Synthesis and antimicrobial activities of novel series of 3-(4-(2-substituted thiazol-4-yl)phenyl)-2-(4-methyl-2-substituted thiazol-5-yl)thiazolidin-4-one derivatives

Article abstract of DOI:10.1002/jhet.1789

In the present investigation, a novel series of 3-(4-(2-substituted thiazol-4-yl)phenyl)-2-(4-methyl-2-substituted thiazol-5-yl)thiazolidin-4-one derivatives were synthesized by condensation of 2-substituted-4-methylthiazole- 5-carbaldehyde with 4-(2-subs

Full text of DOI:10.1002/jhet.1789

July 2014
Synthesis and Antimicrobial Activities of Novel Series of 3-(4-(2-substituted
thiazol-4-yl)phenyl)-2-(4-methyl-2-substituted thiazol-5-yl)thiazolidin-4-
one Derivatives
1151
a
b
c
a
*
Shivaji H. Shelke, Pravin C. Mhaske, Sachin Narkhade, and Vivek D. Bobade
aDepartment of Chemistry, H. P. T. Arts and R. Y. K. Science College, College Road, Nashik 422005, India
bDepartment of Chemistry, Sir Parshurambhau College, Tilak Road, Pune 411030, India
cSPP-School of Pharmacy & Technology Management, SVKM’s NMIMS, Vile Parle, Mumbai 400056, India
*
E-mail: v_bobade31@rediffmail.com
Received March 3, 2012
DOI 10.1002/jhet.1789
Published online 10 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
S
O
R1
S
H2N
O
S
N
N
H3C
HSCH2COOH
Toluene reflux
H3C
CH3COOH
H
H
H
H3C
N
+
N
S
Toluene
reflux
N
R
N
S
N
S
R
S
N
8a-i
7a-i
R1
R
R1
In the present investigation, a novel series of 3-(4-(2-substituted thiazol-4-yl)phenyl)-2-(4-methyl-2-substituted
thiazol-5-yl)thiazolidin-4-one derivatives were synthesized by condensation of 2-substituted-4-methylthiazole-5-
carbaldehyde with 4-(2-substituted thiazol-4-yl)benzenamine followed by cyclo-condensation with thioglycolic
acid in toluene. All the newly synthesized compounds were characterized by spectral (IR, 1H NMR, 13C NMR,
and Mass) methods. The title compounds were screened for quantitative antibacterial activity (minimal inhibitory
concentration). All compounds 7a–h and 8a–h show moderate to good antimicrobial activity, whereas
compounds (7a–h) also show moderate antifungal activity.
J. Heterocyclic Chem., 51, 1151 (2014).
INTRODUCTION
2a–b was then oxidized to corresponding aldehyde 3a–b
using 2-iodoxy benzoic acid (IBX) [38–41].
Thiazole and their derivatives have attracted continuing
interest over the years because of their varied biological
activities [1]. 1,3-Thiazole nucleus containing compounds
have exhibited a broad range of biological activities [2–11].
Thiazolidinones have also received considerable attention
because of their biological importance [12]. The thiazolidi-
none nucleus containing compounds show anti-inflammatory
[13–20], anticonvulsant [21–24], hypnotic and anti-tubercular
[25–27], and antimicrobial and anticancer [28–35] activities.
In view of these observations and as a continuation of our
previous work on thiazolidinone [36], it was thought to syn-
thesize new thiazole based 1,3-thiazolidin-4-one by the con-
densation of 2-substituted-4-methylthiazole-5-carbaldehyde
with 4-(2-substituted thiazol-4-yl)benzene-amine and
thioglycolic acid.
Aldehydes 3a–b were condensed with 4-(2-aryl/benzyl/
methylthiazol-4-yl)benzenamine 6a–f in toluene with
azeotropic separation of water that gave corresponding
Schiff’s base 7a–i. The infrared (IR) spectrum of Schiff’s
bases displayed the disappearance of absorption bands
corresponding to C–H and C═O stretching frequency of
aldehyde while appearance of the absorption band at
1600–1615 cmÀ1 and 3062–3150 cmÀ, 1 characteristic of
C═N and N═CH confirmed the formation of imine func-
tionality. The 1H NMR spectrum of Schiff’s base displayed
the absence of singlet at d 9.8–10.1 (CHO), whereas a new
singlet that appeared between d 7.94–8.66 was attributed to
N═CH proton. Similarly, in the 13C NMR spectrum
disappearance of signal at d 180–182 (C═O) and appearance
of a new signal at d 169.2–171.4 for N═CH carbon
confirmed the structure of Schiff’s base. Schiff’s base on
cyclo-condensation with thioglycolic acid afforded thiazoli-
dinone derivative 8a–i. The physical properties and yield
of synthesized compounds 8a–i are reported in Table 1.
