Synthesis, characterization, and antimicrobial activity of 3′-(4-(2-substituted thiazol-4-yl)phenyl)spiro[indoline-3,2′- thiazolidine]-2,4′-dions

Article abstract of DOI:10.1002/jhet.503

A series of 3′-(4-(2-methyl/phenyl/benzylthiazol-4-yl)phenyl) spiro[indoline-3,2′-thiazolidine]-2,4′-diones was synthesized. The structures of the synthesized compounds were evaluated by analytical and spectral (IR, ¹H NMR, ¹³C NMR, LC-MS, and elemental analysis) methods. All the synthesized compounds were screened for qualitative (Zone of inhibition) and quantitative antimicrobial activities (MIC). Most of the derivatives showed good activity towards Gram-positive and Gram-negative bacteria.

Full text of DOI:10.1002/jhet.503

November 2010
Synthesis, Characterization, and Antimicrobial Activity of
30-(4-(2-Substituted thiazol-4-yl)phenyl)spiro
[indoline-3,20-thiazolidine]-2,40-diones
1415
Pravin C. Mhaske,a Shivaji H. Shelke,b Rahul P. Jadhav,b
Hemant N. Raundal,b Sachin V. Patil,b Amar A. Patil,b and Vivek D. Bobadeb*
aDepartment of Chemistry, S. P. College, Pune 411030, India
bP.G. Department of Chemistry, H. P. T. Arts and R. Y. K. Science College, Nashik 422005, India
*E-mail: v_bobade31@rediffmail.com
Received January 17, 2010
DOI 10.1002/jhet.503
Published online 30 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
A series of 30-(4-(2-methyl/phenyl/benzylthiazol-4-yl)phenyl)spiro[indoline-3,20-thiazolidine]-2,40-dio-
nes was synthesized. The structures of the synthesized compounds were evaluated by analytical and
1
spectral (IR, H NMR, 13C NMR, LC-MS, and elemental analysis) methods. All the synthesized com-
pounds were screened for qualitative (Zone of inhibition) and quantitative antimicrobial activities
(MIC). Most of the derivatives showed good activity towards Gram-positive and Gram-negative
bacteria.
J. Heterocyclic Chem., 47, 1415 (2010).
INTRODUCTION
recrystallized from hexane: ethyl acetate (9:1). The
1
structures of the compounds were established by IR, H
The chemistry of spiro derivatives of isatin continues
to draw attention of synthetic organic chemists due to
their varied biological activities [1–4]. Of these, spi-
ro[indol-thiazolidenes] has attracted our attention
because they show a broad spectrum of pharmacological
properties [5,6]. On the basis of these observations it
was thought that it would be worthwhile to design and
synthesize some new isatin based spirothiazolidine
derivatives derived by coupling spiro[indol-thiazoli-
denes] with biologically active thiazole nucleus. Hence,
we have synthesized several 30-(4-(2-substituted thiazol-
4-yl)phenyl)spiro[indoline-3,20-thiazolidine]-2,40-diones
13–32 and screened for their antimicrobial activity.
NMR, 13C NMR, LCMS, and elemental analysis and the
results are presented in the experimental section. The
spectral data of compounds 13–32 were in accordance
with the assumed structures. The mass spectra of all the
compounds revealed the molecular ion peak Mþ and
Mþ2 ion peak due to S, Br, and/or Cl. The IR spectra
showed presence of characteristic absorption peaks at
3200–3400 cmꢀ1 (>NH), 1730 and 1695 cmꢀ1 (C¼¼O)
indicating that cyclocondensation has occurred which
1
was confirmed by its H NMR and 13C NMR data. The
1H NMR spectra revealed a double doublet integrating
for two geminal protons of thiazolidine nucleus. 13C
NMR spectra showed all expected characteristic peaks
in the aromatic and aliphatic region along with d 110–
111 (spiro carbon atom) [13]. As a representative case,
the IR spectrum of compound 27 showed peaks at 3238
cmꢀ1(>NH), 1735 and 1694 cmꢀ1 (C¼¼O), 1619 cmꢀ1
(C¼¼N) indicating that the cycloaddition has occurred.
This was further confirmed by its 1H NMR spectrum
which revealed an AB quartet of thiazolidine methylene
at d 3.75 and 4.42 with J ¼ 15 Hz. The benzylic meth-
ylene protons appeared at d 4.18. All the aromatic pro-
tons appeared between d 6.88 and 7.67. The lactam
NAH appeared at d 10.17. Further the 13C NMR spec-
trum of 27 revealed two signals at d 33.00 and 38.8 for
RESULTS AND DISCUSSION
The synthesis of 30-(4-(2-methyl/phenyl/benzylthiazol-
4-yl)phenyl)spiro[indoline-3,20-thiazolidine]-2,40-diones
13–32 is illustrated and outlined in Figure 1. The start-
ing materials 2-methyl-4-(4-aminophenyl)thiazole 3, 2-
aryl-4-(4-aminophenyl)thiazole 4–6, 2-benzyl-4-(4-ami-
nophenyl)thiazole 7–12, were prepared according to
reported procedure [7]. The spiro compounds were syn-
thesized by the reported procedure [8–13]. All the com-
pounds were purified by column chromatography or
C
V
2010 HeteroCorporation

1416
P. C. Mhaske, S. H. Shelke, R. P. Jadhav, H. N. Raundal, S. V. Patil,
A. A. Patil, and V. D. Bobade
Vol 47
Figure 1. Synthetic pathway for the formation of the compounds 13–32.
