Synthesis and cytostatic evaluation of some 2-(5-substituted-2-oxoindolin- 3-ylidene)-N-substituted hydrazine carbothioamide

Article abstract of DOI:10.1007/s00044-010-9458-3

Various substituted 2-(5-substituted-2-oxoindolin- 3-ylidene)-N-substituted hydrazine carbothioamide 4a-g and 2-(5-substituted-1-(4-substituted benzyl)-2-oxoindolin- 3-ylidene)-N-substituted hydrazine carbothioamide 5a-k were synthesized. The compounds were evaluated for their cytostatic activity against human Molt4/C8 and CEM T-lymphocytes as well as murine L1210 leukemia cells. Several of these compounds were endowed with low micromolar 50%-inhibitory concentration (IC50) values, and some were virtually equally potent as melphalan. The most potent inhibitors against the murine leukemia cells were also most inhibitory against human T-lymphocyte tumor cells. 2-(5-fluoro-1-(4-fluorobenzyl)-2-oxoindolin-3- ylidene)-N-p-tolylhydrazine carbothioamide (5b) emerged as the most potent cytostatic compound among the tested compounds. The encouraging cytostatic data provide an adequate rationale for further modification of these molecular scaffolds. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9458-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1229–1234
DOI 10.1007/s00044-010-9458-3
ORIGINAL RESEARCH
Synthesis and cytostatic evaluation of some 2-(5-substituted-2-
oxoindolin-3-ylidene)-N-substituted hydrazine carbothioamide
•
Subhas S. Karki Amol Kulkarni Nishith Teraiya
•
•
•
Erik De Clercq Jan Balzarini
Received: 16 May 2010 / Accepted: 25 September 2010 / Published online: 19 October 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Various substituted 2-(5-substituted-2-oxoin-
dolin-3-ylidene)-N-substituted hydrazine carbothioamide
4a–g and 2-(5-substituted-1-(4-substituted benzyl)-2-oxo-
indolin-3-ylidene)-N-substituted hydrazine carbothioamide
5a–k were synthesized. The compounds were evaluated for
their cytostatic activity against human Molt4/C8 and CEM
T-lymphocytes as well as murine L1210 leukemia cells.
Several of these compounds were endowed with low
micromolar 50%-inhibitory concentration (IC50) values,
and some were virtually equally potent as melphalan. The
most potent inhibitors against the murine leukemia cells
were also most inhibitory against human T-lymphocyte
tumor cells. 2-(5-fluoro-1-(4-fluorobenzyl)-2-oxoindolin-3-
ylidene)-N-p-tolylhydrazine carbothioamide (5b) emerged
as the most potent cytostatic compound among the tested
compounds. The encouraging cytostatic data provide an
adequate rationale for further modification of these
molecular scaffolds.
Introduction
Isatin has been known for about 150 years and has recently
been found, like 2,3-dioxo-indoles and endogenous poly-
functional heterocyclic compounds, to exhibit biological
activity in mammals (Somogyi, 2001). Isatin is also a
synthetically versatile substrate that can be used to prepare
a large variety of heterocyclic compounds, such as indoles
and quinolines, and as a raw material for drug synthesis
(Silva et al., 2001). Schiff bases and Mannich bases of
isatin are known to possess a wide range of pharmaco-
logical properties including antibacterial (Pandeya et al.,
1998; Sarangapani and Reddy, 1994; Varma and Nobles,
1975), anticonvulsant (Sridhar et al., 2002; Varma et al.,
2004), anti-HIV (Pandeya et al., 1998 1999a, b 2000;
Sriram et al., 2000), antifungal (Pandeya et al., 1999a, b),
antiviral (Singh et al., 1983), and anticancer activity (Karki
et al., 2004, 2007, 2009).
Thiosemicarbazones of various aldehydes and ketones
occupy a special place among organic ligands, since they
contain various donor atoms and are able to change density
depending on the starting reagents and their reaction con-
ditions. Isatin-3-thiosemicarbazones (1H-indole-2,3-dioxo-
3-thiosemicarbazones) have been studied extensively due
to their important biological activities (Karki et al., 2009),
since 1-methylisatin-3-thiosemicarbazone (Marboran) was
found to be active in the treatment of smallpox. Previous
studies by our group have revealed the promising cytotoxic
properties of various 2,3-dioxo-2,3-dihydroindole thio-
semicarbazones (Karki et al., 2009). Therefore, we have
performed the synthesis of new N-4-aryl thiosemicarba-
zone derivatives of substituted 2,3-dioxo-2,3-dihydroin-
doles and studied their antiproliferative activity against
human Molt 4/C8 and CEM T-lymphocytes as well as
murine L1210 leukemia cells.
Keywords 2,3-dioxo-2,3-dihydroindole ꢀ
Thiosemicarbazones ꢀ Cytostatic assays
S. S. Karki (&) ꢀ A. Kulkarni ꢀ N. Teraiya
Department of Pharmaceutical Chemistry, KLE University’s
College of Pharmacy, Rajajinagar, Bangalore 560010,
Karnataka, India
e-mail: subhasskarki@gmail.com
E. De Clercq ꢀ J. Balzarini
Rega Institute for Medical Research, Katholieke Universiteit
Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
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Med Chem Res (2011) 20:1229–1234
2-(5-bromo-2-oxoindolin-3-ylidene)-N-p-tolylhydrazine
carbothioamide (4c)
Experimental
Chemistry
Yield 76%. mp 255–260°C. FT-IR vmax cm-1 (KBr): 1184,
1
1315, 1692, 3015, 3123, 3212, 3248. H-NMR d: 2.51 (s,
3H, CH3), 6.9–8.0 (m, 7H, Ar–H), 10.86 (s, 1H, CO–NH),
All reagents were obtained from Sigma-Aldrich Mumbai,
and Loba Chemie, Mumbai. All the solvents used in these
studies were dried and distilled before use. Melting points
were recorded on a Veego VMP-PM digital melting point
apparatus, and are uncorrected. FT-IR spectras were
11.36 (s, 1H, N–NH), 12.59 (s, 1H, NH).
2-(5-fluoro-2-oxoindolin-3-ylidene)-N-p-tolylhydrazine
carbothioamide (4d)
1
recorded on Shimadzu 8400 S, FT-IR. H NMR spectra
were recorded on 300 MHz JEOL NMR Spectrophotome-
ter in CDCl3 and DMSO-d6. All spectras were obtained
from Pune University, Maharashtra, India.
Yield 78%. mp 276–280°C. FT-IR vmax cm-1 (KBr): 1154,
1291, 1682, 2995, 3116, 3234, 3256. H-NMR d: 2.51 (s,
3H, CH3), 6.9–7.6 (m, 7H, Ar–H), 10.81 (s, 1H, CO–NH),
1
11.27 (s, 1H, N–NH), 12.65 (s, 1H, NH).
Synthesis of the intermediate indoline-2,3-diones
2-(6-chloro-5-fluoro-2-oxoindolin-3-ylidene)-N-
(4-chlorophenyl)hydrazine carbothioamide (4e)
The synthesis of the intermediate indoline-2,3-diones was
accomplished using a literature methodology (Marvel and
Heirs, 1941), and a previously reported procedure was used
to convert these compounds to the corresponding 1-benzyl-
indoline-2,3-diones (Azizian et al., 2003). The N-4-aryl-
thiosemicarbazides required in the preparation of 4a–g and
5a–k were prepared by a literature methodology (Sen and
Sengupta, 1962; Lieber et al., 1957).
Yield 70%. mp 278–280°C. FT-IR vmax cm-1 (KBr): 1164,
1
1317, 1698, 3019, 3133, 3213, 3243. H-NMR d: 6.9–7.8
(m, 6H, Ar–H), 10.2 (s, 1H, CO–NH), 11.54 (s, 1H, N–
NH), 12.63 (s, 1H, NH).
2-(6-chloro-5-fluoro-2-oxoindolin-3-ylidene)-N-p-
tolylhydrazine carbothioamide (4f)
General procedure for the synthesis of 4a–g and 5a–k
Yield 69%. mp 267–270°C. FT-IR vmax cm-1 (KBr): 1180,
1310, 1672, 3010, 3128, 3215, 3237. H-NMR d: 3.27 (s,
3H, CH3), 6.9–7.8 (m, 6H, Ar–H), 10.14 (s, 1H, CO–NH),
A mixture of the indoline-2,3-diones (2)/1-benzylindoline-
2,3-dihydroindole (3) (0.005 mol), N-(4-substituted aryl)-
thiosemicarbazides (0.005 mol), acetic acid (0.5–1.0 ml),
and ethanol (100 ml) was heated under reflux until the
reaction was completed (approximately 4 h). Approxi-
mately half of the ethanol was removed in vacuo, and the
solution was left overnight at room temperature. The solid
which precipitated was collected by filtration, washed with
cold ethanol, and recrystallized from ethanol:chloroform
(9:1) to give compounds 4a–g and 5a–k, respectively.
1
11.52 (s, 1H, N–NH), 12.62 (s, 1H, NH).
N-(4-chlorophenyl)-2-(5-fluoro-2-oxoindolin-3-
ylidene)hydrazine carbothioamide (4g)
Yield 73%. mp 290–293°C. FT-IR vmax cm-1 (KBr): 1165,
1
1295, 1682, 3008, 3121, 3210, 3238. H-NMR d: 6.6–7.8
(m, 7H, Ar–H), 11.10 (s, 1H, CO–NH), 11.29 (s, 1H, N–
NH), 12.52 (s, 1H, NH).
2-(5-chloro-2-oxoindolin-3-ylidene)-N-
(4-chlorophenyl)hydrazine carbothioamide (4a)
N-(4-chlorophenyl)-2-(5-fluoro-1-(4-fluorobenzyl)-2-
oxoindolin-3-ylidene)hydrazine carbothioamide (5a)
Yield 69%. mp 260–261°C. FT-IR vmax cm-1 (KBr): 1129,
1289, 1686, 3061, 3143, 3226, 3246. H-NMR d: 6.9–7.8
(m, 7H, Ar–H), 10.94 (s, 1H, CO–NH), 11.38 (s, 1H, N–
1
Yield 74%. mp 197–200°C. FT-IR vmax cm-1 (KBr): 1119,
1
1298, 1696, 3042, 3129, 3214, 3257. H-NMR d: 5.0 (s,
2H, CH2), 7.0–7.7 (m, 11H, Ar–H), 10.96 (s, 1H, N–NH),
NH), 12.66 (s, 1H, NH).
12.65 (s, 1H, NH).
2-(5-bromo-2-oxoindolin-3-ylidene)-N-
(4-chlorophenyl)hydrazine carbothioamide (4b)
2-(5-fluoro-1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)-N-
p-tolylhydrazine carbothioamide (5b)
Yield 86%. mp 255–258°C. FT-IR vmax cm-1 (KBr): 1131,
1295, 1672, 3019, 3113, 3220, 3250 H-NMR d: 6.9–8.0
(m, 7H, Ar–H), 10.94 (s, 1H, CO–NH), 11.38 (s, 1H, N–
1
Yield 77%. mp 230–235°C. FT-IR vmax cm-1 (KBr): 1126,
1
1287, 1681, 3054, 3143, 3212, 3251. H-NMR d: 2.35 (s,
NH), 12.66 (s, 1H, NH).
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Med Chem Res (2011) 20:1229–1234
1231
2-(5-bromo-1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)-N-
p-tolylhydrazine carbothioamide (5i)
3H, CH3), 5.0 (s, 2H, CH2), 7.0–7.8 (m, 11H, Ar–H), 10.87
(s, 1H, N–NH), 12.58 (s, 1H, NH).
Yield 72%. mp 217–220°C. FT-IR vmax cm-1 (KBr): 1094,
1269, 1686, 3043, 3113, 3206, 3243. H-NMR d: 2.51 (s,
3H, CH3), 3.35 (s, 2H, CH2), 7.0–8.0 (m, 11H, Ar–H),
2-(5-chloro-1-(4-methylbenzyl)-2-oxoindolin-3-ylidene)-N-
(4-chlorophenyl)hydrazine carbothioamide (5c)
1
10.92 (s, 1H, N–NH), 12.51 (s, 1H, NH).
Yield 86%. mp 235–239°C. FT-IR vmax cm-1 (KBr): 1135,
1294, 1682, 3026, 3119, 3243, 3264. H-NMR d: 2.51 (s,
3H, CH3), 5.01 (s, 2H, CH2), 7.0–8.7 (m, 11H, Ar–H),
1
2-(5-bromo-1-(4-methylbenzyl)-2-oxoindolin-3-ylidene)-N-
p-tolylhydrazine carbothioamide (5j)
11.00 (s, 1H, N–NH), 12.58 (s, 1H, NH).
Yield 79%. mp 185–190°C. FT-IR vmax cm-1 (KBr): 1126,
1309, 1698, 3056, 3133, 3218, 3239. H-NMR d: 2.27 (s,
3H, CH3), 2.51 (s, 3H, CH3), 4.96 (s, 2H, CH2), 6.9–8.0 (m,
1
2-(5-chloro-1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)-N-
(4-chlorophenyl)hydrazine carbothioamide (5d)
11H, Ar–H), 10.92 (s, 1H, N–NH), 12.54 (s, 1H, NH).
Yield 66%. mp 238–240°C. FT-IR vmax cm-1 (KBr): 1126,
1310, 1706, 3047, 3127, 3237, 3276. H-NMR d: 4.96 (s,
2H, CH2), 7.0–7.9 (m, 11H, Ar–H), 10.99 (s, 1H, N–NH),
1
2-(5-bromo-1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)-N-
(4-chlorophenyl)hydrazine carbothioamide (5k)
12.61 (s, 1H, NH).
Yield 76%. mp 230–233°C. FT-IR vmax cm-1 (KBr): 1120,
1296, 1684, 3046, 3135, 3216, 3247. H-NMR d: 4.94 (s,
2H, CH2), 6.4–7.7 (m, 11H, Ar–H), 11.29 (s, 1H, N–NH),
1
2-(5-chloro-1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)-N-
(4-chlorophenyl)hydrazine carbothioamide (5e)
12.52 (s, 1H, NH).
Yield 81%. mp 230–235°C. FT-IR vmax cm-1 (KBr): 1156,
1295, 1696, 3056, 3123, 3219, 3259. H-NMR d: 5.00 (s,
2H, CH2), 7.0–7.9 (m, 11H, Ar–H), 10.99 (s, 1H, N–NH),
1
Cytostatic assays
12.59 (s, 1H, NH).
The methodology for undertaking the antiproliferative
assays has been published previously (Baraldi et al., 2004).
In brief, varying concentrations of the compounds (5-fold
dilutions) were incubated at 37°C for 72 h (Molt4/C8 and
CEM T-lymphocytes) or 48 h (L1210 cells) in 200 ll 96-
well microtiter plates, and the viable tumor cell number
was counted at the end of the incubation period using a
Coulter Counter (Coulter Electronics, Harpenden Hertz,
U.K.).
2-(5-bromo-1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)-N-
(4-chlorophenyl)hydrazine carbothioamide (5f)
Yield 73%. mp 240–245°C. FT-IR vmax cm-1 (KBr): 1134,
1287, 1685, 3014, 3161, 3206, 3245. H-NMR d: 5.0 (s,
2H, CH2), 7.0–8.0 (m, 11H, Ar–H), 11.0 (s, 1H, N–NH),
1
12.59 (s, 1H, NH).
2-(5-bromo-1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)-N-
p-tolylhydrazine carbothioamide (5g)
Results and discussion
Chemistry
Yield 80%. mp 268–270°C. FT-IR vmax cm-1 (KBr): 1125,
1309, 1694, 3081, 3123, 3204, 3261. H-NMR d: 2.37 (s,
3H, CH3), 4.95 (s, 2H, CH2), 6.9–8.0 (m, 11H, Ar–H),
1
The compounds in series 4 and 5 were prepared by the
methodologies outlined in Scheme 1. The synthesis of N-
benzyl-2,3-dioxoindole (3) was carried out by reacting
benzyl chloride with various 2,3-dioxo-indoles in the pres-
ence of potassium carbonate under reflux in DMF. The
synthesis of the 2,3-dioxo-2,3-dihydroindolo-thiosemi-
carbazones (4a–g, 5a–k) was carried out by the condensation
of various 2,3-dioxoindoles/N-arylalkyl-2,3-dioxoindoles
(2,3) with aryl thiosemicarbazide under reflux in ethanol in
the presence of catalytic amounts of glacial acetic acid. 1H
NMR spectroscopy indicated that the compounds exist as
10.92 (s, 1H, N–NH), 12.52 (s, 1H, NH).
2-(5-bromo-1-(4-methylbenzyl)-2-oxoindolin-3-ylidene)-N-
(4-chlorophenyl)hydrazine carbothioamide (5h)
Yield 81%. mp 220–223°C. FT-IR vmax cm-1 (KBr): 1124,
1
1295, 1710, 3004, 3153, 3210, 3251. H-NMR d: 2.27 (s,
3H, CH3), 4.96 (s, 2H, CH2), 7.0–8.0 (m, 11H, Ar–H),
11.00 (s, 1H, N–NH), 12.61 (s, 1H, NH).
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Med Chem Res (2011) 20:1229–1234
O
O
R1
R1
R1
i
ii
O
O
NH
N
R2
NH2
R2
R2
2
1
3
R3
iii
iii
R4
R4
NH
NH
S
S
NH
NH
N
N
R1
O
O
R1
NH
R2
N
R2
4a-g
R3
5a-k
Scheme 1 Synthesis of compounds 4a–g and 5a–k. The reagents used are as follows: i CCl3CH(OH)2/H2SO4/Na2SO4; ii R3-C6H4CH2Cl/
K2CO3/DMF; iii R4-C6H4NHCSNHNH2. The nature of the R1, R2, R3, and R4 substituents are presented in Table 1
single isomers in solution. The compounds adopted the
as murine L1210 leukemia cells. The data are summarized
in Table 1.
Z conformation (Karki et al., 2009).
Several compounds (4c–d and 5b–c) showed IC50 val-
ues in the low micromolar range (1–10 lM). Molt4/C8
cells were slightly more sensitive to the cytostatic activity
of the compounds in both series 4 and 5 than CEM or
L1210 cells.
Biological activity
The compounds were evaluated for their cytostatic activity
against human Molt4/C8 and CEM T-lymphocytes as well
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Med Chem Res (2011) 20:1229–1234
1233
activity against human Molt4/C8 and CEM T-lymphocytes
and murine L1210 leukemia cells. The compounds 4c, 4d,
5b, and 5c had IC50 values in the low micromolar range
(1–10 lM). Among the tested compounds, 5b and 4d had
antiproliferative potencies that were close to those obtained
for melphalan and should be the basis for further synthesis
of more potent cytostatic agents.
Table 1 Cytostatic activity of test compounds against murine L1210
leukemia and human Molt4/C8 and CEM T-lymphocyte cells
Comp.
code
Substituents
IC50* (lM)
R1 R2 R3
R4
L1210
Molt4/C8 CEM
4a
Cl
Br
Br
F
H
H
H
H
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
–
H
H
H
H
H
H
H
F
Cl
Cl
108 18 64 20 61
6
4b
88 39 29 16 61 11
4c
CH3 9.6 1.8 4.9 3.5 6.8 2.4
CH3 8.2 3.6 3.0 0.7 4.8 0.5
Acknowledgments The study was supported by a grant from the
K.U.Leuven (GOA no. 10/014). The authors want to thank Mrs. Li-
zette van Berckelaer for excellent technical assistance.
4d
4e
F
Cl
69 50
43 10 48 18
4f
F
CH3 166 48 112 81 132 75
4g
F
Cl
Cl
34
2
14
7
3
25
6
5a
F
154 73 47
56 14
References
5b
F
F
CH3 6.2 2.1 1.5 1.1 2.5 1.2
5c
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
–
CH3 Cl
9.8 2.1 5.8 4.2 18
124 39 58 13 68
9
1
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103 53 48
196 66 48
5
7
9
50 14
61
132 35
5f
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9
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193 49 74 19 98 14
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CH3 C 500
288 12 C500
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393 27 C500
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* The IC50 values represent the compound concentrations required to
inhibit the growth of the tumor cells by 50%
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were also most inhibitory to human T-lymphocyte CEM
and Molt4/C8 cell proliferation. Also, the scaffold of the
most potent cytostatic compound in the 4 series (4d) was
most inhibitory in the 5 series (5b). In the majority of
cases, introduction of the R3-benzyl substituent in the thi-
osemicarbazone derivative series 5 often led to (slightly)
less potent inhibitors of tumor cell proliferation. In a
number of cases, replacement of the chloro at R4 by a
methyl resulted in a marked potentiation of the cytostatic
activity (compare 4b with 4c; 4g with 4d; 5a with 5b)
(Table 1). In the 5 series of compounds, replacement of the
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