012) 354e362
359
CeN str.); 1H NMR (DMSO-d6):
d
9.77 (s, 1H, eNH), 8.29 (dd, 1H,
1H, eNH), 8.46 (dd, 1H, J ¼ 7.5, 1.4 Hz, H-5), 8.10e7.64 (m, 3H, qui-
nolone), 7.36e6.83 (m, 9H, AreH), 6.11 (s, 1H, H-3), 5.17 (s, 1H, H-
200), 3.56 (br s, 8H, piperazine), 3.38 (s, 3H, H-11), 3.35 (t, J ¼ 7.3 Hz,
H-400), 3.21e3.14 (m, 2H, H-700), 3.07 (s, 6H, 2CH3), 2.39 (q, J ¼ 6.3 Hz,
2H, H-1400), 1.22 (t, J ¼ 6.6 Hz, 3H, H-1500); 13C NMR (DMSO-d6):
173.33 (C-500), 168.42 (C-60), 166.29 (C-40), 164.85 (C-20), 161.79 (C-
2), 152.15 (C-4), 141.22e96.56 (19C, AreC), 67.15 (C-200), 62.78, 59.21
(4C, piperazine), 57.74 (C-700), 54.33 (C-400), 51.40 (C-1400), 36.69 (C-
70, C-80), 32.50 (C-11), 13.55 (C-1500). Anal. Calcd for C37H41N9O3S: C,
64.23; H, 5.97; N, 18.22%. Found: C, 64.27; H, 5.91; N, 18.16%.
J ¼ 7.1, 1.6 Hz, H-5), 7.58 (s, 1H, N]CHePh), 8.10e7.65 (m, 3H, AreH
of quinolone), 6.79e7.41 (m, 9H, AreH), 6.07 (s, 1H, H-3), 3.44 (s,
13
3H, H-11), 3.09 (s, 6H, 2CH3); C NMR (DMSO-d6): 169.17 (C-60),
165.62 (C-40), 164.75 (C-20), 161.47 (C-2), 152.73 (C-4), 141.12 (C]N
of Schiff base), 139.45, 138.63, 138.57, 131.77, 128.90, 128.87, 128.25,
128.31, 127.79, 127.62, 127.33, 127.39, 123.90, 123.39, 123.20, 122.72,
115.90, 115.33, 96.87 (19C, AreC), 37.16 (C-70, C-80), 32.65 (C-11).
Anal. Calcd for C28H25N7O2: C, 68.42; H, 5.13; N, 19.95%. Found: C,
68.37; H, 5.16; N, 19.86%. Other Schiff bases 8ber were obtained in
similar manner.
5.7.2. 4-(4-{4-[2-(2,4-Dichlorophenyl)-5-(4-ethylpiperazin-1-
ylmethyl)-4-oxothiazolidin-3-yl]-phenylamino}-6-dimethylamino-
[1,3,5]triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12b)
5.5. General procedure for the synthesis of thiazolidinones 10aer
A mixture of compound 8a (1.0 g; 0.002 mol) and thioglycolic
acid (0.36 g; 0.004 mol) in dry benzene (40 mL) was refluxed for
6 h. Water formed during the reaction was removed azeotropically
by DeaneStark 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 puri-
fied by crystallization from methanol to get 4-{4-dimethylamino-6-
[4-(4-oxo-2-phenylthiazolidin-3-yl)-phenylamino]-[1,3,5]triazin-
2-yloxy}-1-methyl-1H-quinolin-2-one (10a). Yield: 69%. M.p.
256e261 ꢀC; IR (KBr, cmꢁ1): 3366 (eNH), 1722 (C]O of thiazoli-
dinone), 1667 (C]O of quinolone), 807 (s-triazine, CeN str.); 1H
Recrystallization from DMF. Yield: 71%. M.p. 235e239 ꢀC; IR
(KBr, cmꢁ1): 3361 (eNH), 1719 (C]O of thiazolidinone), 1664 (C]O
of quinolone), 807 (s-triazine, CeN str.), 784 (eCl); 1H NMR (DMSO-
d6):
d
9.76 (s, 1H, eNH), 8.42 (dd, 1H, J ¼ 7.4, 1.5 Hz, H-5), 8.12e7.56
(m, 3H, quinolone), 7.41e6.83 (m, 7H, AreH), 6.15 (s, 1H, H-3), 5.14
(s, 1H, H-200), 3.58 (br s, 8H, piperazine), 3.41 (s, 3H, H-11), 3.32 (t,
J ¼ 7.5 Hz, H-400), 3.24e3.11 (m, 2H, H-700), 3.04 (s, 6H, 2CH3), 2.33 (q,
J ¼ 6.4 Hz, 2H, H-1400), 1.08 (t, J ¼ 6.2 Hz, 3H, H-1500); 13C NMR
(DMSO-d6): 172.20 (C-500), 168.33 (C-60), 166.14 (C-40), 164.75 (C-20),
162.14 (C-2), 151.83 (C-4), 134.60 (CeCl), 133.42 (CeCl),
141.16e96.41 (17C, AreC), 66.22 (C-200), 64.19, 60.55 (4C, pipera-
zine), 57.69 (C-700), 54.41 (C-400), 51.33 (C-1400), 36.89 (C-70, C-80),
32.60 (C-11), 13.67 (C-1500). Anal. Calcd for C37H39Cl2N9O3S: C,
58.42; H, 5.17; N, 16.57%. Found: C, 58.36; H, 5.21; N, 16.51%.