benzylic and thiazolidine methylene carbons, in addition
the spiro carbon appeared at d 110.9. The aromatic ipso
carbon attached to fluorine appeared as doublet with J
peak Mþ at m/z 427. The elemental analysis C (63.71),
H (3.93), N (9.06), and S (12.87) was within 60.4% of
the calculated.
1
¼ 246.8 Hz (CAF). The ortho and the meta carbon
Antimicrobial evaluation. The in vitro antibacterial
activity was performed against Gram-positive bacteria
including Staphylococcus aureus (NCIM 2079), Bacillus
subtilis (NCIM 2250), and Gram-negative bacteria
including Escherichia coli (NCIM 2109). The antifungal
activity was against fungi including Candida albicans
atoms in the same ring also appeared as doublets with
3
2J ¼ 21.5 Hz and J ¼ 8.3 Hz. All other aromatic car-
bon atoms appeared between d 113–119 and 163.8 and
the two carbonyl carbons appeared downfield at d 172.6
and 176.8. The mass spectrum showed a molecular ion
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis, Characterization, and Antimicrobial Activity of 30-(4-(2-Substituted
thiazol-4-yl)phenyl)spiro[indoline-3,20-thiazolidine]-2,40-diones
1417
Table 1
Antimicrobial screening of synthesized compounds 13–32.
Microorganisms
Compoundsa
B. subtilis
S. aureus
E. coli
C. albicans
A. niger
13
14
15.64
–
12.52
16.00
10.11
9.00
–
14.97
–
–
–
–
–
15
16
11.95
13.78
12.88
9.76
–
–
–
–
–
–
17
18
19
20
21
22
23
24
12.13
8.00
11.80
–
10.12
–
–
–
–
–
–
–
11.65
10.28
11.23
12.88
10.47
–
11.50
15.06
–
–
10.12
–
9.80
–
–
–
–
–
–
–
–
10.97
12.79
10.38
–
11.74
8.34
–
–
–
25
26
11.90
10.04
12.71
9.52
–
–
–
–
27
28
–
–
–
–
–
–
9.36
11.98
10.34
–
29
30
31
10.20
9.88
–
12.94
11.04
10.02
8.60
–
–
–
–
–
–
32
Ciprofloxacina
Nystatina
–
26
–
25
–
NA
20.5
–
NA
22.1
28
NA
NA
NA
Zone diameter of growth inhibition in mm.
NA, not applicable; –, inactive.
a Ciprofloxacin (10 lg/disc) and Nystatin (100 U/disc) were used as reference; synthesized compounds (100 lg/disc).
(NCIM 3471) and Aspergillus niger (NCIM 545). To
Table 2
evaluate the activity of the synthesized compounds
against bacteria, the zone of inhibition and minimum in-
hibitory concentrations (MICs) were determined. Known
antibiotic Ciprofloxacin (the reference for antibacterial
drugs) and Nystatin (the reference antifungal drug) were
used for comparison. The zone of inhibition and MIC
against micro organisms tested is reported in (Tables 1
and 2), respectively.
Antibacterial activity of compounds 13–32.
Microorganisms
Compounds
B. subtilis
S. aureus
E. coli
13
14
–
–
50
50
60
60
–
15
16
17
18
19
20
21
22
100
100
90
90
100
85
–
85
–
100
–
–
The results of the antibacterial activity showed that the
tested compounds are effective against the Gram-positive
bacteria S. aureus and B. subtilis and Gram-negative bac-
teria E. coli. The investigation showed moderate inhibi-
tory effects, with the majority of the compounds with the
MIC values between 50 and 100 lg/mL. As shown in
Table 2, all the compounds were active against S. aureus
except compound 24. The 4-methoxy substituted com-
pounds 29 and 30 were active against all the three species.
In general, compound with methyl group and the benzyl
ring at 2 position of thiazole moiety showed enhanced
activity.
100
100
80
100
60
–
90
60
50
85
–
–
23
24
–
–
70
90
100
–
80
90
–
25
26
100
100
90
100
80
27
28
–
–
100
80
90
–
29
30
31
32
100
100
–
90
80
The results of antifungal activity showed that all the
compounds were inactive except compound 21, which
showed moderate activity against C. albicans and
A. niger.
–
100
4
–
4
Ciprofloxacin
4
MIC in lg/mL.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1418
P. C. Mhaske, S. H. Shelke, R. P. Jadhav, H. N. Raundal, S. V. Patil,
A. A. Patil, and V. D. Bobade
Vol 47
EXPERIMENTAL
3440, 3221 (NH); 3118, 3021 (CH, Ar-H); 1731 (CO); 1695
(CO); 1612 (C¼¼N); 1H NMR (DMSO): d 4.05 (d, 1H, J ¼
15.4 Hz, Thiazolidine); 4.17 (d, H, J ¼ 15.4 Hz, Thiazolidine);
6.76–8.00 (m, 12H, Ar-H); 8.15 (s, 1H, Thiazole); 10.94
(s, 1H, NH, D2O exchangeable); ms: m/z 490.0 (Mþ),
492.0 (Mþ2). Anal. Calcd. for C25H16ClN3O2S2: C, 61.28; H,
3.29; N, 8.58; S, 13.09. Found: C, 60.80; H, 3.55; N, 8.41; S,
12.81.
Melting points were determined in an open capillary using
Veego melting point apparatus and are uncorrected. The purity
of the compounds was checked on silica gel-G plates. Infrared
spectra (cmꢀ1) were recorded in KBr on a Shimadzu Model
FTIR-435 spectrophotometer. 1H NMR and 13C NMR spectra
were recorded in CDCl3 and DMSO-d6 solution on a Varian
Mercury YH-300 spectrometer operating at 300 MHz or on
BRUKER ADVANCE II 400 spectrometer operating at 400
MHz for 1H and 75 MHz for 13C. Chemical shifts are
expressed relative to tetramethylsilane (TMS) and were
reported as d (ppm). LCMS measurements were made on a
Jeol-JMS-DX 303 mass spectrometer. The elemental analysis
was performed on FLASH EA 1112 analyzer.
30-(4-(2-(4-Chlorophenyl)thiazol-4-yl)phenyl)spiro[indoline-
3,20-thiazolidine]-2,40-dione (17) Yield: 74%; mp 222ꢁC,
recrystallized from hexane–ethyl acetate (9:1); IR (KBr, cmꢀ1
)
3436, 3216 (NH); 3118, 3011 (CH, Ar-H); 1730 (CO); 1694
(CO); 1605 (C¼¼N); 1H NMR (DMSO): d 4.02 (d, 1H, J ¼
15.2 Hz, Thiazolidine); 4.18 (d, 1H, J ¼ 15.2 Hz, Thiazoli-
dine); 6.75–8.01 (m, 12H, Ar-H); 8.16 (s, 1H, Thiazole); 10.80
(s, 1H, NH, D2O exchangeable); ms: m/z 490.0 (Mþ), 492.0
(Mþ2). Anal. Calcd. for C25H16ClN3O2S2: C, 61.28; H, 3.29;
N, 8.58; S, 13.09. Found: C, 61.40; H, 3.45; N, 8.50; S, 13.21.
5-Chloro-30-(4-(2-(4-chlorophenyl)thiazol-4-yl)phenyl)spiro
[indoline-3,20-thiazolidine]-2,40-dione (18) Yield: 74%; mp
230ꢁC dec., recrystallized from hexane–ethyl acetate (9:1); IR
(KBr, cmꢀ1) 3442, 3227 (NH); 3115, 3016 (CH, Ar-H); 1731
General procedure for compounds (13–32). To a solution
of isatin 1 (0.37 g, 2.5 mmol) in glacial acetic acid (1 mL)
and dry toluene (30 mL), 2-methyl-4-(4-aminophenyl)thiazole,
3 (0.48 g, 2.5 mmol) was added. The mixture was refluxed
using a Dean-Stark apparatus for 5–8 h to obtain the Schiff’s
base. After the completion of the reaction as monitored on
TLC, thioglycolic acid (3.0 mmol) was added and mixture was
further refluxed for 7–10 h. The solvent was removed under
reduced pressure and the residue was treated with saturated so-
lution of NaHCO3 to remove the unreacted acid. The product
was extracted with ethyl acetate, washed with water, brine and
dried (Na2SO4). The solvent was removed under vacuum, the
thick liquid thus obtained was added dropwise to a stirred so-
lution of hexane to obtain crystalline solid.
1
(CO); 1694 (CO); 1615 (C¼¼N); H NMR (CDCl3): d 4.04 (d,
1H, J ¼ 15.6 Hz, Thiazolidine); 4.17 (d, H, J ¼ 15.6 Hz,
Thiazolidine); 6.76–8.02 (m, 11H, Ar-H); 8.18 (s, 1H, Thia-
zole); 10.94 (s, 1H, NH, D2O exchangeable); ms: m/z 524.0
(Mþ), 525.9 (Mþ2). Anal. Calcd. for C25H15Cl2N3O2S2: C,
57.25; H, 2.88; N, 8.01; S, 12.23. Found: C, 57.39; H, 2.98;
N, 9.19; S, 12.44.