The IR spectrum of thiazolidin-4-one 8a–i revealed char-
acteristic absorption peak at 1685–1693cmÀ1 (C═O) that
indicated the formation of thiazolidin-4-one compound,
which was further confirmed by its 1H NMR spectrum which
displayed an AB quartet between d 3.88–4.00 integrated for
two geminal protons of thiazolidine-4-one nucleus and
singlet at d 6.34–6.52 integrated for one proton of
RESULTS AND DISCUSSION
The synthesis of 3-(4-(2-methyl/aryl/benzylthiazol-4-yl)
phenyl)-2-(4-methyl-2-aryl/benzylthiazol-5-yl)thiazolidin-4-
one 8a–i is illustrated in Figure 1. The starting material
ethyl-2-aryl/benzyl-4-methylthiazole-5-carboxylate 1a–b
and 4-(2-aryl/benzyl/methylthiazol-4-yl)benzenamine were
prepared according to earlier reported procedure [37]. Ester
1a–b was reduced to corresponding alcohol 2a–b using
lithium aluminum hydride in dry diethyl ether. The alcohol
© 2013 HeteroCorporation

1152
S. H. Shivaji, P. C. Mhaske, S. Narkhade, and V. D. Bobade
Vol 51
O
O
H3C
OH
H
H3C
OEt
H3C
IBX, DMSO
LiAlH4, Et2O
N
S
S
N
S
N
O0C-rt, 0.5 h
86-95%
O0C-rt, 3 h
82-90%
R
R
R
2a-b
3a-b
1a-b
NHCOCH3
1. EtOH, reflux
S
2. 6N HCl, reflux
S
+
H2N
H2N
R1
N
3. 2N NaOH
R1
R1 = methyl/aryl/substituted benzyl
O
Cl
6a-g
5a-g
4
S
R1
O
N
H2N
S
O
H
N
H3C
SHCH2COOH
H3C
CH3COOH
H
H3C
N
H
+
N
S
Toluene
reflux
Toluene
reflux, 60- 70 %
N
S
N
S
N
S
R
S
R
N
R
R1
R1
7a-i
8a-i
R = Phenyl / 4-Chlorobenzyl
3a-b
6a-f
R1 = methyl/aryl/substituted benzyl
Figure 1. Synthetic pathway for formation of compounds 7a-i and 8a-i.
Table 1
The physical properties and yield of synthesized compounds 7a–i and 8a–i.
Compound
R
R1
mpa
Yieldb
7a
7b
7c
7d
7e
7f
7g
7h
7i
8a
8b
8c
8d
8e
8f
8g
8h
8i
C6H5
CH3
3-FC6H4
89–90
92–94
139–140
94–96
78–80
93–94
85–87
86–88
79–80
89–91
92–93
138–140
95–96
78–80
93–94
84–86
86–88
78–80
84
86
89
80
86
76
86
72
70
68
67
70
70
69
65
66
66
60
C6H5
C6H5
C6H5
C6H5
C6H5
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
C6H5
C6H5
C6H5
C6H5
C6H5
4-ClC6H4CH2
2,4-Cl2C6H3CH2
3,4-Cl2C6H3CH2
4-OMeC6H4CH2
CH3
4-ClC6H4
4-OMeC6H4CH2
CH3
3-FC6H4
4-ClC6H4CH2
2,4-Cl2C6H3CH2
3,4-Cl2C6H3CH2
4-OMeC6H4CH2
CH3
C6H5
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4
4-OMeC6H4CH2
mp, melting point.
a
ꢀC
bIsolated yield.
thiazolidin-4-one ring. The formation of the thiazolidin-4-
which revealed peaks around 33, 58, and 171 due to CH2,
CH, and C═O of thizolidinone nucleus in each compound.
one ring was further confirmed by its 13C NMR spectra,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis and Antimicrobial Activities of Thiozolidin-4-one Derivatives
1153
Antimicrobial and antifungal testing. All the synthesized
their corresponding thiazolidin-4-one derivatives showed
good activities. This result can be attributed because
of the presence of thiazolidin-4-one ring in compounds
8a–h. Compounds 8b (R = Ph, R1 = 3-F-C6H4), 8g and 8h
(R = 4-Cl-C6H4-CH2- and R1 = CH3 or 4-Cl-C6H4)
exhibited good activities against yeast species with MIC
value 12.5 mg/mL, whereas compounds 8a, 8c, 8d, 8e,
and 8f (R1 = methyl or substituted benzyl) are moderately
active with MIC values 25–50 mg/mL. Thus, it is
concluded that compounds with R1 = substituted phenyl
group show good antifungal activity whereas compounds
with substituted benzyl group show moderate activity.
compounds were quantitatively evaluated for antimicrobial
activity using the minimum inhibitory concentration (MIC)
assay [42]. These compounds were tested against a number
of reference test organisms including Gram-negative
(Escherichia coli American Type Culture Collection
(ATCC) 25922, Pseudomonas aeruginosa ATCC 27853)
and Gram-positive (Staphylococcus aureus ATCC 25923,
Staphylococcus fecalis ATCC 29212, Bacillus subtilis
ATCC 6633) and fungi (Candida albicans ATCC 10231,
Aspergillus niger ATCC 9029). The in vitro antimicrobial
MIC screening results of synthesized compounds 7a–i and
8a–i are given in Table 2.