NMR (DMSO-d6):
d
9.69 (s, 1H, eNH), 8.32 (dd, 1H, J ¼ 7.6, 1.5 Hz, H-
5), 8.06e7.77 (m, 3H, AreH of quinolone), 6.83e7.37 (m, 9H, AreH),
6.10 (s, 1H, H-3), 5.12 (s, 1H, H-200), 3.76 (d, J ¼ 12.1 Hz, 1H), 3.66 (d,
J ¼ 12.1 Hz, 1H), 3.41 (s, 3H, H-11), 3.04 (s, 6H, 2CH3); 13C NMR
(DMSO-d6): 170.95 (C-500), 169.23 (C-60), 166.10 (C-40), 164.71 (C-20),
161.59 (C-2), 151.97 (C-4), 140.12, 138.72, 138.62, 131.62, 128.83,
128.90, 128.11, 128.05, 127.56, 127.45, 126.98, 126.77, 123.86, 123.48,
123.35, 121.90, 115.79, 115.15, 98.29 (19C, AreC), 68.19 (C-200), 37.10
(C-70, C-80), 33.94 (eCH2 of thiazolidinone), 32.57 (C-11). Anal. Calcd
for C30H27N7O3S: C, 63.70; H, 4.81; N, 17.33%. Found: C, 63.65; H,
4.86; N, 17.37%. Similarly, other compounds 10ber have been
synthesized.
5.7.3. 4-(4-{4-[2-(3,4-Dichlorophenyl)-5-(4-ethylpiperazin-1-
ylmethyl)-4-oxothiazolidin-3-yl]-phenylamino}-6-dimethylamino-
[1,3,5]triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12c)
Recrystallization from DMF. Yield: 65%. M.p. 256e259 ꢀC; IR
(KBr, cmꢁ1): 3363 (eNH), 1714 (C]O of thiazolidinone), 1667 (C]O
of quinolone), 807 (s-triazine, CeN str.), 791 (eCl); 1H NMR (DMSO-
d6):
d
9.80 (s, 1H, eNH), 8.45 (dd, 1H, J ¼ 7.6, 1.3 Hz, H-5), 8.07e7.66
(m, 3H, quinolone), 7.31e6.87 (m, 7H, AreH), 6.19 (s, 1H, H-3), 5.10
(s, 1H, H-200), 3.56 (br s, 8H, piperazine), 3.36 (s, 3H, H-11), 3.19 (t,
J ¼ 7.3 Hz, H-400), 3.17e3.03 (m, 2H, H-700), 3.08 (s, 6H, 2CH3), 2.40 (q,
J ¼ 6.3 Hz, 2H, H-1400), 1.11 (t, J ¼ 6.5 Hz, 3H, H-1500); 13C NMR
(DMSO-d6): 171.69 (C-500), 167.47 (C-60), 165.35 (C-40), 164.56 (C-20),
161.92 (C-2), 152.14 (C-4), 135.06 (CeCl), 133.19 (CeCl),
142.22e97.10 (17C, AreC), 67.31 (C-200), 62.73, 58.61 (4C, pipera-
zine), 57.49 (C-700), 55.62 (C-400), 51.39 (C-1400), 36.77 (C-70, C-80),
32.30 (C-11), 12.89 (C-1500). Anal. Calcd for C37H39Cl2N9O3S: C,
58.42; H, 5.17; N, 16.57%. Found: C, 58.38; H, 5.23; N, 16.49%.
5.6. General procedure for the synthesis of target compounds
12aer
A mixture of paraformaldehyde (0.21 g; 0.002 mol) and N-eth-
ylpiperazine (0.5 g; 0.0043 mol) was taken in 25 mL of absolute
ethanol and it was refluxed for 30 min. So, the solubility of para-
formaldehyde achieved. Then warmed solution of compound 10a
(4.86 g, 0.0086 mol) in 30 mL of ethanol was subsequently added to
the reaction mixture. The whole reaction mixture was refluxed for
10e12 h and left at room temperature under stirring for three days
and after that the volatile material was evaporated. The dry residue
was extracted with DMF to form 4-(4-dimethylamino-6-{4-[5-(4-
ethylpiperazin-1-ylmethyl)-4-oxo-2-phenylthiazolidin-3-yl]-phe-
nylamino}-[1,3,5]triazin-2-yloxy)-1-methyl-1H-quinolin-2-one
(12a). Similarly, other final compounds have been synthesized.
5.7.4. 4-(4-Dimethylamino-6-{4-[5-(4-ethylpiperazin-1-ylmethyl)-
4-oxo-2-p-tolylthiazolidin-3-yl]-phenylamino}-[1,3,5]triazin-2-
yloxy)-1-methyl-1H-quinolin-2-one (12d)
Recrystallization from THF. Yield: 62%. M.p. 223e228 ꢀC; IR (KBr,
cmꢁ1): 3359 (eNH), 1722 (C]O of thiazolidinone), 1666 (C]O of
quinolone), 1446 (eCH3), 807 (s-triazine, CeN str.); 1H NMR
(DMSO-d6):
d
9.77 (s, 1H, eNH), 8.31 (dd, 1H, J ¼ 7.1, 1.6 Hz, H-5),
8.16e7.67 (m, 3H, quinolone), 7.39e6.78 (m, 8H, AreH), 6.11 (s, 1H,
H-3), 5.09 (s,1H, H-200), 3.56 (br s, 8H, piperazine), 3.37 (s, 3H, H-11),
3.35 (t, J ¼ 7.2 Hz, H-400), 3.19e3.13 (m, 2H, H-700), 3.07 (s, 6H, 2CH3),
2.38 (q, J ¼ 6.6 Hz, 2H, H-1400), 2.21 (s, 3H, CH3 at phenyl), 1.34 (t,
5.7. Characterization data of synthesized compounds 12aer
13
J ¼ 6.3 Hz, 3H, H-1500); C NMR (DMSO-d6): 171.32 (C-500), 169.03
5.7.1. 4-(4-Dimethylamino-6-{4-[5-(4-ethylpiperazin-1-ylmethyl)-
4-oxo-2-phenylthiazolidin-3-yl]-phenylamino}-[1,3,5]triazin-2-
yloxy)-1-methyl-1H-quinolin-2-one (12a)
(C-60), 165.20 (C-40), 164.66 (C-20), 161.19 (C-2), 152.45 (C-4), 138.89
(CeCH3), 141.40e101.24 (18C, AreC), 67.38 (C-200), 62.75, 59.67 (4C,
piperazine), 56.60 (C-700), 55.20 (C-400), 51.23 (C-1400), 36.78 (C-70, C-
80), 32.71 (C-11), 14.36 (CH3 at phenyl), 12.17 (C-1500). Anal. Calcd
for: C38H43N9O3S: C, 64.66; H, 6.14; N, 17.86%. Found: C, 64.61; H,
6.17; N, 17.92%.
Recrystallization from THF. Yield: 68%. M.p. 254e258 ꢀC; IR (KBr,
cmꢁ1): 3363 (eNH), 1724 (C]O of thiazolidinone), 1664 (C]O of
quinolone), 806 (s-triazine, CeN str.); 1H NMR (DMSO-d6):
d 9.72 (s,

360
D. Patel et al. / European Journal of Medicinal Chemistry 48 (2012) 354e362
5.7.5. 4-(4-Dimethylamino-6-{4-[5-(4-ethylpiperazin-1-ylmethyl)-
2-(4-fluorophenyl)-4-oxothiazolidin-3-yl]-phenylamino}-[1,3,5]
triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12e)
3.10 (s, 6H, 2CH3), 2.34 (q, J ¼ 6.4 Hz, 2H, H-1400), 1.05 (t, J ¼ 6.6 Hz,
13
3H, H-1500); C NMR (DMSO-d6): 171.24 (C-500), 169.33 (C-60),
165.89 (C-40), 165.19 (C-20), 162.28 (C-2), 151.47 (C-4), 148.52
(CeNO2), 145.02e101.67 (18C, AreC), 66.58 (C-200), 63.80, 59.21
(4C, piperazine), 58.70 (C-700), 55.24 (C-400), 50.17 (C-1400), 36.79
(C-70, C-80), 32.45 (C-11), 12.77 (C-1500). Anal. Calcd for:
Recrystallization from DMF. Yield: 60%. M.p. 239e243 ꢀC; IR
(KBr, cmꢁ1): 3354 (eNH),1724 (C]O of thiazolidinone),1666 (C]O
of quinolone), 1160 (CeF), 806 (s-triazine, CeN str.); 1H NMR
(DMSO-d6):
d
9.68 (s, 1H, eNH), 8.35 (dd, 1H, J ¼ 7.4, 1.4 Hz, H-5),
C37H40N10O5S: C, 60.31; H, 5.47; N, 19.01%. Found: C, 60.36; H,
5.53; N, 19.04%.
8.13e7.60 (m, 3H, quinolone), 7.43e6.85 (m, 8H, AreH), 6.17 (s, 1H,
H-3), 5.12 (s, 1H, H-200), 3.57 (br s, 8H, piperazine), 3.39 (s, 3H, H-11),
3.37 (t, J ¼ 7.6 Hz, H-400), 3.21e3.17 (m, 2H, H-700), 3.03 (s, 6H, 2CH3),
2.29 (q, J ¼ 6.5 Hz, 2H, H-1400), 1.01 (t, J ¼ 6.3 Hz, 3H, H-1500); 13C
NMR (DMSO-d6): 172.11 (C-500), 168.45 (C-60), 167.70 (CeF), 164.88
(C-40), 164.53 (C-20), 160.76 (C-2), 151.43 (C-4), 140.95e101.54 (18C,
AreC), 66.15 (C-200), 63.19, 58.75 (4C, piperazine), 55.89 (C-700),
55.11 (C-400), 50.41 (C-1400), 37.02 (C-70, C-80), 31.86 (C-11), 13.30 (C-
1500). Anal. Calcd for: C37H40FN9O3S: C, 62.61; H, 5.68; N, 17.76%.
Found: C, 62.65; H, 5.62; N, 17.81%.
5.7.9. 4-(4-Dimethylamino-6-{4-[5-(4-ethylpiperazin-1-ylmethyl)-
2-(2-nitrophenyl)-4-oxothiazolidin-3-yl]-phenylamino}-[1,3,5]
triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12i)
Recrystallization from DMF. Yield: 55%. M.p. 272e276 ꢀC; IR
(KBr, cmꢁ1): 3363 (eNH), 1722 (C]O of thiazolidinone), 1667
(C]O of quinolone), 1543 (N]O str.), 807 (s-triazine, CeN str.);
1H NMR (DMSO-d6):
d
9.78 (s, 1H, eNH), 8.50 (dd, 1H, J ¼ 7.2,
1.1 Hz, H-5), 8.13e7.53 (m, 3H, quinolone), 7.38e6.79 (m, 8H,
AreH), 6.21 (s, 1H, H-3), 5.15 (s, 1H, H-200), 3.52 (br s, 8H,
piperazine), 3.49 (s, 3H, H-11), 3.34 (t, J ¼ 7.1 Hz, H-400), 3.29e3.08
(m, 2H, H-700), 3.04 (s, 6H, 2CH3), 2.27 (q, J ¼ 6.3 Hz, 2H, H-1400),
1.18 (t, J ¼ 6.5 Hz, 3H, H-1500); 13C NMR (DMSO-d6): 172.33 (C-500),
168.51 (C-60), 165.83 (C-40), 165.12 (C-20), 162.43 (C-2), 151.65
(C-4), 149.17 (CeNO2), 143.10e101.75 (18C, AreC), 67.19 (C-200),
63.92, 60.41 (4C, piperazine), 57.94 (C-700), 54.21 (C-400), 51.65
(C-1400), 36.69 (C-70, C-80), 32.51 (C-11), 12.89 (C-1500). Anal. Calcd
for: C37H40N10O5S: C, 60.31; H, 5.47; N, 19.01%. Found: C, 60.34;
H, 5.51; N, 19.05%.