30-(4-(2-Methylthiazol-4-yl)phenyl)spiro[indoline-3,20-thia-
zolidine]-2,40-dione (13) Yield: 67%; mp 200–202ꢁC dec.,
30-(4-(2-(3-Fluorophenyl)thiazol-4-yl)phenyl)spiro[indoline-
3,20-thiazolidine]-2,40-dione (19) Yield: 64%; mp 86–87ꢁC,
recrystallized from hexane–ethyl acetate (9:1); IR (KBr, cmꢀ1
)
recrystallized from hexane–ethyl acetate (9:1); IR (KBr, cmꢀ1
)
3221 (NH); 3118, 3020 (CH, Ar-H); 1730 (CO); 1695 (CO);
1609 (C¼¼N); 1H NMR (CDCl3): d 2.71 (s, 3H, ACH3); 3.87
(d, 1H, J ¼ 15.6 Hz, Thiazolidine); 4.37 (d, 1H, J ¼ 15.6 Hz,
Thiazolidine); 6.67–7.74 (m, 8H, Ar-H); 7.39 (s, 1H, Thiazole)
ppm; ms: m/z 394.0 (Mþ) Anal. Calcd. for C20H15N3O2S2: C,
60.05; H, 3.84; N, 10.86; S, 16.30. Found: C, 59.97; H, 3.78;
N, 10.58; S, 15.95.
3440, 3222 (NH); 3121, 3008 (CH, Ar-H); 1731 (CO); 1696
(CO); 1609 (C¼¼N); 1H NMR (CDCl3): d 3.89 (d, 1H, J ¼
15.3 Hz, Thiazolidine); 4.10 (d, H, J ¼ 15.3 Hz, Thiazolidine);
6.75–7.75 (m, 12H, Ar-H); 8.67 (s, 1H, Thiazole); 13C NMR
(CDCl3):
d 33.2 (CH2, Thiazolidine); 111.12 (Spiro C);
113.14–164.57 (21C-Ar-C, Thiazole-C); 172.7 (CONH); 177.1
(CONH); ms: m/z 473.6 (Mþ). Anal. Calcd. for
C25H16FN3O2S2: C, 63.41; H, 3.41; N, 8.87; S, 13.54. Found:
C, 63.35; H, 3.82; N, 8.27; S, 11.35.
5-Chloro-30-(4-(2-methylthiazol-4-yl)phenyl)spiro[indoline-
3,20-thiazolidine]-2,40-dione (14) Yield: 62%; mp 193–195ꢁC
dec., recrystallized from hexane–ethyl acetate (9:1); IR (KBr,
cmꢀ1) 3437, 3224 (NH); 3123, 3022 (CH, Ar-H); 1730 (CO);
1694 (CO); 1607 (C¼¼N); 1H NMR (CDCl3): d 2.77 (s, 3H,
CH3); 3.88 (d, 1H, J ¼ 15 Hz, Thiazolidine); 4.36 (d, H, J ¼
15.6 Hz, Thiazolidine); 6.71–7.82 (m, 7H, Ar-H); 7.48 (s, 1H,
Thiazole) ppm; ms: m/z 429.0 (Mþ), 431(Mþ2). Anal. Calcd.
for C20H14ClN3O2S2: C, 56.13; H, 3.30; N, 9.82; S, 14.99.
Found: C, 56.30; H, 3.38; N, 9.93; S, 15.12.
5-Chloro-30-(4-(2-(3-fluorophenyl)thiazol-4-yl)phenyl)spiro
[indoline-3,20-thiazolidine]-2,40-dione (20) Yield: 62%; mp
140ꢁC, recrystallized from hexane–ethyl acetate (9:1); IR
(KBr, cmꢀ1) 3442, 3219 (NH); 3122, 3021 (CH, Ar-H); 1731
1
(CO); 1697 (CO); 1611 (C¼¼N); H NMR (CDCl3): d 3.92 (d,
1H, J ¼ 15.3 Hz, Thiazolidine); 4.30 (d, H, J ¼ 15.3 Hz,
Thiazolidine); 6.77–7.82 (m, 11H, Ar-H); 8.65 (s, 1H, Thia-
zole); ms: m/z 508.6 (Mþ), 510.2 (Mþ2). Anal. Calcd. for
C25H15ClFN3O2S2: C, 59.11; H, 2.98; N, 8.27; S, 12.62.
Found: C, 59.41; H, 3.17; N, 8.12; S, 13.01.
30-(4-(2-Phenylthiazol-4-yl)phenyl)spiro[indoline-3,20-thia-
zolidine]-2,40-dione (15) Yield: 67%; mp 66ꢁC dec., recrystal-
lized from hexane–ethyl acetate (9.5:0.5); IR (KBr, cmꢀ1
3435, 3224 (NH); 3115, 3024 (CH, Ar-H); 1730 (CO); 1694
)
30-(4-(2-Benzylthiazol-4-yl)phenyl)spiro[indoline-3,20-thia-
zolidine]-2,40-dione (21) Yield: 72%; mp 194ꢁC, recrystal-
lized from hexane–ethyl acetate (9:1); IR (KBr, cmꢀ1) 3443,
3200 (NH); 3109, 3026 (CH, Ar-H); 1736 (CO); 1697 (CO);
1
(CO); 1607 (C¼¼N); H NMR (CDCl3): d 3.88 (d, 1H, J ¼ 16
Hz, Thiazolidine); 4.38 (d, H, J ¼ 16 Hz, Thiazolidine); 6.71–
7.98 (m, 13H, Ar-H); 7.40 (s, 1H, Thiazole); ms: m/z 456.1
(Mþ). Anal. Calcd. For C25H17N3O2S2: C, 65.91; H, 3.76; N,
9.22; S, 14.08. Found: C, 65.58; H, 3.55; N, 9.46; S, 14.31.
5-Chloro-30-(4-(2-phenylthiazol-4-yl)phenyl)spiro[indoline-
3,20-thiazolidine]-2,40-dione (16) Yield: 72%; mp 84ꢁC,
1
1617 (C¼¼N); H NMR (CDCl3): d 3.88 (d, 1H, J ¼ 15.4 Hz,
Thiazolidine); 4.31 (s, 2H, CH2); 4.37 (d, 1H, J ¼ 15.4 Hz,
Thiazolidine); 6.71–7.75 (m, 13H, Ar-H); 8.05 (s, 1H, Thia-
zole); 13C NMR (CDCl3): d 33 (CH2, Thiazolidine); 39.7
(CH2, Benzyl); 110.82 (Spiro C); 113.85–154 (21C, Ar-C Thi-
azole-C); 170.7 (CONH); 172.5 (CONH); ms: m/z 469.0 (Mþ).
recrystallized from hexane–ethyl acetate (9:1); IR (KBr, cmꢀ1
)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis, Characterization, and Antimicrobial Activity of 30-(4-(2-Substituted
thiazol-4-yl)phenyl)spiro[indoline-3,20-thiazolidine]-2,40-diones
1419
Anal. Calcd. for C26H19N3O2S2: C, 66.50; H, 4.08; N, 8.95; S,
13.66. Found: C, 66.20; H, 4.01; N, 9.11; S, 13.78.
recrystallized from hexane–ethyl acetate (9:1); IR (KBr, cmꢀ1
)
3439, 3228 (NH); 3101(CH, Ar-H); 1735 (CO); 1694 (CO);
1619 (C¼¼N); 1H NMR (CDCl3): d 3.75 (d, 1H, J ¼ 15 Hz,
Thiazolidine); 4.18 (s, 2H, CH2); 4.22 (d, 1H, J ¼ 15 Hz,
Thiazolidine); 6.56–7.67 (m, 12H, Ar-H); 7.21 (s, 1H, Thia-
zole); 10.17 (s, 1H, NH, D2O exchangeable); ms: m/z 487.6
(Mþ). Anal. Calcd. for C26H18FN3O2S2: C, 64.05; H, 3.72; N,
8.62; S, 13.15. Found: C, 63.71; H, 3.93; N, 9.06; S, 12.87.
5-Chloro-30-(4-(2-(4-fluorobenzyl)thiazol-4-yl)phenyl)spiro
[indoline-3,20-thiazolidine]-2,40-dione (28) Yield: 66%; mp
139–140ꢁC, recrystallized from hexane–ethyl acetate (9:1); IR
(KBr, cmꢀ1) 3404, 3257 (NH); 3113, 3043 (CH, Ar-H); 1730
(CO); 1694 (CO); 1609 (C¼¼N); 864 (Ar-Cl); 1H NMR
(CDCl3): d 3.71 (d, 1H, J ¼ 7.6 Hz, Thiazolidine); 4.20 (s,
2H, CH2); 4.28 (d, 1H, J ¼ 7.6 Hz, Thiazolidine); 6.56–7.67
(m, 11H, Ar-H); 7.35 (s, 1H, Thiazole); 10.42 (s, 1H, NH,
D2O exchangeable); 13C NMR (CDCl3): d 33 (CH2, Thiazoli-
dine); 38(CH2, Benzyl); 111.7 (Spiro C); 113.9–160.2 (21C,
Ar-C, Thiazole-C); 172.2 (CONH); 175.9 (CONH); ms: m/z
521.2 (Mþ), 523.3 (Mþ2). Anal. Calcd. for C26H17ClFN3O2S2:
C, 59.82; H, 3.28; N, 8.05; S, 12.29. Found: C, 60.05; H, 3.51;
N, 8.26; S, 11.97.
30-(4-(2-Benzylthiazol-4-yl)phenyl)-5-chlorospiro[indoline-
3,20-thiazolidine]-2,40-dione (22) Yield: 72%; mp 112ꢁC,
recrystallized from hexane–ethyl acetate (9:1); IR (KBr, cmꢀ1
)
3411, 3248 (NH); 3108, 3030 (CH, Ar-H); 1737 (CO); 1697
(CO); 1618 (C¼¼N); 1H NMR (CDCl3): d 3.88 (d, 1H, J ¼
15.3 Hz, Thiazolidine); 4.30 (s, 2H, CH2); 4.35 (d, 1H, J ¼
15.3 Hz, Thiazolidine); 6.65–7.79 (m, 12H, Ar-H); 7.92 (s,
1H, Thiazole); 9.5 (s, 1H, NH, D2O exchangeable); ms: m/z
503.0 (Mþ), 505.0 (Mþ2). Anal. Calcd. for C26H18ClN3O2S2:
C, 61.96; H, 3.60; N, 8.34; S, 12.72. Found: C, 62.06; H, 3.79;
N, 8.86; S, 11.56.
30-(4-(2-(4-Bromobenzyl)thiazol-4-yl)phenyl)spiro[indoline-
3,20-thiazolidine]-2,40-dione (23) Yield: 72%; mp 204–207ꢁC,
recrystallized from hexane–ethyl acetate (9:1); IR (KBr, cmꢀ1
)
3411, 3205 (NH); 3111, 3052 (CH, Ar-H); 1731 (CO); 1694
(CO); 1606 (C¼¼N); 1H NMR (CDCl3): d 3.87 (d, 1H, J ¼
15.3 Hz, Thiazolidine); 4.25 (s, 2H, CH2); 4.36 (d, 1H, J ¼
15.3 Hz, Thiazolidine); 6.70–7.75 (m, 12H, Ar-H); 7.98 (s,
1H, Thiazole); 13C NMR (CDCl3): d 33 (CH2, Thiazolidine);
39.05 (CH2, Benzyl); 110.76 (Spiro C); 113.9–164.1 (21C, Ar-
C, Thiazole-C); 171 (CONH); 173.2 (CONH); ms: m/z 547.5
(Mþ), 549.6 (Mþ2). Anal. Calcd. for C26H18BrN3O2S2: C,
56.94; H, 3.31; N, 7.66; S, 11.69. Found: C, 57.06; H, 3.36;
N, 8.07; S, 11.85.
30-(4-(2-(4-Methoxybenzyl)thiazol-4-yl)phenyl)spiro[indoline-
3,20-thiazolidine]-2,40-dione (29) Yield: 58%; mp 62ꢁC, recrys-
tallized from hexane–ethyl acetate (9:1); IR (KBr, cmꢀ1) 3440,
3230 (NH); 3118(CH, Ar-H); 1732 (CO); 1696 (CO); 1609
1
30-(4-(2-(4-Bromobenzyl)thiazol-4-yl)phenyl)-5-chlorospiro
[indoline-3,20-thiazolidine]-2,40-dione (24) Yield: 65%; mp
190–192ꢁC, recrystallized from hexane–ethyl acetate (9:1); IR
(KBr, cmꢀ1) 3411, 3236 (NH); 3110, 3039 (CH, Ar-H); 1731
(C¼¼N); H NMR (CDCl3): d 3.80 (d, 1H, J ¼ 15 Hz, Thiazo-
lidine); 4.18 (s, 2H, CH2); 4.27 (d, 1H, J ¼ 15 Hz, Thiazoli-
dine); 4.33 (s, 3H, CH3); 6.66–7.74 (m, 12H, Ar-H); 7.68 (s,
1H, Thiazole); 10.17 (s, 1H, NH, D2O exchangeable); 13C
NMR (CDCl3): d 33.1 (CH2, Thiazolidine); 38.4 (CH2, Ben-
zyl); 58.4 (OACH3); 111.4 (Spiro C); 113.4–164.4 (21C, Ar-
C, Thiazole-C); 171.4 (CONH); 176.2 (CONH); ms: m/z 499.6
(Mþ). Anal. Calcd. for C27H21N3O3S2: C, 64.91; H, 4.24; N,
8.41; S, 12.84. Found: C, 65.11; H, 4.36; N, 8.52; S, 13.11.
5-Chloro-30-(4-(2-(4-methoxybenzyl)thiazol-4-yl)phenyl)spiro
[indoline-3,20-thiazolidine]-2,40-dione (30) Yield: 60%; mp
41ꢁC, recrystallized from hexane–ethyl acetate (9:1); IR (KBr,
cmꢀ1) 3412, 3252 (NH); 3121, 3033 (CH, Ar-H); 1734 (CO);
1696 (CO); 1612 (C¼¼N); 864 (Ar-Cl); 1H NMR (CDCl3): d
3.82 (d, 1H, J ¼ 15.3 Hz, Thiazolidine); 4.20 (s, 2H, CH2);
4.28 (d, 1H, J ¼ 15.3 Hz, Thiazolidine); 4.36 (s, 3H, CH3);
6.68–7.88 (m, 11H, Ar-H); 7.76 (s, 1H, Thiazole); 10.42 (s,
1H, NH, D2O exchangeable); ms: m/z 533.2 (Mþ), 535.6
(Mþ2). Anal. Calcd. for C27H20ClN3O3S2: C, 60.72; H, 3.77;
N, 7.87; S, 12.01. Found: C, 60. 81; H, 3.89; N, 8.04; S,
12.23.
1
(CO), 1695 (CO); 1614 (C¼¼N); H NMR (CDCl3): d 3.88 (d,
1H, J ¼ 15.4 Hz, Thiazolidine); 4.27 (s, 2H, CH2); 4.36 (d, 1H,
J ¼ 15.4 Hz, Thiazolidine); 6.64–7.78 (m, 11H, Ar-H); 7.68 (s,
1H, Thiazole); ms: m/z 581.9 (Mþ), 583.9 (Mþ2), 585.9
(Mþ4). Anal. Calcd. for C26H17BrClN3O2S2: C, 53.48; H, 3.11;
N, 7.20; S, 10.98. Found: C, 53.78; H, 3.33; N, 7.51; S, 11.17.
30-(4-(2-(4-Chlorobenzyl)thiazol-4-yl)phenyl)spiro[indoline-
3,20-thiazolidine]-2,40-dione (25) Yield: 70%; mp 56ꢁC,
recrystallized from hexane–ethyl acetate (9:1); IR (KBr, cmꢀ1
)
3414, 3240 (NH); 3118, 3022 (CH, Ar-H); 1731 (CO); 1694
(CO); 1612 (C¼¼N); 1H NMR (CDCl3): d 3.87 (d, 1H, J ¼
15.2 Hz, Thiazolidine); 4.28 (s, 2H, CH2); 4.37 (d, 1H, J ¼
15.2 Hz, Thiazolidine); 6.70–7.75 (m, 12H, Ar-H); 7.45 (s,
1H, Thiazole); ms: m/z 504.0 (Mþ), 506.0 (Mþ2). Anal.
Calcd. for C26H18ClN3O2S2: C, 61.96; H, 3.60; N, 8.34; S,
12.72. Found: C, 61.99; H, 3.82; N, 8.46; S, 11.28.
5-Chloro-30-(4-(2-(4-chlorobenzyl)thiazol-4-yl)phenyl)spiro
[indoline-3,20-thiazolidine]-2,40-dione (26) Yield: 65%; mp
99ꢁC dec., recrystallized from hexane–ethyl acetate (9:1); IR
(KBr, cmꢀ1) 3418, 3239 (NH); 3120, 3014 (CH, Ar-H); 1732
30-(4-(2-(3,4-Dichlorobenzyl)thiazol-4-yl)phenyl)spiro[indo-
line-3,20-thiazolidine]-2,40-dione (31) Yield: 65%; mp 97ꢁC,
recrystallized from hexane–ethyl acetate (9:1); IR (KBr, cmꢀ1
3414, 3246 (NH); 3103, 3048 (CH, Ar-H); 1729 (CO); 1695
)
1
(CO); 1695 (CO); 1612 (C¼¼N); H NMR (CDCl3): d 3.76 (d,
1
1H, J ¼ 15.4 Hz, Thiazolidine); 4.28 (s, 2H, CH2); 4.34 (d,
1H, J ¼ 15.4 Hz, Thiazolidine); 6.70–7.75 (m, 11H, Ar-H);
7.68 (s, 1H, Thiazole); 13C NMR (CDCl3): d 33 (CH2, Thiazo-
lidine); 39.04 (CH2, Benzyl); 111 (Spiro C); 113.4–165.6
(21C, Ar-C, Thiazole-C); 172.7 (CONH); 175.4 (CONH); ms:
m/z 538.0 (Mþ), 540.0 (Mþ2), 542.1 (Mþ4). Anal. Calcd. for
C26H17Cl2N3O2S2: C, 56.99; H, 3.18; N, 7.8; S, 11.91. Found:
C, 57.23; H, 3.26; N, 7.96; S, 12.13.
(CO); 1613 (C¼¼N); 864 (Ar-Cl); H NMR (CDCl3): d 3.88 (d,
1H, J ¼ 15.3 Hz, Thiazolidine); 4.35 (d, 1H, J ¼ 15.3 Hz,
Thiazolidine); 4.37 (s, 2H, CH2); 6.70–7.73 (m, 11H, Ar-H);
7.40 (s, 1H, Thiazole); 8.6 (s, 1H, NH, D2O exchangeable);
13C NMR (CDCl3): d 33 (CH2, Thiazolidine); 36.5 (CH2, Ben-
zyl); 110.97 (Spiro C); 113.9–168.1 (21C, Ar-C, Thiazole-C);
172.6 (CONH); 176.9 (CONH); ms: m/z 537.7 (Mþ), 539.7
(Mþ2), 541.8 (Mþ4). Anal. Calcd. for C26H17Cl2N3O2S2: C,
57.99; H, 3.18; N, 7.80; S, 11.91. Found: C, 58.23; H, 3.29;
N, 8.02; S, 12.21.
30-(4-(2-(4-Fluorobenzyl)thiazol-4-yl)phenyl)spiro[indoline-
3,20-thiazolidine]-2,40-dione (27) Yield: 60%; mp 133–135ꢁC,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1420
P. C. Mhaske, S. H. Shelke, R. P. Jadhav, H. N. Raundal, S. V. Patil,
A. A. Patil, and V. D. Bobade
Vol 47
5-Chloro-30-(4-(2-(3,4-dichlorobenzyl)thiazol-4-yl)phenyl)-
-2,40-diones 13–32 was synthesized. The pharmacologi-
cal studies were undertaken to evaluate the effects of
substituents on the antimicrobial activities. Most of the
synthesized compounds exhibited moderate activity
towards Gram-positive and Gram-negative bacteria.
These compounds, however, did not show any promising
antifungal activity except compound 21. Compounds
with methyl group and benzyl ring at 2-position of thia-
zole nucleus showed enhanced antibacterial activity.
spiro[indoline-3,20-thiazolidine]-2,40-dione (32) Yield: 65%;
mp 198–202ꢁC, recrystallized from hexane–ethyl acetate (9:1);
IR (KBr, cmꢀ1) 3409, 3233 (NH); 3113, 3041 (CH, Ar-H);
1730 (CO); 1696 (CO); 1610 (C¼¼N); 860 (Ar-Cl); 1H NMR
(CDCl3): d 3.88 (d, 1H, J ¼ 15 Hz, Thiazolidine); 4.34 (d,
1H, J ¼ 15.Hz, Thiazolidine); 4.41 (s, 2H, CH2); 6.63–7.77
(m, 10H, Ar-H); 8.03 (s, 1H, Thiazole); 8.9 (s, 1H, NH, D2O
exchangeable); ms: m/z 571.9 (Mþ), 573.9 (Mþ2), 575.9
(Mþ4), 577.8 (Mþ6). Anal. Calcd. for C26H16Cl3N3O2S2: C,
54.51; H, 2.81; N, 7.33; S, 11.19. Found: C, 54.65; H, 2.93;
N, 7.46; S, 11.51.
Acknowledgments. The authors thank Garware Research
Center, University of Pune, India, for providing facilities
for spectral studies of compounds. Financial support from
UGC, New Delhi, is gratefully acknowledged.
Antimicrobial activity. Compounds 14–32 were screened
for their in vitro antimicrobial activity against the standard
strains B. subtilis, S. aureus, and E. coli by the disk diffusion
method [14,15]. Disks measuring 6 mm in diameter were
punched from Whatman no.1 filter paper. Batches of 100 disks
were dispensed to each screw-caped bottle and sterilized by
dry heat at 145ꢁC for 1 h. The test compounds were prepared
with 100 lg/mL concentration in dimethyl sulfoxide. Disks of
each concentration were placed in nutrient agar medium inocu-
lated with fresh bacteria strains separately. The incubation was
carried out at 37ꢁC for 48 h. Ciprofloxacin was used as stand-
ard drugs at a concentration of 10 lg/mL. Solvent and growth
controls were kept and zones of inhibition were noted.
The two-fold dilution technique [16] was followed to deter-
mine the minimum inhibitory concentration (MIC) of the syn-
thesized compounds. The test compounds were dissolved in di-
methyl sulfoxide and then diluted with culture medium (Muel-
ler-Hinton agar medium) at the required final concentration
150–155 lg/mL. A plate containing only the culture medium
and DMSO in the same dilution was used as negative control.
The MIC values were recorded after incubation at 37ꢁC for a
period of 24 h. The lowest concentration of the test substance
that completely inhibited the growth of the microorganism was
reported as MIC expressed in terms of lg/mL.
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against C. albicans (MTCC 1637) and A. niger (AIIMS) in
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using Sabourad Dextrose Agar medium as described by
NCCLS [17]. Sterile filter paper discs (6 mm diameter) con-
taining specific amount of anti fungal agent (100 lg for the
synthesized compounds) were placed on the surface of an agar
plate inoculated with the standardized suspension of microor-
ganisms tested. The plates were incubated at 37ꢁC for 7 days
for evaluating antifungal activity. The diameters of inhibition
zones (in mm) were measured. Nystatin was used as standard
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[10] Bhambi, D.; Sharma, C.; Sharma, S.; Salvi, V. K.; Talesara,
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CONCLUSIONS
In conclusion, a series of new 30-(4-(2-methyl/phenyl/
benzylthiazol-4-yl)phenyl)spiro[indoline-3,20-thiazolidine]
[17] NCCLS Approval Standard Document M2-A7. National
Committee for Clinical Laboratory Standards: Vilanova, PA, 2000.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet