Design and synthesis of spiro[indole-thiazolidine]spiro[indole-pyrans] as antimicrobial agents

Article abstract of DOI:10.1016/j.bmcl.2011.06.121

A series of novel spiro[indole-thiazolidine]spiro[indole-pyran] derivatives were synthesized from N-(bromoalkyl)indol-2,3-diones via monospiro-bisindole intermediates; the two indole nuclei being connected via N-(CH₂) _n-N linker. Syn

Full text of DOI:10.1016/j.bmcl.2011.06.121

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5465–5469
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of spiro[indole-thiazolidine]spiro[indole-pyrans]
as antimicrobial agents
⇑
Rajeev Sakhuja, Siva S. Panda, Leena Khanna, Shilpi Khurana, Subhash C. Jain
Department of Chemistry, University of Delhi, Delhi 110 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel spiro[indole-thiazolidine]spiro[indole-pyran] derivatives were synthesized from N-
(bromoalkyl)indol-2,3-diones via monospiro-bisindole intermediates; the two indole nuclei being con-
nected via N–(CH2)n–N linker. Synthesized compounds were evaluated for their antimicrobial activities
in vitro against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, and Staphylococcus
epidermis), four Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, and
Klebsiella pneumonia) as well as four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, and
Candida albicans) using Cup plate method. Bis spiro-indoles exhibited stronger antibacterial and anti-
fungal efficiency than their corresponding mono spiro-indoles. Compound 10e, the most active derivative
was shown to inhibit the growth of all bacterial strains and two fungal strains (A. niger and C. albicans)
Ó 2011 Elsevier Ltd. All rights reserved.
Received 25 April 2011
Revised 21 June 2011
Accepted 28 June 2011
Available online 2 July 2011
Keywords:
Antibacterial
Antifungal
Antimicrobial
Spiro compounds
Cycloaddition
Infections caused by multi-drug resistant bacteria are of major
health concern worldwide. Particularly important are infections
caused by the Gram-positive bacteria Staphylococcus aureus and
species of the genus Enterococcus, due to increasing incidence of
infections caused by these microorganisms in hospitals and com-
munities, and their ability of developing antibiotic resistance to
multiple antibiotics. Due to some serious side effects in newly
introduced antibacterial agents such as semi-synthetic streptogra-
mins quinupristin/dalfopristin, daptomycin, the development of a
diversified series of antimicrobials still remains a necessity.1a
Indole and its analogous are good pharmacophores for design-
ing several chemotherapeutic reagents which exhibit wide spec-
trum of antimicrobial activities.1b–e Spiro-indoles possessing a
stereogenic center at C-3 are important naturally occurring and
pharmaceutically active molecules with more advanced activities.2
Synthetic methods such as intermolecular alkylations,3 palladium-
catalyzed reactions,4 cycloadditions,5 and sigmatropic rearrange-
ments6 have been developed for the synthesis of spiro-indoles,
including some naturally occurring bioactive alkaloids such as
Welwitindolinone A, Spirotryprostatin A, and Rhynchophylline7
(Fig. 1).
synthetic spiroheterocycles, containing both indole and pyran
heterocycles, possess anticonvulsant, analgesic,9b herbicidal,9c
and antimicrobial activities.9d
Bis-heterocycles separated with a suitable spacer constitute an-
other important class of compounds with antitumor10a and antimi-
crobial10b activities, based on the DNA binding affinity and enzyme
inhibiting actions. Biological activities are usually enhanced when
different functionalities or substitutions are present on the two
heterocyclic moieties in the bis-compound.10c,d However, the
extreme steric congestion in bis-heterocycles makes the construc-
tion of all-carbon quaternary centers a formidable challenge for
synthetic organic chemists.11 Thus, we could not locate even one
example in literature of a bis-heterocycle possessing two spirocy-
clic rings, each constructed using different heterocyclic moiety.
As a part of our ongoing research on the synthesis of biologically
active spiroheterocycles,12a–e herein we report a clean and efficient
O
O
Cl
O
N
O
H
Spiro[indole-thiazolidines] are one of the most studied 3-
spiroindole derivatives with broad spectrum of pharmacological
properties such as antimicrobial,8a antifungal,8b antileukemic,8c
and anticonvulsant.8d Spiro[indole-pyrans] are photochromic
compounds useful in various high-tech applications.9a Several
H
O
H
H
N
N
CN
O
O
O
N
H
N
N
MeO
H
H
Welwitindolinone A
Spirotryprostatin A
Rhynchophylline
⇑
Corresponding author. Tel.: +91 11 27667725x1387; fax: +91 11 27666605.
E-mail address: jainsc48@hotmail.com (S.C. Jain).
Fig. 1. Representative examples of naturally occurring spiroindoles.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.121

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R. Sakhuja et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5465–5469
Table 1
methodology for the synthesis of novel spiro[indole-thiazolidine]
spiro[indole-pyran] derivatives; the two spirocyclic heterocyclic
systems being connected via N–(CH2)n–N linker. The synthesized
compounds were evaluated for their antimicrobial activities.
N-(6-bromohexyl)indol-2,3-diones (3a–c) were prepared in 73–
77% by the N-alkylation of isatins (1a–c) with 1,6-dibromohexane
(2) in the presence of NaH/DMF at ꢀ10 °C following our published
procedure.12c (Scheme 1, Table 1).13
Synthesis of N-(6-bromohexyl)indol-2,3-diones (3a–c)
Substituent R
Product
Yield (%)
Mp (°C)
Lit. mp (°C)
H
F
CH3
3a
3b
3c
77
73
77
71–72
76
64–66
7212c
7612c
–
Condensation of N-(6-bromohexyl)indol-2,3-diones (3a–c)
through the amino group of 4-amino-1,5-dimethyl-2-phenyl-1H-
pyrazol-3(2H)-one (4) in absolute ethanol yielded corresponding
Schiff base (5a–c) in 82–86% yield (Scheme 2, Table 2)14 as colored
solids. For 5a, the IR spectrum showed characteristic absorption
band at 1648 cmꢀ1 for >C@N– stretching, thus indicated the forma-
tion of a Schiff’s base. The methyl protons singlets of the pyrazoline
nucleus at d 3.26 and 2.46 in its 1H spectrum and the imine carbon
((>C@N–) at C-3) at d 138.1 in its 13C NMR were the final evidence
for the formation of azomethineylide.
Cycloaddition of mercaptoacetic acid (6) on 5a–c by heating in
toluene under reflux using Dean-Stark apparatus yielded spiro[in-
dol-pyrazolin-thiazolidine]-2,40-diones (7a–c) in 79–87% yield.
(Scheme 2, Table 2)15 The reaction progress was monitored by
TLC. In addition, the cycloadducts were characterized by spectral
analysis. For 7a, two one proton characteristic doublets, at d 4.49
and 4.33 (J = 14.8 Hz) for the methylene of the newly formed thia-
zolidinone ring supported the formation of spiro[indole-thiazoli-
dine]-2,40-diones.
N
N
N
N
Ph
O
H2N
R
Ph
Br
N
R
O
4
O
N
O
N
O
Br
EtOH, rt
3a-c
5a-c
Toluene,
HS COOH
6
Ph
N
N
O
O
N
3a,5a,7a: R = H
3b,5b,7b: R = F
3c,5c,7c: R = CH3
R
S
N
O
Br
7a-c
Scheme 2.
N-alkylation of another 1H-indol-2,3-dione derivatives (1a–c)
were carried using N-bromohexyl-spiro[indole-thiazolidine]-2,40-
diones (7a–c) as alkylating agents in NaH/DMF under controlled
conditions (ꢀ10 °C) to obtain monospiro bis indole intermediates
(8a–i) as colored compounds in 59–66% yields (Scheme 3, Table
3).16 We observed that the addition of bromides 7a–c at tempera-
tures greater than 10 °C leads to the destruction of the thiazolidi-
none ring in 7a–c and with the result the yields of the expected
products were extremely low. For 8a, a four proton multiplet at d
3.62 for the two methylenes attached to the two nitrogen atoms
of the two oxoindole system and the two one proton doublets at
d 4.38 and 4.28 (J = 14.2 Hz) were observed, indicating the forma-
tion of bisindole and conservation of spiro[indol-pyrazolinyl-thia-
zolidinone] system, respectively. The other spectral data further
supported the formation of the products.
Finally the reaction of monospiro bis indole intermediates (8a–
i) with double equivalents of 3-methyl-1-phenyl-1H-pyrazol-
5(4H)-one (9) in absolute ethanol at room temperatures yielded
spiro[indole-pyrazolinyl-thiazolidine]spiro[dipyrazolopyran-in-
doles] (10a–i) in 60–69% yield (Scheme 3, Table 3).17 For 10a, two
three proton singlets at d 3.01 and 2.03 and two one proton dou-
blets at d 4.66 and 4.22 (J = 14.6 Hz) in its 1H NMR spectrum, ac-
counted the existence of spiro[indol-pyrazolinyl-thiazolidine] on
one of the two indole nuclei. While, two more three proton singlets
at d 2.20 and 2.10 indicated the possibility of condensing two mol-
ecules of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one as earlier
mentioned in literature.18 High resolution mass further supported
Table 2
Synthesis of azomethine ylides (5a–c) and spiro [indole-thiazolidines] (7a–c)
Substituent R
Azomethine ylides
Spiro [indole-thiazolidines]
5
Yield (%)
mp (°C)
7
Yield (%)
mp (°C)
H
F
CH3
5a
5b
5c
85
82
86
139–140
173–175
135–136
7a
7b
7c
79
82
87
75–77
87–89
93–94
Ph
N
Ph
N
N
O
N
O
1a-c (R = R1)
O
N
O
N
R
R
S
O
S
(i) NaH/DMF/-10ºC
O
N
N
O
N
O
(ii) r t, 4-6 h
Br
N
R1
8a-i
7a-c
EtOH, rt
N
O
Ph
9
Ph
N
N
O
Ph
N
O
N
N
O
R
O
Ph
S
N
N
N
O
N
R1
10a-i
Scheme 3.
O
R
O
R
(i) NaH/DMF/-10ºC
Br
+
Br
N
H
O
4
N
O
(ii) rt, 20 h
the formation of two spiro heterocyclic systems on bisindolyl
compound.
Br
1a-c
2
3a-c
The absence of any minor signals in the 1H NMR spectra of com-
pounds 10a–i and their univocal correspondence to the expected
structure showed that spiro compounds containing two chiral cen-
ters are not a mixture of four possible stereoisomers but a
racemate of one enantiomeric pair out of two possible pairs. Thus
1a,3a: R = H
1b,3b: R = F
1c,3c: R = CH3
Scheme 1.

R. Sakhuja et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5465–5469
5467
Table 3
Synthesis of 8a-i and spiro [indole-thiazolidine]-spiro[indole-pyrans] (10a-i)
Substituents
Monospiro bis indole
%
Spiro [indole-thiazolidine]-spiro[indole-pyrans]
R
R1
8
Mp (° C)
10
%
Mp (° C)
H
H
H
F
F
F
CH3
CH3
CH3
H
F
CH3
H
F
CH3
H
F
8a
8b
8c
8d
8e
8f
8g
8h
8i
65
62
60
65
61
64
59
66
63
98–99
10a
10b
10c
10d
10e
10f
10g
10h
10i
69
62
68
66
62
64
63
62
60
137–139
135–136
138–139
133–135
101–103
139–140
135–136
134–135
137–139
103–105
123–125
91–93
101–103
105–106
115–117
107–108
97–98
CH3
Table 5
Antifungal evaluation of 7a–c and 10a–i (zone of inhibition in mm)
the formation of second spirocyclic ring is diastereospecific, prob-
ably because of steric hindrance. However, the products were not
crystalline and thus a complete assignment of the absolute config-
uration at the two chiral centers is not possible at this stage.
Among all, compounds 7a–c and 10a–i were screened for their
in vitro antimicrobial activities to determine zone of inhibition at
Compound
A. niger
A. fumigatus
A. flavus
C. albicans
7a
7b
7c
15
16
15
16
16
17
16
20
17
16
18
16
18
–
–
–
–
14
–
16
17
15
17
18
18
18
21
18
17
19
18
19
10a
10b
10c
10d
10e
10f
10g
10h
10i
13
14
–
14
15
12
12
13
14
15
14
15
15
14
16
15
12
12
14
17
100 lg/mL against three Gram-positive bacteria (S. aureus MTCC
096, Bacillus subtilis MTCC 441 and Staphylococcus epidermis MTCC
435), four Gram-negative bacteria (Escherichia coli MTCC 443, Pseu-
domonas aeruginosa MTCC 424, Salmonella typhi MTCC 733, and
Klebsiella pneumoniae MTCC 432) as well as four fungi (Aspergillus
niger MTCC 282, Aspergillus fumigatus MTCC 343, Aspergillus flavus
MTCC 277, and Candida albicans MTCC 227) using Cup plate meth-
od19,20 where inoculated Muller-Hilton agar for bacteria and Sab-
ouraud dextrose agar for fungi was poured onto the sterilized
petri dishes (25–30 mL: each petri dish). The poured material
was allowed to set (30 min.) and thereafter the ‘CUPS’ (08 mm
diameter) was made by punching into the agar surface with a ster-
ile cork borer and scooping out the punched part of the agar. Into
these cups the test compound solution (0.1 mL) was added with
the help of a micro pipette. The plates were incubated at 37 °C
for 14 h for bacteria and 30 h for fungi and the results were noted.
The test solution was prepared by DMSO as solvent. Clinically anti-
microbial drugs Ciprofloxacin and Miconazole were used as the po-
sitive control and DMSO was used for blank.
The obtained results, depicted in Tables 4 and 5, revealed that
spiro-indoles 7a–c and bis spiro-indoles 10a–i could effectively,
to some extent, inhibit the growth of all tested strains in vitro. In
antibacterial studies, all the compounds tested were less active to-
wards S. epidermis and P. aeruginosa in compared to other five
strains of bacteria, where as all the compounds showed moderate
to comparable activity against S. aureus and K. pneumonia. Out of
four strains of fungi, these spiro-indoles were showed significant
activity against A. niger and C. albicans, where as moderate to mild
activity against A. fumigatus and A. flavus.
Miconazole
The prepared mono spiro-indoles 7a–c demonstrated moderate
to good antimicrobial activities towards the tested microorgan-
isms. Noticeably, the fluoro derivative of spiro-indoles gave com-
parably better activity than others against all the
microorganisms. These showed that halogen-containing heterocy-
clic compounds exerted important influence on antimicrobial
activities.
It was particularly pointed out that, among these tested bis
spiro-indoles 10a–i linked via (CH2)6 linker possessed significant
antimicrobial activities with respect to standard drugs and it gave
the better zone of inhibition value in compare to mono spiro-in-
doles. These results further indicated that moiety was specifically
favorable for antimicrobial activities, which could not only broaden
the antimicrobial spectrum, but also increase the bioactivity signif-
icantly. Particularly, compound 10e could efficiently inhibit the
growth of all tested Gram-positive and -negative bacteria, which
was almost equipotent to Ciprofloxacin, and its antifungal potency
against A. niger and C. albicans was also comparable to positive con-
trol Miconazole. It was also suggested that bis spiro-indoles
Table 4
Antibacterial evaluation of 7a-c and 10a-i (zone of inhibition in mm)
Compound
S. aureus
B. subtilis
S. epidermis
E. coli
P. aeruginosa
S. typhi
K. pneumonia
7a
7b
7c
10a
10b
10c
10d
10e
10f
10g
14
16
15
16
17
15
16
19
15
15
18
17
19
13
15
14
15
16
15
17
19
16
15
16
14
18
–
15
17
15
16
16
16
17
19
17
15
15
14
20
14
15
–
12
17
15
16
16
15
18
20
16
17
19
17
19
13
16
15
15
17
16
17
19
17
18
18
16
17
14
12
13
15
–
15
16
15
13
12
14
16
–
16
12
16
19
16
15
17
15
18
10h
10i
Ciprofloxacin

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R. Sakhuja et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5465–5469
1996, 61, 8141; (b) Shaker, R. M. Phosphorus, Sulfur Silicon Relat. Elem. 1999,
149, 7; (c) Kamal, A.; Laxman, N.; Ramesh, G.; Neelima, K.; Kondapi, A. K. Chem.
Commun. 2001, 437; (d) Raasch, A.; Scharfenstein, O.; Traenkle, C.; Holzgrabe,
U.; Mohr, K. J. Med. Chem. 2002, 45, 3809.
10a–i were worthy for further investigations as potential antimi-
crobial agent.
For tested mono spiro-indoles 7a–c and bis spiro-indoles 10a–i,
the structural parameters of spacers including substituents, the
types of linkers and the lengths of aliphatic chains markedly influ-
enced their antimicrobial efficacy. Moreover, the antimicrobial po-
tency for spiro-indoles 7a–c and 10a–i, depended on the
substituent and lengths of aliphatic chains, and the activities
seemed to decrease with the increase of aliphatic chain length.
Obviously, the bridged linkers have large effect on their antimicro-
bial efficiency, and further works are essential in order to deduce
the structure–activity relationship.
Twenty five novel heterocycles including the intermediates were
synthesizedin good to excellentyields and fully characterizedonthe
basis of their detailed spectral studies. In summary, we have devel-
oped a clean and efficient methodology for the synthesis of novel
spiro[indole-thiazolidine]spiro[indole-pyran] derivatives; the two
spirocyclic heterocyclic systems being connected via N–(CH2)n –N
linker using molecular modification approach. The methodology
could be further extended and used for the synthesis of other asym-
metric bis(spiro-heterocycles) of biological importance.
11. Christoffers, J.; Mann, A. Angew. Chem. Int. Ed. 2001, 40, 4591.
12. (a) Jain, S. C.; Bhagat, S.; Rajwanshi, V. K.; Babu, B. R.; Sinha, J. Indian J. Chem. B
1997, 36B, 633; (b) Jain, M.; Khanna, P.; Saxena, A.; Bhagat, S.; Olsen, C. E.; Jain,
S. C. Synth. Commun. 2006, 36, 1863; (c) Jain, M.; Sakhuja, R.; Khanna, P.;
Bhagat, S.; Jain, S. C. Arkivoc 2008, 54; (d) Jain, S. C.; Khanna, P.; Bhagat, S.; Jain,
M.; Sakhuja, R. Phosphorus, Sulphur Silicon Relat. Elem. 2005, 180, 1829; (e)
Khanna, P.; Saxena, A.; Khanna, L.; Bhagat, S.; Jain, S. C. Arkivoc 2009, 119.
13. Representative procedure for 1-(6-bromohexyl)-5-methylindoline-2,3-dione
(3c): To a stirred solution of sodium hydride (40 mmol) in DMF (10 mL) was
added dropwise a solution of 5-methyl-1H-indol-2,3-dione (1c; 30 mmol) in
DMF (10 mL) during 20 min at ꢀ10 °C, under inert atmosphere of nitrogen. To
the deep purple colored suspension that resulted, 1,6-dibromohexane (2;
30 mmol) was added dropwise at the same temperature. The contents were
allowed to stir overnight at room temperature and thereafter quenched with
ice water to yield
a red colored semisolid. This was extracted with
dichloromethane (3 ꢁ 50 mL) and the organic layer was purified by flash
column chromatography in petroleum ether/dichloromethane (70:30) as
eluant to yield pure 3c as red microcrystals; IR
(KBr): 2936, 2854, 1737,
max
1620, 1610, 1482, 1463, 1347, 1260, and 1220 cmꢀ1.1H NMR (300 MHz, CDCl3):
dH 7.32 (m, 2H), 6.81 (m, 1H), 3.76 (t, J = 6.8 Hz, 2H), 3.38 (t, J = 6.9 Hz, 2H), 2.20
(s, 3H), 1.83 (m, 2H), 1.71 (m, 2H), 1.46 (m, 4H).13C NMR (75.47 MHz, CDCl3): dC
183.8, 174.0, 154.8, 137.1, 128.1, 126.0, 115.1, 113.0, 41.6, 34.6, 33.2, 29.7,
27.8, 27.6, 21.4. EIMS m/z (%): 325 (M++2, 28), 323 (M+, 30), 297 (15), 244 (M+-
Br, 12), 217 (50), 190 (38). Anal. Calcd for C15H18BrNO2: C, 55.57; H, 5.60; N,
4.32. Found: C, 55.72; H, 5.48; N, 4.43. This procedure for followed for all the
substrates.
Acknowledgments
14. Representative procedure for 1-(6-bromohexyl)-3-((1,5-dimethyl-3-oxo-
2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino)indolin-2-one (5a):
A mixture
N-(6-bromohexyl)indol-2,3-dione (3a; 9.5 mmol) and 4-amino-1,5-dimethyl-
2-phenyl-1H-pyrazol-3(2H)-one (4; 9.5 mmol) in absolute ethanol (20 mL) was
stirred at room temperature for 2 h. The colored solids thus obtained were
filtered and recrystallized from dichloromethane to yield Schiff’s base (5a) as
Authors (R.S. and S.K.) and author (S.S.P.) are thankful, respec-
tively, to CSIR and UGC, New Delhi for research fellowship.
orange solid; IR
(KBr): 2931, 2858, 1714, 1648, 1605, 1548, 1487, 1432,
max
Supplementary data
1357, 1310, and 1247 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 7.44 (m, 5H), 7.34
.
(m, 2H), 7.05 (t, J = 7.3 Hz, 1H), 6.81 (d, J = 8.2 Hz,1H), 3.77 (t, J = 6.9 Hz, 2H),
3.39 (t, J = 6.8 Hz, 2H), 3.26 (s, 3H), 2.46 (s, 3H), 1.86 (m, 2H), 1.82 (m, 2H), 1.46
(m, 4H). 13C NMR (75.47 MHz, CDCl3): dC 171.2 (C-2), 161.3, 138.1 (C-3), 132.1–
108.2 (aromatic carbons), 39.9, 35.8, 33.6, 32.5, 27.7, 27.5, 27.2, 11.3. EIMS m/z
(%): 496 (M++2, 60), 494 (M+, 58), 450 (12), 415 (M+-Br, 6), 291 (32), 240 (19).
Anal. Calcd for C25H27BrN4O2: C, 60.61; H, 5.49; N, 11.31. Found: C, 60.48; H,
5.56; N, 11.29. This procedure for followed for all the substrates.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.06.121.
References and notes
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3. (a) Huang, A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc. 2004, 126, 14043;
(b) Bagul, T. D.; Lakshmaiah, G.; Kawabata, T.; Fuji, K. Org. Lett. 2002, 4, 249.
4. Ruck, R. T.; Huffman, M. A.; Kim, M. M.; Shevlin, M.; Kandur, W. V.; Davies, I. W.
Angew. Chem. Int. Ed. 2008, 47, 4711.
5. (a) Yong, S. R.; Williams, M. C.; Pyne, S. G.; Ung, A. T.; Skelton, B. W.; White, A.
H.; Turner, P. Tetrahedron 2005, 61, 8120; (b) Beccalli, E. M.; Clerici, F.; Gelmi,
M. L. Tetrahedron 2003, 59, 4615.
6. (a) Kawasaki, T.; Ogawa, A.; Terashima, R.; Saheki, T.; Ban, N.; Sekiguchi, H.;
Sakaguchi, K.; Sakamoto, M. J. Org. Chem. 2005, 70, 2957; (b) Mao, Z.; Baldwin,
S. W. Org. Lett. 2004, 6, 2425.
7. (a) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.; Patterson, G. M. L.;
Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am. Chem. Soc. 1994, 116, 9935; (b)
Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem. Soc.
1999, 121, 2147.
8. (a) Mhaske, P. C.; Shelke, S. H.; Jadhav, R. P.; Raundal, H. N.; Patil, S. V.; Patil, A.
A.; Bobade, V. D. J. Heterocycl. Chem. 2010, 47, 1415; (b) Dandia, A.; Singh, R.;
Khaturia, S.; Merienne, C.; Morgant, G.; Loupy, A. Bioorg. Med. Chem. 2006, 14,
2409; (c) Rajopadhye, M.; Popp, F. D. J. Heterocycl. Chem. 1987, 24, 1637; (d)
Rajopadhye, M.; Popp, F. D. J. Heterocycl. Chem. 1984, 21, 289.
9. (a) Abe Abe, Y.; Ebara, H.; Okada, S.; Akaki, R.; Horii, T.; Nakao, R. Dyes and
Pigments 2002, 52, 23; (b) Joshi, K. C.; Jain, R.; Sharma, K.; Bhattacharya, S. K.;
Goel, R. K. J. Indian Chem. Soc. 1988, 65, 202; (c) Joshi, K. C.; Jain, R.; Arora, S. J.
Indian Chem. Soc. 1988, 65, 277; (d) Nandakumar, A.; Thirumurugan, P.;
Perumal, P. T.; Vembu, P.; Ponnuswamy, M. N.; Ramesh, P. Bioorg. Med. Chem.
Lett. 2010, 20, 4252.
(7a):
A mixture of 1-(6-bromohexyl)-3-((1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-yl)imino)indolin-2-one (5a; 6 mmol) and mercaptoacetic
acid (6) (6.5 mmol) was heated under reflux in dry toluene for 9 h, with
azeotropic removal of water simultaneously, using Dean Stark apparatus. The
reaction mixture turned light yellow in color and a sticky yellow solid was
formed. The toluene was distilled out and the oily mixture left was treated
with saturated solution of sodium bicarbonate to remove excess acid. The solid
obtained was stirred for an hour at room temperature and filtered, dried
and recrystallized from dichloromethane/methanol to obtain spiro[indol-
pyrazolin-thiazolidine]-2,4-dione (7a) as dirty white solid; IR
(KBr):
max
2932, 2857, 1720, 1701, 1684, 1611, 1489, 1467, 1359, 1285, and 1209 cmꢀ1
.
1H NMR (300 MHz, CDCl3): dH 7.36 (m, 2H), 7.27 (m, 3H), 7.18 (m, 3H), 6.74 (d,
J = 7.8 Hz, 1H), 4.49 & 4.33 (2d, J = 14.8 Hz, 1H each), 3.69 (t, J = 6.8 Hz, 2H),
3.39 (t, J = 6.9 Hz, 2H), 3.01 (s, 3H), 2.14 (s, 3H), 1.84 (m, 2H), 1.68 (m, 2H), 1.48
(m, 2H), 1.39 (m, 2H). 13C NMR (75.47 MHz, CDCl3): dC 177.4, 172.1, 162.2,
134.4–108.0 (aromatic carbons), 67.3, 40.1, 35.0, 33.4, 32.4, 27.6, 26.9, 26.3,
25.8, 10.7. EIMS m/z (%): 570 (M++2, 24), 568 (M+, 23), 506 (36), 489 (100), 433
(56), 341 (17), 260 (30), 245 (32), 203 (31), 190 (48). Anal. Calcd for
C
27H29BrN4O3S: C, 56.94; H, 5.13; N, 9.84. Found: C, 56.76; H, 5.19; N, 10.04.
This procedure for followed for all the substrates.
16. Representative procedure for 3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazo-4-yl)-1-(6-(2,3-dioxoindolin-1-yl)hexyl)spiro[indoline-3,2-thiazolidine]-
2,4-dione (8a): To a stirred solution of sodium hydride (1.08 mmol) in DMF
(10 mL) was added dropwise solution of 1H-indol-2,3-dione (1a; 0.9 mmol) in
DMF (10 mL) during 20 min at ꢀ10 °C under inert atmosphere of nitrogen. To
the deep purple colored suspension that resulted, spiro[indol-pyrazolin-
thiazolidine]-2,4-dione (7a; 0.9 mmol) was added dropwise at the same
temperature. The contents were allowed to stir at room temperature for
4–6 h and thereafter quenched with ice water to yield colored solids, which
were filtered and recrystallized from dichloromethane/methanol to give pure
monospiro bisindoles (8a) intermediate as deep orange needles; IR
(KBr):
2929, 2857, 1725, 1701, 1684, 1611, 1488, 1467, 1355, and 1164 cmꢀ1max
.
1H NMR
(300 MHz, CDCl3): dH 7.97 (m, 1H), 7.59 (m, 2H), 7.32 (m, 3H), 7.17–7.10 (m,
5H), 6.85 (m, 1H), 6.74 (d, J = 6.7 Hz, 1H), 4.38 and 4.28 (2d, J = 14.2 Hz, 1H
each), 3.62 (m, 4H), 2.95 (s, 3H), 2.12 (s, 3H), 1.68 (m, 4H), 1.42 (m, 4H). 13C
NMR (75.47 MHz, CDCl3): dC 180.1, 175.2, 172.3, 158.0, 154.2–108.0 (aromatic
carbons), 69.2, 39.8, 34.9, 32.8, 32.2, 29.5, 26.9, 26.3, 10.7. Anal. Calcd for
C
35H33N5O5S: C, 66.12; H, 5.23; N, 11.02. Found: C, 66.38; H, 5.62; N, 10.73.
10. (a) Thurston, D. E.; Bose, D. S.; Thompson, A. S.; Howard, P. W.; Leoni, A.;
Croker, S. J.; Jenkins, T. C.; Neidle, S.; Hartley, J. A.; Hurley, L. H. J. Org. Chem.
This procedure for followed for all the substrates.

R. Sakhuja et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5465–5469
5469
17. Representative procedure for 1-(6-(3,5-dimethyl-2-oxo-1,7-diphenyl-1,7-dihy-
drospiro[indoline-3,4-pyrano[2,3-c:6,5-c]dipyrazol]-1-yl)hexyl)-3-(1,5-dimethyl-
3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)spiro[indoline-3,2-thiazolidine]-
2,4-dione (10a): A solution of monospiro bisindoles (8a–i; 1.5 mmol) and
3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (9; 3.01 mmol) was stirred in
absolute ethanol for about 8–10 h at room temperature, till the color of
reaction mixture fades and a dirty white solid separated out. The solid thus
precipitated was filtered, dried and purified by flash column chromatography
using dichloromethane/methanol (97:3) to yield spiro[indole-thiazolidine]
3H), 7.19 (m, 5H), 7.03 (m, 1H), 6.81 (m, 1H), 6.78 (m, 1H), 4.66 and 4.22
(2d, J = 14.6 Hz, 1H each), 3.77 (m, 4H), 3.01 (s, 3H), 2.20 & 2.10 (2s, 3H each),
2.03 (s, 3H), 1.86 (m, 2H), 1.72 (m, 2H), 1.60 (m, 4H). 13C NMR (75.47 MHz,
CDCl3): dC 175.1, 172.2, 158.6, 153.2–108.6 (aromatic carbons), 67.3, 50.9, 40.5,
35.2, 33.2, 27.3, 26.6, 17.9, 17.1, 11.2. HRMS: m/z [M
55H50N9O5S: 948.3650; found: 948.3662. This procedure for followed for all
the substrates.
+
H]+ calcd for
C
18. Joshi, K. C.; Pardasani, R. T.; Dandia, A.; Bhagat, S. Heterocycles 1991, 32, 1491.
19. Barry, A. L. In The Antimicrobic Susceptibility Test: Principles and Practices; Lea &
Febiger: Philadelphia, 1976; p 180.
20. Reddy, P. M.; Ho, Y. P.; Shanker, K.; Rohini, R.; Ravinder, V. Eur. J. Med. Chem.
2009, 44, 2621.
spiro[indole-pyrans] (10a–i) as white solid; IR
(KBr): 2928, 2854, 1717,
max
1611, 1493, 1361, 1306, 1284, and 1160 cmꢀ1
.
1H NMR (300 MHz, CDCl3): dH
7.98 (m, 1H), 7.96 (m, 1H), 7.87 (m, 1H), 7.53 (m, 5H), 7.38 (m, 4H), 7.29 (m,