5.7.6. 4-(4-Dimethylamino-6-{4-[5-(4-ethylpiperazin-1-ylmethyl)-
2-(3-fluorophenyl)-4-oxothiazolidin-3-yl]-phenylamino}-[1,3,5]
triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12f)
Recrystallization from DMF. Yield: 54%. M.p. 264e269 ꢀC; IR
(KBr, cmꢁ1): 3359 (eNH), 1718 (C]O of thiazolidinone), 1667
(C]O of quinolone), 1164 (CeF), 806 (s-triazine, CeN str.); 1H
NMR (DMSO-d6):
d
9.75 (s, 1H, eNH), 8.29 (dd, 1H, J ¼ 7.3, 1.1 Hz,
H-5), 8.17e7.64 (m, 3H, quinolone), 7.35e6.88 (m, 8H, AreH),
6.23 (s, 1H, H-3), 5.19 (s, 1H, H-200), 3.61 (br s, 8H, piperazine),
3.44 (s, 3H, H-11), 3.25 (t, J ¼ 7.6 Hz, H-400), 3.17e3.11 (m, 2H, H-
700), 3.10 (s, 6H, 2CH3), 2.45 (q, J ¼ 6.4 Hz, 2H, H-1400), 1.03 (t,
J ¼ 6.6 Hz, 3H, H-1500); 13C NMR (DMSO-d6): 174.24 (C-500), 168.09
(CeF), 167.41 (C-60), 165.34 (C-40), 164.51 (C-20), 161.49 (C-2),
152.45 (C-4), 142.29e98.44 (18C, AreC), 66.24 (C-200), 64.83,
60.72 (4C, piperazine), 58.25 (C-700), 56.40 (C-400), 52.43 (C-1400),
36.86 (C-70, C-80), 32.47 (C-11), 12.27 (C-1500). Anal. Calcd for:
5.7.10. 4-(4-Dimethylamino-6-{4-[5-(4-ethylpiperazin-1-ylmethyl)-
2-(4-hydroxyphenyl)-4-oxothiazolidin-3-yl]-phenylamino}-[1,3,5]
triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12j)
Recrystallization from DMF. Yield: 73%. M.p. 247e255 ꢀC; IR
(KBr, cmꢁ1): 3362 (eNH), 3223 (eOH), 1723 (C]O of thiazolidi-
none), 1666 (C]O of quinolone), 806 (s-triazine, CeN str.); 1H
C
37H40FN9O3S: C, 62.61; H, 5.68; N, 17.76%. Found: C, 62.67; H,
NMR (DMSO-d6):
d
9.82 (s, 1H, eNH), 8.36 (dd, 1H, J ¼ 7.4, 1.5 Hz,
5.64; N, 17.80%.
H-5), 8.17e7.64 (m, 3H, quinolone), 7.40e6.88 (m, 8H, AreH), 6.09
(s, 1H, H-3), 5.17 (s, 1H, H-200), 4.63 (s, 1H, eOH), 3.62 (br s, 8H,
piperazine), 3.48 (s, 3H, H-11), 3.45 (t, J ¼ 7.4 Hz, H-400), 3.43e3.29
(m, 2H, H-700), 3.13 (s, 6H, 2CH3), 2.38 (q, J ¼ 6.1 Hz, 2H, H-1400),1.04
5.7.7. 4-(4-{4-[2-(4-Chlorophenyl)-5-(4-ethylpiperazin-1-
ylmethyl)-4-oxothiazolidin-3-yl]-phenylamino}-6-dimethylamino-
[1,3,5]triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12g)
13
(t, J ¼ 6.5 Hz, 3H, H-1500); C NMR (DMSO-d6): 172.13 (C-500),
Recrystallization from THF. Yield: 67%. M.p. 244e248 ꢀC; IR (KBr,
cmꢁ1): 3357 (eNH), 1725 (C]O of thiazolidinone), 1664 (C]O of
quinolone), 808 (s-triazine, CeN str.), 784 (Cl); 1H NMR (DMSO-d6):
168.29 (C-60), 164.77 (C-40), 163.12 (C-20), 161.44 (C-2), 158.61
(CeOH), 152.71 (C-4), 141.24e97.54 (18C, AreC), 67.12 (C-200),
62.73, 58.19 (4C, piperazine), 56.34 (C-700), 55.51 (C-400), 52.25 (C-
1400), 36.85 (C-70, C-80), 32.37 (C-11), 12.63 (C-1500). Anal. Calcd for:
C37H41N9O4S: C, 62.78; H, 5.84; N, 17.81%. Found: C, 62.72; H, 5.89;
N, 17.76%.
d
9.66 (s, 1H, eNH), 8.45 (dd, 1H, J ¼ 7.5, 1.6 Hz, H-5), 8.10e7.54 (m,
3H, quinolone), 7.49e6.90 (m, 8H, AreH), 6.10 (s, 1H, H-3), 5.18 (s,
1H, H-200), 3.53 (br s, 8H, piperazine), 3.42 (s, 3H, H-11), 3.40 (t,
J ¼ 7.3 Hz, H-400), 3.25e3.18 (m, 2H, H-700), 3.07 (s, 6H, 2CH3), 2.37 (q,
J ¼ 6.3 Hz, 2H, H-1400), 1.41 (t, J ¼ 6.3 Hz, 3H, H-1500); 13C NMR
(DMSO-d6): 174.60 (C-500), 168.12 (C-60), 165.24 (C-40), 163.81 (C-20),
161.19 (C-2), 152.33 (C-4), 133.19 (CeCl), 143.27e97.54 (18C, AreC),
67.24 (C-200), 62.74, 57.70 (4C, piperazine), 55.80 (C-700), 54.92 (C-
400), 52.13 (C-1400), 36.88 (C-70, C-80), 32.86 (C-11), 12.70 (C-1500).
Anal. Calcd for: C37H40ClN9O3S: C, 61.19; H, 5.55; N, 17.36%. Found:
C, 61.23; H, 5.47; N, 17.40%.
5.7.11. 4-(4-{4-[2-(4-Bromophenyl)-5-(4-ethylpiperazin-1-ylmethyl)-
4-oxothiazolidin-3-yl]-phenylamino}-6-dimethylamino-[1,3,5]triazin-
2-yloxy)-1-methyl-1H-quinolin-2-one (12k)
Recrystallization from DMF. Yield: 64%. M.p. 271e274 ꢀC; IR
(KBr, cmꢁ1): 3360 (eNH), 1716 (C]O of thiazolidinone), 1667
(C]O of quinolone), 808 (s-triazine, CeN str.), 729 (eBr); 1H
NMR (DMSO-d6):
d
9.64 (s, 1H, eNH), 8.42 (dd, 1H, J ¼ 7.3, 1.4 Hz,
H-5), 8.11e7.59 (m, 3H, quinolone), 7.48e6.86 (m, 8H, AreH),
6.14 (s, 1H, H-3), 5.11 (s, 1H, H-200), 3.55 (br s, 8H, piperazine),
3.39 (s, 3H, H-11), 3.25 (t, J ¼ 7.4 Hz, H-400), 3.23e3.10 (m, 2H, H-
700), 3.06 (s, 6H, 2CH3), 2.33 (q, J ¼ 6.6 Hz, 2H, H-1400), 1.15 (t,
5.7.8. 4-(4-Dimethylamino-6-{4-[5-(4-ethylpiperazin-1-ylmethyl)-
2-(4-nitrophenyl)-4-oxothiazolidin-3-yl]-phenylamino}-[1,3,5]
triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12h)
13
Recrystallization from DMF. Yield: 59%. M.p. 260e262 ꢀC; IR
(KBr, cmꢁ1): 3361 (eNH), 1719 (C]O of thiazolidinone), 1665 (C]
O of quinolone), 1540 (N]O str.), 806 (s-triazine, CeN str.); 1H
J ¼ 6.3 Hz, 3H, H-1500); C NMR (DMSO-d6): 172.24 (C-500), 167.31
(C-60), 164.83 (C-40), 163.08 (C-20), 161.37 (C-2), 151.89 (C-4),
121.70 (CeBr), 140.33e96.51 (18C, AreC), 66.58 (C-200), 63.83,
59.47 (4C, piperazine), 57.51 (C-700), 55.49 (C-400), 51.39 (C-1400),
37.08 (C-70, C-80), 32.40 (C-11), 12.58 (C-1500). Anal. Calcd for:
NMR (DMSO-d6):
d
9.69 (s, 1H, eNH), 8.31 (dd, 1H, J ¼ 7.4, 1.2 Hz,
H-5), 8.06e7.67 (m, 3H, quinolone), 7.42e6.86 (m, 8H, AreH),
6.13 (s, 1H, H-3), 5.11 (s, 1H, H-200), 3.59 (br s, 8H, piperazine), 3.45
(s, 3H, H-11), 3.41 (t, J ¼ 7.1 Hz, H-400), 3.31e3.23 (m, 2H, H-700),
C
37H40BrN9O3S: C, 57.66; H, 5.23; N, 16.36%. Found: C, 57.74; H,
5.16; N, 16.43%.

D. Patel et al. / European Journal of Medicinal Chemistry 48 (2012) 354e362
361
5.7.12. 4-(4-{4-[2-(2-Bromophenyl)-5-(4-ethylpiperazin-1-
ylmethyl)-4-oxothiazolidin-3-yl]-phenylamino}-6-dimethylamino-
[1,3,5]triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12l)
H-3), 5.12 (s, 1H, H-200), 3.87 (s, 3H, eOCH3), 3.56 (br s, 8H, piper-
azine), 3.41 (s, 3H, H-11), 3.32 (t, J ¼ 7.5 Hz, H-400), 3.29e3.18 (m, 2H,
H-700), 3.12 (s, 6H, 2CH3), 2.34 (q, J ¼ 6.2 Hz, 2H, H-1400), 1.08 (t,
J ¼ 6.2 Hz, 3H, H-1500); 13C NMR (DMSO-d6): 171.45 (C-500), 167.12 (C-
60), 164.29 (C-40), 162.83 (C-20), 162.05 (C-2), 160.10 (CeOCH3),
151.20 (C-4), 145.46e101.73 (18C, AreC), 68.11 (C-200), 64.18, 61.79
(4C, piperazine), 56.08 (eOCH3), 57.86 (C-700), 55.66 (C-400), 49.17
(C-1400), 37.03 (C-70, C-80), 32.48 (C-11), 12.55 (C-1500). Anal. Calcd
for: C38H43N9O4S: C, 63.23; H, 6.00; N, 17.46%. Found: C, 63.18; H,
6.07; N, 17.55%.
Recrystallization from DMF. Yield: 57%. M.p. 283e287 ꢀC; IR
(KBr, cmꢁ1): 3363 (eNH), 1721 (C]O of thiazolidinone), 1666 (C]O
of quinolone), 807 (s-triazine, CeN str.), 733 (eBr); 1H NMR (DMSO-
d6):
d
9.77 (s, 1H, eNH), 8.31 (dd, 1H, J ¼ 7.4, 1.2 Hz, H-5), 8.23e7.71
(m, 3H, quinolone), 7.54e6.91 (m, 8H, AreH), 6.25 (s, 1H, H-3), 5.15
(s, 1H, H-200), 3.59 (br s, 8H, piperazine), 3.43 (s, 3H, H-11), 3.37 (t,
J ¼ 7.6 Hz, H-400), 3.29e3.14 (m, 2H, H-700), 3.11 (s, 6H, 2CH3), 2.27 (q,
J ¼ 6.6 Hz, 2H, H-1400), 1.26 (t, J ¼ 6.5 Hz, 3H, H-1500); 13C NMR
(DMSO-d6): 171.30 (C-500), 168.12 (C-60), 165.79 (C-40), 163.64 (C-20),
161.43 (C-2), 152.26 (C-4), 121.60 (CeBr), 144.38e98.16 (18C, AreC),
66.31 (C-200), 62.54, 60.47 (4C, piperazine), 58.47 (C-700), 56.12 (C-
400), 50.34 (C-1400), 36.15 (C-70, C-80), 31.89 (C-11), 12.67 (C-1500).
Anal. Calcd for: C37H40BrN9O3S: C, 57.66; H, 5.23; N, 16.36%. Found:
C, 57.72; H, 5.19; N, 16.45%.
5.7.16. 4-(4-{4-[2-(3,4-Dimethoxyphenyl)-5-(4-ethylpiperazin-1-
ylmethyl)-4-oxothiazolidin-3-yl]-phenylamino}-6-dimethylamino-
[1,3,5]triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12p)
Recrystallization from DMF. Yield: 73%. M.p. 291e297 ꢀC; IR
(KBr, cmꢁ1): 3361 (eNH), 1714 (C]O of thiazolidinone), 1668 (C]O
of quinolone), 1288 (eOCH3), 807 (s-triazine, CeN str.); 1H NMR
(DMSO-d6):
d
9.87 (s, 1H, eNH), 8.48 (dd, 1H, J ¼ 7.3, 1.3 Hz, H-5),
5.7.13. 2-[3-{4-[4-Dimethylamino-6-(1-methyl-2-oxo-1,2-
dihydro-quinolin-4-yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-5-
(4-ethylpiperazin-1-ylmethyl)-4-oxothiazolidin-2-yl]-benzoic
acid (12m)
8.04e7.51 (m, 3H, quinolone), 7.33e6.83 (m, 7H, AreH), 6.11 (s, 1H,
H-3), 5.09 (s, 1H, H-200), 3.84 (s, 3H, eOCH3), 3.71 (s, 3H, eOCH3),
3.63 (br s, 8H, piperazine), 3.43 (s, 3H, H-11), 3.40 (t, J ¼ 7.3 Hz, H-
400), 3.21e2.97 (m, 2H, H-700), 2.91 (s, 6H, 2CH3), 2.29 (q, J ¼ 6.6 Hz,
2H, H-1400), 1.12 (t, J ¼ 6.1 Hz, 3H, H-1500); 13C NMR (DMSO-d6):
172.69 (C-500),168.15 (C-60),164.43 (C-40),163.87 (C-20),161.90 (C-2),
152.34 (C-4), 150.23 (CeOCH3), 148.18 (CeOCH3), 142.28e98.64
(17C, AreC), 67.15 (C-200), 63.81, 58.75 (4C, piperazine), 57.89 (C-700),
56.10 (eOCH3), 54.89 (C-400), 51.25 (C-1400), 36.12 (C-70, C-80), 32.61
(C-11), 12.47 (C-1500). Anal. Calcd for: C39H45N9O5S: C, 62.30; H,
6.03; N, 16.77%. Found: C, 62.25; H, 6.08; N, 16.84%.
Recrystallization from THF. Yield: 79%. M.p. >300 ꢀC; IR (KBr,
cmꢁ1): 3363 (eNH), 1722 (C]O of thiazolidinone), 1720 (eCOOH),
1668 (C]O of quinolone), 806 (s-triazine, CeN str.); 1H NMR
(DMSO-d6):
d
9.84 (s, 1H, eNH), 8.45 (dd, 1H, J ¼ 7.3, 1.5 Hz, H-5),
8.12e7.55 (m, 3H, quinolone), 7.43e6.78 (m, 8H, AreH), 6.07
(s, 1H, H-3), 5.17 (s, 1H, H-200), 3.60 (br s, 8H, piperazine), 3.43 (s,
3H, H-11), 3.31 (t, J ¼ 7.3 Hz, H-400), 3.29e3.24 (m, 2H, H-700), 3.09
(s, 6H, 2CH3), 2.32 (q, J ¼ 6.6 Hz, 2H, H-1400), 1.34 (t, J ¼ 6.4 Hz, 3H,
13
H-1500); C NMR (DMSO-d6): 172.32 (C-500), 170.40 (C]O of
5.7.17. 4-(4-{4-[2-(2,4-Dihydroxyphenyl)-5-(4-ethylpiperazin-1-
ylmethyl)-4-oxothiazolidin-3-yl]-phenylamino}-6-dimethylamino-
[1,3,5]triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12q)
COOH), 168.19 (C-60), 163.13 (C-40), 162.89 (C-20), 161.31 (C-2),
152.35 (C-4), 131.29 (CeCOOH), 138.30e95.42 (18C, AreC), 67.15
(C-200), 63.14, 61.69 (4C, piperazine), 57.74 (C-700), 55.61 (C-400),
50.23 (C-1400), 36.94 (C-70, C-80), 32.37 (C-11), 12.52 (C-1500). Anal.
Calcd for: C38H41N9O5S: C, 62.02; H, 5.62; N, 17.13%. Found: C,
62.05; H, 5.57; N, 17.17%.
Recrystallization from DMF. Yield: 80%. M.p. >300 ꢀC; IR (KBr,
cmꢁ1): 3364 (eNH), 3229 (eOH), 1722 (C]O of thiazolidinone),
1666 (C]O of quinolone), 806 (s-triazine, CeN str.); 1H NMR
(DMSO-d6):
d 9.71 (s, 1H, eNH), 8.73 (s, 1H, eOH), 8.39 (dd, 1H,
J ¼ 7.2,1.5 Hz, H-5), 8.10e7.65 (m, 3H, quinolone), 7.46e6.85 (m, 7H,
AreH), 6.16 (s, 1H, H-3), 5.12 (s, 1H, H-200), 4.63 (s, 1H, eOH), 3.59 (br
s, 8H, piperazine), 3.46 (s, 3H, H-11), 3.35 (t, J ¼ 7.2 Hz, H-400),
3.29e3.10 (m, 2H, H-700), 3.07 (s, 6H, 2CH3), 2.34 (q, J ¼ 6.3 Hz, 2H,
H-1400), 1.05 (t, J ¼ 6.4 Hz, 3H, H-1500); 13C NMR (DMSO-d6): 172.54
(C-500), 167.32 (C-60), 163.44 (C-40), 162.92 (C-20), 161.78 (C-2), 158.13
(CeOH), 155.43 (CeOH), 151.45 (C-4), 139.39e97.23 (17C, AreC),
68.21 (C-200), 64.15, 61.70 (4C, piperazine), 58.31 (C-700), 54.57 (C-
400), 51.63 (C-1400), 37.15 (C-70, C-80), 32.43 (C-11),12.67 (C-1500). Anal.
Calcd for: C37H41N9O5S: C, 61.39; H, 5.71; N, 17.42%. Found: C, 61.36;
H, 5.64; N, 17.47%.
5.7.14. 4-[3-{4-[4-Dimethylamino-6-(1-methyl-2-oxo-1,2-
dihydro-quinolin-4-yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-5-
(4-ethylpiperazin-1-ylmethyl)-4-oxothiazolidin-2-yl]-benzoic
acid (12n)
Recrystallization from THF. Yield: 84%. M.p. >300 ꢀC; IR (KBr,
cmꢁ1): 3361 (eNH), 1725 (C]O of thiazolidinone), 1722 (eCOOH),
1666 (C]O of quinolone), 807 (s-triazine, CeN str.); 1H NMR
(DMSO-d6):
d
9.65 (s, 1H, eNH), 8.38 (dd, 1H, J ¼ 7.4, 1.6 Hz, H-5),
8.09e7.55 (m, 3H, quinolone), 7.36e6.89 (m, 8H, AreH), 6.24 (s, 1H,
H-3), 5.10 (s,1H, H-200), 3.63 (br s, 8H, piperazine), 3.49 (s, 3H, H-11),
3.44 (t, J ¼ 7.1 Hz, H-400), 3.31e3.12 (m, 2H, H-700), 3.04 (s, 6H, 2CH3),
2.40 (q, J ¼ 6.4 Hz, 2H, H-1400), 1.20 (t, J ¼ 6.5 Hz, 3H, H-1500); 13C
NMR (DMSO-d6): 172.40 (C-500), 170.13 (C]O of COOH), 167.23 (C-
60), 164.56 (C-40), 162.77 (C-20), 161.46 (C-2), 152.39 (C-4), 131.34
(CeCOOH), 142.25e96.29 (18C, AreC), 66.08 (C-200), 62.17, 60.76
(4C, piperazine), 58.71 (C-700), 56.24 (C-400), 51.27 (C-1400), 37.16 (C-
70, C-80), 31.84 (C-11), 13.30 (C-1500). Anal. Calcd for: C38H41N9O5S: C,
62.02; H, 5.62; N, 17.13%. Found: C, 62.07; H, 5.59; N, 17.19%.
5.7.18. 4-(4-{4-[2-(2,3-Dihydroxyphenyl)-5-(4-ethylpiperazin-1-
ylmethyl)-4-oxothiazolidin-3-yl]-phenylamino}-6-dimethylamino-
[1,3,5]triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12r)
Recrystallization from DMF. Yield: 86%. M.p. 295e299 ꢀC; IR
(KBr, cmꢁ1): 3360 (eNH), 3231 (eOH), 1725 (C]O of thiazolidi-
none), 1667 (C]O of quinolone), 806 (s-triazine, CeN str.); 1H NMR
(DMSO-d6):
d 9.70 (s, 1H, eNH), 8.69 (s, 1H, eOH), 8.27 (dd, 1H,
J ¼ 7.4,1.2 Hz, H-5), 8.14e7.55 (m, 3H, quinolone), 7.40e6.83 (m, 7H,
AreH), 6.25 (s,1H, H-3), 5.17 (s,1H, H-200), 4.66 (s,1H, eOH), 3.53 (br
s, 8H, piperazine), 3.40 (s, 3H, H-11), 3.32 (t, J ¼ 7.5 Hz, H-400),
3.30e3.18 (m, 2H, H-700), 3.11 (s, 6H, 2CH3), 2.37 (q, J ¼ 6.5 Hz, 2H, H-
1400), 1.23 (t, J ¼ 6.3 Hz, 3H, H-1500); 13C NMR (DMSO-d6): 172.69 (C-
500), 168.46 (C-60), 164.41 (C-40), 162.97 (C-20), 161.84 (C-2), 158.17
(CeOH), 155.40 (CeOH), 152.10 (C-4), 142.61e96.81 (17C, AreC),
67.30 (C-200), 62.67, 58.24 (4C, piperazine), 57.15 (C-700), 55.63 (C-
400), 51.33 (C-1400), 36.19 (C-70, C-80), 31.97 (C-11), 12.79 (C-1500). Anal.
5.7.15. 4-(4-Dimethylamino-6-{4-[5-(4-ethylpiperazin-1-ylmethyl)-
2-(4-methoxyphenyl)-4-oxothiazolidin-3-yl]-phenylamino}-[1,3,5]
triazin-2-yloxy)-1-methyl-1H-quinolin-2-one (12o)
Recrystallization from DMF. Yield: 69%. M.p. >300 ꢀC; IR (KBr,
cmꢁ1): 3365 (eNH), 1718 (C]O of thiazolidinone), 1666 (C]O of
quinolone), 1290 (eOCH3), 807 (s-triazine, CeN str.); 1H NMR
(DMSO-d6):
d
9.79 (s, 1H, eNH), 8.30 (dd, 1H, J ¼ 7.2, 1.1 Hz, H-5),
8.11e7.66 (m, 3H, quinolone), 7.47e6.90 (m, 8H, AreH), 6.16 (s, 1H,

362
D. Patel et al. / European Journal of Medicinal Chemistry 48 (2012) 354e362
Calcd for: C37H41N9O5S: C, 61.39; H, 5.71; N, 17.42%. Found: C, 61.33;
H, 5.65; N, 17.49%.
prepared and applied to plates with serially diluted compounds
with concentrations in the range of 3.12e100 g/mL in dimethyl
m
sulfoxide and incubated at (37 ꢄ 1) ꢀC for 24 h (bacteria) or 48 h
(fungi). The lowest concentration of the substance that prevents
the development of visible growth is considered to be the MIC
value.
5.8. Antimicrobial assay
The synthesized thiazolidinone derivatives 12aer were exam-
ined for antimicrobial activity against several bacteria (S. aureus,
B. cereus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris,
S. flexneri) and fungi (A. niger, A. fumigatus, A. clavatus, C. albicans)
species using paper disc diffusion technique [18]. The Muel-
lereHinton agar media were sterilized (autoclaved at 120 ꢀC for
30 min), poured at uniform depth of 5 mm and allowed to solidify.
The microbial suspension (105 CFU/mL) (0.5 McFarland Neph-
elometery Standards) was streaked over the surface of media using
a sterile cotton swab to ensure even growth of the organisms. The
tested compounds were dissolved in dimethyl sulfoxide to give
References
[1] M. Saleh, S. Abbott, V.C. Lauzon, C. Penney, B. Zacharie, Bioorg. Med. Chem.
Lett. 20 (2010) 945e949.
[2] C. Zhou, J. Min, L. Zhigang, Y. Anne, D. Heather, G. Tian, C. Young-tae,
R.K. Neville, Bioorg. Med. Chem. Lett. 18 (2008) 1308e1311.
[3] K. Srinivas, U. Srinivas, K. Bhanuprakash, K. Harakishore, U.S.N. Murthy,
R.V. Jayathirtha, Eur. J. Med. Chem. 41 (2006) 1240e1246.
[4] B. Alessandro, J.B. Gorka, L.S. Mhairi, Y. Vanessa, B. Reto, P.B. Michael, H.G. Ian,
J. Med. Chem. 48 (2005) 5570e5579.
[5] M. Rita, S. Simona, S. Giovanni, V. Francesca, D.V. Lisa, J. Med. Chem. 47 (2004)
4649e4652.
solutions of 3.12e100 mg/mL. Sterile filter paper discs measuring
[6] M. Sergio, P. Davide, C. Paolo, B. Nicoletta, M. Diego, ChemMedChem 3 (2008)
873e876.
[7] X. Yuan-Zhen, C. Fen-Er, B. Jan, D.C. Erik, P. Christophe, Eur. J. Med. Chem. 43
(2008) 1230e1236.
[8] A. Verma, S.K. Saraf, Eur. J. Med. Chem. 43 (2008) 897e905.
[9] D. Karl, Z. Xilin, Microbiol. Mol. Biol. Rev. 61 (1997) 377e392.
[10] F. Enrica, C. Gabriele, T. Oriana, C. Violetta, F. Arnaldo, ACS Symp. Ser. 15
(2001) 203e217.
[11] C. Sun, J. Keumnyeo, R. Jaesang, Arch. Pharm. Res. 29 (2006) 369e374.
[12] D. Anastasia, B. Dionysia, C.P. Kyriakos, K. Maria, A. Giorgos, M. Georgia,
A. Antreas, I. Olga, K. Christos, J.H. Dimitra, J. Med. Chem. 50 (2007)
2450e2458.
[13] I.V. Ukrainets, S.G. Taran, O.L. Kodolova, O.V. Gorokhova, V.N. Kravchenko,
Chem. Heterocycl. Compd. 33 (1997) 959e963.
[14] R.J. Kerns, M.J. Rybak, G.W. Kaatz, F. Vaka, R. Cha, R.G. Grucz, V.U. Diwadkar,
Bioorg. Med. Chem. Lett. 13 (2003) 2109e2112.
[15] A. Ryckebusch, R. Deprez-Poulain, L. Maes, M.A. Debreu-Fontaine, E. Mouray,
P. Grellier, C.J. Sergheraert, J. Med. Chem. 46 (2003) 542e557.
[16] U. Ram Shankar, S. Neelima, J. Sanjay, K. Nawal, C. Ramesh, A. Sudershan,
Bioorg. Med. Chem. 12 (2004) 2225e2238.
[17] M.M. Bahgat, A.S. Maghraby, M.E. Heiba, A. Ruppel, O.A. Fathalla, Arch. Pharm.
Res. 28 (2005) 1002e1012.
6.25 mm in diameter (Whatman no. 1 filter paper), previously
soaked in a known concentration of the respective test compound
in dimethyl sulfoxide were placed on the solidified nutrient agar
medium that had been inoculated with the respective microor-
ganism and the plates were incubated for 24 h at (37 ꢄ 1)ꢀC. A
control disc impregnated with an equivalent amount of dimethyl
sulfoxide without any sample was also used and did not produce
any inhibition. Ciprofloxacin and ketoconazole (100 mg/disc) were
used as control drugs for antibacterial and antifungal activity,
respectively.
MIC of the compound was determined by agar streak dilution
method [19]. A stock solution of the synthesized compound
(100 mg/mL) in dimethyl sulfoxide was prepared and graded
quantities of the test compounds were incorporated in a speci-
fied quantity of molten sterile agar, i.e. nutrient agar for evalu-
ation of antibacterial and Sabouraud dextrose agar for antifungal
activity, respectively. The medium containing the test compound
was poured into a Petri dish at a depth of 4e5 mm and allowed
[18] S.H. Gillespie, Medical Microbiology e Illustrated, Butterworth Heinemann
Ltd., United Kingdom, 1994, pp 234e247.
[19] P.M. Hawkey, D.A. Lewis, Medical Bacteriology e A Practical Approach, Oxford
University Press, United Kingdom, 1994, pp 181e194.
to solidify under aseptic conditions.
A suspension of the
respective microorganism of approximately 105 CFU/mL was