Most of the synthesized compounds (except 7i and 8i)
exhibited moderate to good antimicrobial activities. The
compounds 7h, 8a, 8b, and 8 h showed good activity (MIC
values are twofold as compared with the standard) against
Gram-positive bacteria strain S. fecalis. Compounds 7h and
8h (R = 4-Cl-C6H4-CH2 and R1 = 4-Cl-C6H4-) in Schiff’s
base as well as thiazolidin-4-one, compound 8a (R = Ph
and R1 = CH3) and 8b (R = Ph and R1 = 3-F-C6H4-) were
found to be more active for S. fecalis strain as compared with
other antibacterial strains. Compounds 7b, 7c, 7d, 7e, 7g, 8c,
8d, 8f, and 8g showed moderate antibacterial activities (MIC
values are fourfold or more as compared with the standard)
against Gram-negative and/or Gram-positive species.
The result of antifungal activities revealed that Schiff’s
base (7a–i) did not show any significant activity, whereas
CONCLUSION
In summary, we have synthesized a series of novel
4-(2-(substituted thiazol-4-yl)-N-((4-methyl-2-phenyl/
benzylthiazol-5-yl)methylene)benzenamine (7a–i) and
3-(4-(2-substituted thiazol-4-yl)phenyl)-2-(4-methyl-2-aryl/
benzylthiazol-5-yl)thiazolidin-4-one (8a–i). The in vitro
antimicrobial results revealed that synthesized Schiff’s bases
(7a–h) shows only moderate to good antibacterial activity,
whereas thiazolidin-4-one (8a–h) shows good to significant
antibacterial as well as antifungal activities. The antimicro-
bial activity results make them interesting lead molecules
for further synthetic and biological evaluation. Further
studies are in progress to acquire more information regarding
structure activity relationship.
Table 2
Antimicrobial activity of novel 4-(2-(methyl/phenyl/benzyl)thiazol-4-yl)-N-((4-methyl-2-phenyl/benzylthiazol-5-yl)methylene)benzenamine 7a–i and
3-(4-(2-methyl/aryl/benzylthiazol-4-yl)phenyl)-2-(4-methyl-2-aryl/benzylthiazol-5-yl)thiazolidin-4-one 8a–i.
Compound
Pathogen MIC mg/mL (mM)
Ec
Pa
Sa
Sf
Bs
Ca
An
7a
7b
7c
7d
7e
7f
7g
7h
7i
8a
8b
8c
8d
8e
8f
8g
25 (66.66)
12.5 (27.47)
25 (51.49)
50 (96.15)
25 (48.07)
50 (103.95)
12.5 (30.52)
12.5 (24.70)
100 (193.98)
12.5 (27.83)
12.5 (23.62)
12.5 (22.34)
25 (42.08)
25 (42.08)
25 (45.20)
12.5 (21.42)
25 (43.10)
>100
50 (133.33)
50 (109.88)
50 (102.98)
25(48.07)
50 (96.15)
50 (103.95)
12.5 (30.52
25 (49.40)
>100
12.5 (27.83)
12.5 (23.62)
25 (44.68)
50 (84.16)
50 (84.16)
50 (90.41)
12.5 (21.42)
50 (86.20)
>100
50 (133.33)
25 (54.94)
50 (102.98)
25 (48.07)
25 (48.07)
50 (103.95)
12.5 (30.52)
25 (49.40)
>100
12.5 (27.83)
25 (47.25)
25 (44.68)
50 (84.16)
50 (84.16)
50 (90.41)
50 (85.68)
25 (43.10)
>100
50 (133.33)
25 (54.94)
25 (51.49)
25 (48.07)
25 (48.07)
25 (51.97)
25 (61.04)
12.5 (24.70)
100 (193.98)
12.5 (27.83)
12.5 (23.62)
25 (44.68)
50 (84.16)
50 (84.16)
25 (45.20)
25 (42.84)
12.5 (21.55)
50
>100
50 (109.88)
50 (102.98)
25 (48.07)
25 (48.07)
50 (103.95)
25 (61.04)
25 (49.40)
>100
25 (55.67)
25 (47.25)
25 (44.68)
50 (84.16)
100 (168.3)
50 (90.41)
50 (85.68)
50 (86.20)
50
>100
100 (219.78)
100 (205.96)
>100
>100
>100
100 (205.96)
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
25 (55.67)
12.5 (23.62)
25 (44.68)
50 (84.17)
50 (84.16)
50 (90.41)
12.5 (21.42)
12.5 (21.55)
>100
25 (55.67)
12.5 (23.62)
25 (44.68)
50 (84.17)
50 (84.16)
50 (90.41)
25 (42.84)
12.5 (21.55)
>100
8h
8i
Ciproflox.
Fluconazole
0.78 (2.35)
—
0.78 (2.35)
—
1.56 (4.70)
—
6.25 (18.8)
—
6.25 (18.8)
—
—
—
0.78 (2.54)
1.56 (5.09)
Ec, Escherichia coli (ATCC 25922); Pa, Pseudomonas aeruginosa (ATCC 27853); Sa, Staphylococcus aureus (ATCC 25923); Sf, Staphylococcus fecalis
(ATCC 29212); Bc, Bacillus subtilis (ATCC 6633); Ca, Candida albican (ATCC 10231); An, Aspergillus niger (ATCC 9029).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1154
S. H. Shivaji, P. C. Mhaske, S. Narkhade, and V. D. Bobade
Vol 51
(M+ 2), 524.1 (M+ 4). Anal. Calcd. for C27H19Cl2N3S2: C, 62.30;
EXPERIMENTAL
H, 3.68; N, 8.07. Found: C, 62.26; H, 3.70; N, 8.10.
Melting points were determined in an open capillary on Veego
melting point apparatus (Mumbai, India) and are uncorrected. All
reactions were monitored by thin layer chromatography on
0.25 mm E. Merck silica gel plates (F-254) using UV light or
iodine vapors as the visualizing methods. IR spectra (cmÀ1) were
recorded in KBr on a Shimadzu Model FTIR-435 spectrophotometer
4-(2-(3,4-dichlorobenzyl)thiazol-4-yl)-N-((4-methyl-2-
phenylthiazol-5-yl)methylene)benzenamine 7e. IR: 3071, 1600,
1583, 1484, 1320, 1200 cmÀ1 1H NMR (300 MHz, CDCl3): d
;
2.65 (s, 3H); 4.25 (s, 2H); 6.90–7.23 (m, 7H); 7.41–7.43 (m, 3H);
13
7.90–7.94 (m, 4H);
C NMR (75 MHz, CDCl3): 16.1, 39.3,
113.2, 116.5, 122.8, 127.3, 128.6, 128.8, 129.0, 129.6, 130.1,
130.4, 130.8, 131.9, 132.9, 133.5, 135.8, 137.5, 151.3, 152.1,
162.0, 169.1, 169.6; ms: m/z 520 (M+), 522.1 (M+ 2), 524.1
(M+ 4). Anal. Calcd. for C27H19Cl2N3S2: C, 62.30; H, 3.68; N,
1
(Kyoto, Japan). H NMR and 13C NMR spectra were recorded in
CDCl3 and DMSO-d6 solution on a Varian Mercury YH-300
1
spectrometer (Darmstadt, Germany) operating at 300 MHz for H
and 75 MHz for 13C, respectively. Chemical shifts are expressed
relative to tetramethylsilane and were reported as d (ppm). Liquid
Cromatography Mass Spectrometry (LCMS) measurements were
made on a Jeol-JMS-DX 303 mass spectrometer (Tokyo, Japan).
The elemental analysis was performed on FLASH EA 1112 analyzer
(Thermo Scientific, Cambridge, UK) and results were found within
the Æ0.4% of theoretical values.
8.07. Found: C, 62.27; H, 3.70; N, 8.11.
4-(2-(4-methoxybenzyl)thiazol-4-yl)-N-((4-methyl-2-phenylthiazol-
5-yl)methylene)benzenamine 7f. IR: 3070, 3047, 1612, 1575,
1518, 1460, 1315, 1248, 1178 cmÀ1 1H NMR (300MHz,
;
CDCl3): d 2.65 (s, 3H), 3.76 (s, 3H), 4.29 (s, 2H), 6.85 (d, 2H,
J = 8.6Hz), 7.21–7.29 (m, 5H), 7.40–7.42 (m, 3H), 7.89 (d, 2H,
J = 8.6Hz); 7.94–7.97 (m, 2H), 8.61 (s, 1H); 13 C NMR (75MHz,
CDCl3): d 16.1, 39.0, 55.2, 112.6, 114.1, 121.4, 126.8, 127.2,
129.0, 129.9, 130.2, 130.8, 131.7, 132.8, 133.2, 150.4, 150.9,
154.7, 157.3, 158.7, 169.9, 171.4; ms: m/z 481.1 (M+), 483.1
(M+ 2). Anal. Calcd. for C28H23N3OS2: C, 69.83; H, 4.81; N,
General procedure for compounds (7a–i). To a solution of
4-methyl-2-phenylthiazole-5-carbaldehyde 3a (0.005 mol) in dry
toluene (30 mL), 4-(2-(3-fluorophenyl)thiazol-4-yl)benzenamine,
6b (0.006mol), and glacial acetic acid (0.2 mL) was added. The
reaction mixture was refluxed for 5–6 h with azeotropic separation
of water. After the completion of the reaction (TLC) solvent was
removed under reduced pressure. The product was recrystalized
8.72. Found: C, 69.85; H, 4.77; N, 8.75.
((2-(4-chlorobenzyl)-4-methylthiazol-5-yl)methylene)-4-(2-
methylthiazol-4-yl)benzenamine 7g.
1488, 1323, 1235, 1182 cmÀ1 1H NMR (300 MHz, CDCl3):
d 2.49 (s, 3H), 2.66 (s, 3H), 4.37 (s, 2H), 6.88–7.38 (m,
IR: 3064, 1611, 1585,
from dry ethanol.
N-((4-methyl-2-phenylthiazol-5-yl)methylene)-4-(2-methylthiazol-
;
4-yl)benzenamine 7a. IR: 3051, 1612, 1583, 1500, 1460, 1429,
13
5H), 7.90–7.94 (m, 4H), 8.55 (s, 1H);
C NMR (75 MHz,
1373, 1325, 1201, 1172cmÀ1 1H NMR (300 MHz, CDCl3):
;
CDCl3): d 15.5, 19.4, 39.0, 112.8, 122.5, 127.9, 128.8,
130.5, 131.5, 131.9, 133.9, 135.0, 137.3, 151.2, 153.7,
161.0, 168.8, 169.2; ms: m/z 423.6 (M+), 425.6 (M+ 2). Anal.
Calcd. for C22H18ClN3S2: C, 62.32; H, 4.28; N, 9.91. Found: C,
d 2.69 (s, 3H), 2.78 (s, 3H), 7.18 (s, 1H), 7.27–7.31 (m, 2H),
7.45–7.48 (m, 3H), 7.92 (d, J = 8.4Hz, 2H), 7.98–8.01 (m, 2H),
13
8.66 (s, 1H); C NMR (75 MHz, CDCl3): d 15.8, 21.1, 117.4,
121.8, 126.9, 127.8, 128.9, 129.2, 129.6, 132.6, 133.5, 142.9,
151.5, 159.3, 162.2, 169.1, 169.6; ms: m/z 375 (M+), 377.1
(M+ 2). Anal. Calcd. for C21H17N3S2: C, 67.17; H, 4.56; N,
11.19. Found: C, 67.19; H, 4.55; N, 11.15.
4-(2-(3-fluorophenyl)thiazol-4-yl)-N-((4-methyl-2-phenylthiazol-
62.30; H, 4.26; N, 9.83.
((2-(4-chlorobenzyl)-4-methylthiazol-5-yl)methylene)-4-(2-(4-
chlorophenyl)thiazol-4-yl)benzenamine 7h.
1588, 1486, 1322, 1208, 1189 cmÀ1 1H NMR (300 MHz,
CDCl3): d 2.62 (s, 3H), 4.28 (s, 2H), 6.92 (d, J = 8.4 Hz, 2H,),
IR: 3065, 1613,
;
5-yl)methylene)benzenamine 7b.
IR: 3074, 2964, 1612, 1581,
13
1479, 1375, 1319, 1261, 1174 cmÀ1; 1H NMR (300 MHz, CDCl3):
7.10–7.35 (m, 9H), 7.80 (d, J = 8.4 Hz, 2H), 8.56 (s, 1H);
C
NMR (75 MHz, CDCl3): d 15.6, 39.5, 112.4, 123.5, 126.0,
127.9, 128.6, 129.0, 129.5, 130.5, 130.9, 131.2, 131.7, 133.5,
134.0, 137.0, 151.2, 152.9, 160.8, 168.0, 169.8; ms: m/z 520.0
(M+), 522.1 (M + 2), 524.1 (M + 4). Anal. Calcd. for
C27H19Cl2N3S2: C, 62.30; H, 3.68; N, 8.07. Found: C, 62.34;
H, 3.62; N, 8.11.
d 2.67 (s, 3H), 7.10–7.23 (m, 4H), 7.26–7.45 (m, 4H), 7.72–7.79
13
(m, 2H), 7.96–8.01 (m, 4H), 8.62 (s, 1H);
C NMR (75MHz,
CDCl3): d 15.2, 114.5, 114.9, 117.5, 123.2, 126.6, 126.9, 127.7,
128.4, 128.9, 129.3, 130.9, 131.7, 133.5, 135.2, 139.5, 152.2,
155.1, 161.0, 162.1, 167.9, 170.0; ms: m/z 455 (M+), 457.1 (M + 2).
Anal. Calcd. for C26H18FN3S2: C, 68.55; H, 3.98; N, 9.22. Found:
C, 68.50; H, 4.00; N, 9.25.
4-(2-(4-chlorobenzyl)thiazol-4-yl)-N-((4-methyl-2-phenylthiazol-
((2-(4-chlorobenzyl)-4-methylthiazol-5-yl)methylene)-4-(2-(4-
methoxybenzyl)thiazol-4-yl)benzenamine 7i. IR: 3059, 1612,
1
1594, 1484, 1377, 1318, 1242, 1178 cmÀ1; H NMR (300 MHz,
5-yl)methylene)benzenamine 7c.
IR: 3062, 1610, 1575, 1491,
1
1419, 1375,1317, 1205, 1176 cmÀ1; H NMR (300 MHz, CDCl3):
d 2.71 (s, 3H), 4.37 (s, 2H), 7.25–7.45 (m, 10H), 7.95–8.02 (m,
4H), 8.67 (s, 1H); 13 C NMR (75 MHz, CDCl3): 16.1, 39.1, 112.7,
117.5, 121.5, 126.8, 127.2, 128.9, 129.0, 129.6, 130.4, 130.8,
132.6, 133.2, 136.2, 150.5, 151.1, 157.4, 162.2, 169.1, 169.6; ms:
m/z 485.5 (M+), 487.6 (M + 2). Anal. Calcd. for C27H20ClN3S2: C,
CDCl3): d 2.60 (s, 3H), 3.79 (s, 3H), 4.25 (s, 2H), 4.32 (s, 2H),
6.88 (d, 2H, J = 8.4 Hz), 7.10–7.35 (m, 9H), 7.88 (d, 2H,
13
J = 8.4 Hz), 8.56 (s, 1H);
C NMR (75 MHz, CDCl3): d 15.2,
38.8, 39.2, 55.2, 113.9, 114.5, 120.3, 126.5, 127.2, 129.1,
129.7, 130.3, 130.5, 132.2, 133.0, 134.0, 136.8, 150.9, 152.2
156.8, 158.7, 168.7, 169.5; ms: m/z 529.5 (M+), 531.6 (M + 2).
Anal. Calcd. for C29H24ClN3OS2: C, 65.71; H, 4.56; N, 7.93.
66.72; H, 4.15; N, 8.65. Found: C, 66.76; H, 4.11; N, 8.69.
4-(2-(2,4-dichlorobenzyl)thiazol-4-yl)-N-((4-methyl-2-
Found: C, 65.67; H, 4.59; N, 7.96.
General procedure for compounds (8a–i). To a solution of
phenylthiazol-5-yl)methylene)benzenamine 7d. IR: 3070, 1600,
1584, 1480, 1319, 1199cmÀ1 1H NMR (300 MHz, CDCl3): d
;
4-(2-(3-fluorophenyl) thiazol-4-yl)-N-((4-methyl-2-phenylthiazol-
5-yl) methylene) benzenamine 7b (0.5 mmol) in dry toluene
(20 mL), thioglycolic acid (0.6 mmol) was added and the reaction
mixture was refluxed for 8–10h (TLC). The solvent was removed
under reduced pressure and the residue was treated with saturated
solution of NaHCO3, the aqueous layer was extracted with ethyl
2.68 (s, 3H); 4.26 (s, 2H); 6.94–7.29 (m, 6H); 7.35–7.44 (m, 3H);
13
7.49–7.53 (m, 2H); 7.88–7.94 (m, 3H);
C NMR (75 MHz,
CDCl3): 16.0, 36.2, 112.9, 116.8, 122.0, 126.8, 127.3, 128.7,
129.0, 129.3, 130.4, 130.8, 131.8, 132.6, 133.2, 135.9, 136.2,
151.1, 151.8, 155.0, 162.0, 169.0, 169.8; ms: m/z 520 (M+), 522.1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis and Antimicrobial Activities of Thiozolidin-4-one Derivatives
1155
2H); 4.28 (s, 2H); 6.41 (s, 1H); 6.85–6.90(m, 2H); 7.18–7.29 (m,
5H); 7.38–7.43 (m, 3H); 7.83–7.87 (m, 4H); 13C NMR (75MHz,
CDCl3): d 15.0, 33.5, 39.6, 55.5, 58.1, 113.2, 114.6, 122.7, 127.3,
127.5, 128.2, 128.5, 128.9, 129.2, 129.5, 130.3, 133.5, 137.1,
158.2, 151.2, 152.0, 168.1, 169.2, 171.2; ms: m/z 555.0 (M+),
557.0 (M + 2). Anal. Calcd. for C30H25N3O2S3: C, 64.84; H, 4.53;
acetate (25 mL Â 3). The organic layer was washed with water, brine,
and dried over Na2SO4. The solvent was removed under reduced
pressure. The crude product was purified by column chromatography
to afford 3-(4-(2-(3-fluorophenyl)thiazol-4-yl)phenyl)-2-(4-methyl-2-
phenylthiazol-5-yl)thiazolidin-4-one 8b 1.30 g (67%).
2-(4-methyl-2-phenylthiazol-5-yl)-3-(4-(2-methylthiazol-4-yl)
N, 7.56. Found: C, 64.80; H, 4.49; N, 7.61.
phenyl)thiazolidin-4-one 8a. IR: 1689, 1602, 1533, 1500, 1373,
1317, 1242, 1174, 999, 848, 763, 692 cmÀ1; 2.24 (s, 3H); 2.29 (s,
3H); 4.09 (AB quartet, 2H); 6.52 (s,1H); 7.00 (t, 1H); 7.19 (m, 2H);
2-(2-(4-chlorobenzyl)-4-methylthiazol-5-yl)-3-(4-(2-methylthiazol-
4-yl)phenyl)thiazolidin-4-one 8g. IR: 1685, 1601, 1535, 1496,
1373, 1217, 1176, 1095, 1018, 977, 846, 752, 663 cmÀ1 1H
;
13
7.35–7.43 (m, 5H); 7.67 (m, 2H); C NMR (75MHz, CDCl3): d
NMR (300MHz, CDCl3): d 2.12 (s, 3H); 2.76 (s, 3H); 3.88
(AB quartet, 2H); 4.12 (s, 2H); 6.32 (s, 1H); 7.09–7.16 (m, 3H);
7.26–7.30 (m, 4H); 7.84 (d, J = 8.6 Hz 2H); 13C NMR (75MHz,
CDCl3): d 15.0, 19.3, 33.3, 39.1 58.2, 113.1, 126.7, 126.9, 127.2,
129.0, 130.3, 132.3, 134.1, 135.7, 136.1, 151.0, 153.8, 166.2,
169.8, 170.1; ms: m/z 497.6 (M+), 499.6 (M+ 2). Anal. Calcd. for
C24H20ClN3OS3: C, 57.87; H, 4.05; N, 8.44. Found: C, 57.90; H,
14.8, 19.5, 33.3, 58.1, 115.5, 126.5, 127.3, 127.9, 128.4, 128.8,
129.0, 129.6, 133.3, 137.8, 151.0, 151.8, 166.8, 169.0, 170.1; ms:
m/z 449.0 (M+), 451.0 (M + 2). Anal. Calcd. for C23H19N3OS3 C,
61.44; H, 4.26; N, 9.35. Found: C, 61.40; H, 4.22; N, 9.39.
3-(4-(2-(3-fluorophenyl)thiazol-4-yl)phenyl)-2-(4-methyl-2-
phenylthiazol-5-yl)thiazolidin-4-one 8b. IR: 1690, 1603, 1591,
1
1531, 1479, 1375, 1263, 1178, 1066, 790, 686 cmÀ1; H NMR
4.01; N, 8.49.
(300MHz, CDCl3): d : 2.23 (s, 3H); 4.00 (AB quartet, 2H);
6.43 (s, 1H); 7.12 (t, J = 6.8 Hz, 1H); 7.24 (d, J = 8.1 Hz, 2H);
7.39–7.41 (m, 4H); 7.76 (s, 1H); 7.73 (d, J = 7.8 Hz, 2H);
2-(2-(4-chlorobenzyl)-4-methylthiazol-5-yl)-3-(4-(2-(4-
chlorophenyl)thiazol-4-yl)phenyl)thiazolidin-4-one 8h. IR: 1693,
1599, 1529, 1481, 1352, 1240, 1095, 972, 840, 750 cmÀ1; 1H NMR
(300 MHz, CDCl3): d 2.15 (s, 3H); 3.90 (AB quartet, 2H); 4.13
(s, 2H); 6.35 (s, 1H); 7.14–7.17 (m, 4H); 7.22–7.30 (m, 2H);
7.41–7.46 (m, 3H); 7.92–7.97 (m, 4H); 13C NMR (75MHz,
CDCl3): d 15.1, 33.4, 39.2, 58.2, 113.6, 126.7, 127.3, 127.8, 129.0,
129.2, 130.3, 132.0, 132.4, 133.2, 133.8, 135.7, 136.1, 136.5,
151.0, 155.1, 166.8, 169.8, 170.0; ms: m/z 594.0 (M+), 596.1
(M + 2), 598.1 (M + 4). Anal. Calcd. for C29H21Cl2N3OS3: C,
13
7.83–7.86 (m, 2H); 7.95 (d, J = 8.1 Hz, 2H) C NMR (75 MHz,
CDCl3): d 15.2, 33.4, 58.5, 113.4, 113.8, 116.9, 122.2, 126.4,
126.7, 127.1, 127.4, 128.9, 130.4, 130.5, 132.0, 133.0, 133.8,
136.5, 152.1, 155.1, 163.0, 166.1, 167.9, 170.0; ms: m/z 529.0
(M+), 531.0 (M + 2). Anal. Calcd. for C28H20FN3OS3: C, 63.49;
H, 3.81; N, 7.93. Found: C, 63.44; H, 3.85; N, 7.97.
3-(4-(2-(4-chlorobenzyl)thiazol-4-yl)phenyl)-2-(4-methyl-2-
phenylthiazol-5-yl)thiazolidin-4-one 8c. IR: 1685, 1601, 1537,
58.58; H, 3.56; N, 7.07. Found: C, 58.55; H, 3.51; N, 7.10.
1494, 1410, 1377, 1323, 1242, 1178, 842, 756, 688 cmÀ1 1H
;
2-(2-(4-chlorobenzyl)-4-methylthiazol-5-yl)-3-(4-(2-(4-
NMR (300 MHz, CDCl3): d 2.24 (s, 3H); 4.00 (AB quartet, 2H);
4.33 (s, 2H); 6.44 (s, 1H); 67.21–7.70 (m, 10H); 7.85–7.88 (m,
4H); 13C NMR (75 MHz, CDCl3): d 15.0, 33.6, 39.5, 58.0, 113.5,
117.2, 122.7, 127.3, 127.5, 128.5, 128.9, 129.2, 129.6, 130.5,
131.2, 133.2, 134.1, 137.0, 151.1, 152.3, 168.0, 169.2, 171.0; ms:
m/z 559.6 (M+), 561.6 (M+ 2). Anal. Calcd. for C29H22ClN3OS3:
methoxybenzyl)thiazol-4-yl)phenyl)thiazolidin-4-one 8i. IR: 1690,
1604, 1508, 1373, 1307, 1249, 1182, 1030, 844, 758, 646cmÀ1
;
1H NMR (300 MHz, CDCl3): d 2.15 (s, 3H); 3.90 (s, 3H); 3.96
(AB quartet, 2H); 4.15 (s, 2H); 4.32 (s, 2H); 6.34 (s, 1H); 6.91 (d,
2H); 7.17 (m, 4H); 7.21–7.31(m, 4H); 7.65 (s, 1H); 7.86 (d, 2H);
13 C NMR (75 MHz, CDCl3): d 14.9, 33.3, 38.8, 39.0, 55.2, 58.2,
113.8, 114.2, 120.2, 126.7, 127.0, 129.0, 129.7, 130.2, 130.3,
132.4, 133.2, 134.1, 135.6, 136.1, 150.9, 153.9, 158.8, 169.8,
171.9; ms: m/z 603.5 (M+), 605.5 (M + 2). Anal. Calcd. for
C31H26ClN3O2S3 : C, 61.62; H, 4.34; N, 6.95. Found: C, 61.59;
H, 4.36; N, 6.99.
C, 62.18; H, 3.96; N, 7.50. Found: C, 62.15; H, 4.00; N, 7.53.
3-(4-(2-(2,4-dichlorobenzyl)thiazol-4-yl)phenyl)-2-(4-methyl-
2-phenylthiazol-5-yl)thiazolidin-4-one 8d.
IR: 1693, 1601,
1535, 1496, 1465, 1373, 1242, 1030,819, 761, 688 cm-1; 1H
NMR (300 MHz, CDCl3): d 2.22 (s, 3H); 3.98 (AB quartet, 2H);
4.29 (s, 2H); 6.42 (s, 1H); 7.15 - 7.22 (m, 3H); 7.33 – 7.41 (m,
13
Antimicrobial activity. The MIC values of the synthesized
compounds were determined in duplicate based on the micro
dilution method in 96 multi-well microtiter plates as previously
described [42]. The tested strains were obtained from the
American type culture collection (ATCC). The following micro
organisms were used in the present work: E. coli (ATCC
25922), S. fecalis (ATCC29212), S. aureus (ATCC 25923), P.
aeruginosa (ATCC 27853) B. subtilis (ATCC6633) C. albicans
(ATCC 10231), A. Niger (ATCC 9029). A total of 100 mL of
Mueller Hilton broth or potato dextrose broth media was added
into each well of the 96 well microtiter plates leaving the
peripheral wells blank. The samples were dissolved in DMSO at
1.0 mg mLÀ1. Approximately 100 mL test compound was added
into the two wells B2 and C2 (for duplicate MIC readings) of a
particular concentration and serially diluted (twofold dilutions)
until B6 and C6 well. The final concentration of the test
compounds adopted to evaluate antimicrobial activity was from
100 to 6.25 mg. A total of 100 mL of homogenized bacterial or
fungal cell culture suspension (106 cells per well) was added to
all the wells (wells with and without drug). Then, the plates
were labeled and incubated at 37 ꢀC for 48 h in an incubator.
6H); 7.85 (d, J = 7.9Hz 4H);
C NMR (75 MHz, CDCl3): d
14.9, 33.5, 39.6, 58.1, 113.6, 122.9, 127.0, 127.4, 127.6, 128.5,
128.8, 129.2, 129.9, 130.2, 131.8, 132.7, 133.2, 135.6, 136.0,
137.0, 151.1, 152.3, 168.0, 169.2, 170.8; ms: m/z 594.1 (M+),
596.1 (M+ 2), 598.1 (M+ 4). Anal. Calcd. for C29H21Cl2N3OS3:
C, 58.58; H, 3.56; N, 7.07. Found: C, 58.55; H, 3.60; N, 7.11.
3-(4-(2-(3,4-dichlorobenzyl)thiazol-4-yl)phenyl)-2-(4-methyl-
2-phenylthiazol-5-yl)thiazolidin-4-one 8e.
IR: 1687, 1597,
1535, 1494, 1377, 1321, 1242, 1182, 1053, 846, 760,
1
690 cmÀ1; H NMR (300 MHz, CDCl3): d 2.21(s, 3H);3.98 (AB
quartet, 2H); 4.44 (s, 2H); 6.42 (s, 1H); 7.19–7.41 (m, 9H);
13
7.84 (m, 4H); C NMR (75 MHz, CDCl3): d 15.0, 33.4, 39.5,
58.0, 113.5, 123.0, 127.4, 127.6, 128.0, 128.5, 128.8, 129.0,
129.3, 129.9, 130.2, 130.4, 133.1, 133.5, 135.8, 137.3, 151.2,
152.2, 168.2, 169.2, 171.1; ms: m/z 594.0 (M+), 596.0 (M + 2),
598.0 (M + 4). Anal. Calcd. for C29H21Cl2N3OS3: C, 58.58; H,
3.56; N, 7.07. Found: C, 58.54; H, 3.61; N, 7.10.
3-(4-(2-(4-methoxybenzyl)thiazol-4-yl)phenyl)-2-(4-methyl-2-
phenylthiazol-5-yl)thiazolidin-4-one 8f. IR: 1692, 1601, 1536,
1489, 1477, 1326, 1241, 1055, 844, 761, 688cmÀ1 1H NMR
;
(300MHz, CDCl3): d 2.21 (s, 3H); 3.80 (s, 3H); 3.98 (AB quartet,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1156
S. H. Shivaji, P. C. Mhaske, S. Narkhade, and V. D. Bobade
Vol 51
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reported are the average of two experiments (B and C).
Acknowledgments. The authors thank the Department of Chemistry,
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UGC, New Delhi for the financial assistance.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet